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Sample records for th17 cell-mediated experimental

  1. RGC-32 Promotes Th17 Cell Differentiation and Enhances Experimental Autoimmune Encephalomyelitis.

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    Rus, Violeta; Nguyen, Vinh; Tatomir, Alexandru; Lees, Jason R; Mekala, Armugam P; Boodhoo, Dallas; Tegla, Cosmin A; Luzina, Irina G; Antony, Paul A; Cudrici, Cornelia D; Badea, Tudor C; Rus, Horea G

    2017-05-15

    Th17 cells play a critical role in autoimmune diseases, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Response gene to complement (RGC)-32 is a cell cycle regulator and a downstream target of TGF-β that mediates its profibrotic activity. In this study, we report that RGC-32 is preferentially upregulated during Th17 cell differentiation. RGC-32(-/-) mice have normal Th1, Th2, and regulatory T cell differentiation but show defective Th17 differentiation in vitro. The impaired Th17 differentiation is associated with defects in IFN regulatory factor 4, B cell-activating transcription factor, retinoic acid-related orphan receptor γt, and SMAD2 activation. In vivo, RGC-32(-/-) mice display an attenuated experimental autoimmune encephalomyelitis phenotype accompanied by decreased CNS inflammation and reduced frequency of IL-17- and GM-CSF-producing CD4(+) T cells. Collectively, our results identify RGC-32 as a novel regulator of Th17 cell differentiation in vitro and in vivo and suggest that RGC-32 is a potential therapeutic target in multiple sclerosis and other Th17-mediated autoimmune diseases. Copyright © 2017 by The American Association of Immunologists, Inc.

  2. CD209a Synergizes with Dectin-2 and Mincle to Drive Severe Th17 Cell-Mediated Schistosome Egg-Induced Immunopathology

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    Parisa Kalantari

    2018-01-01

    Full Text Available The immunopathology caused by schistosome helminths varies greatly in humans and among mouse strains. A severe form of parasite egg-induced hepatic granulomatous inflammation, seen in CBA mice, is driven by Th17 cells stimulated by IL-1β and IL-23 produced by dendritic cells that express CD209a (SIGNR5, a C-type lectin receptor (CLR related to human DC-SIGN. Here, we show that CD209a-deficient CBA mice display decreased Th17 responses and are protected from severe immunopathology. In vitro, CD209a augments the egg-induced IL-1β and IL-23 production initiated by the related CLRs Dectin-2 and Mincle. While Dectin-2 and Mincle trigger an FcRγ-dependent signaling cascade that involves the tyrosine kinase Syk and the trimolecular Card9-Bcl10-Malt1 complex, CD209a promotes the sustained activation of Raf-1. Our findings demonstrate that CD209a drives severe Th17 cell-mediated immunopathology in a helminthic disease based on synergy between DC-SIGN- and Dectin-2-related CLRs.

  3. Th1-Th17 cells mediate protective adaptive immunity against Staphylococcus aureus and Candida albicans infection in mice.

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    Lin Lin

    2009-12-01

    Full Text Available We sought to define protective mechanisms of immunity to Staphylococcus aureus and Candida albicans bloodstream infections in mice immunized with the recombinant N-terminus of Als3p (rAls3p-N vaccine plus aluminum hydroxide (Al(OH(3 adjuvant, or adjuvant controls. Deficiency of IFN-gamma but not IL-17A enhanced susceptibility of control mice to both infections. However, vaccine-induced protective immunity against both infections required CD4+ T-cell-derived IFN-gamma and IL-17A, and functional phagocytic effectors. Vaccination primed Th1, Th17, and Th1/17 lymphocytes, which produced pro-inflammatory cytokines that enhanced phagocytic killing of both organisms. Vaccinated, infected mice had increased IFN-gamma, IL-17, and KC, increased neutrophil influx, and decreased organism burden in tissues. In summary, rAls3p-N vaccination induced a Th1/Th17 response, resulting in recruitment and activation of phagocytes at sites of infection, and more effective clearance of S. aureus and C. albicans from tissues. Thus, vaccine-mediated adaptive immunity can protect against both infections by targeting microbes for destruction by innate effectors.

  4. Anandamide attenuates Th-17 cell-mediated delayed-type hypersensitivity response by triggering IL-10 production and consequent microRNA induction.

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    Austin R Jackson

    Full Text Available Endogenous cannabinoids [endocannabinoids] are lipid signaling molecules that have been shown to modulate immune functions. However, their role in the regulation of Th17 cells has not been studied previously. In the current study, we used methylated Bovine Serum Albumin [mBSA]-induced delayed type hypersensitivity [DTH] response in C57BL/6 mice, mediated by Th17 cells, as a model to test the anti-inflammatory effects of endocannabinoids. Administration of anandamide [AEA], a member of the endocannabinoid family, into mice resulted in significant mitigation of mBSA-induced inflammation, including foot pad swelling, cell infiltration, and cell proliferation in the draining lymph nodes [LN]. AEA treatment significantly reduced IL-17 and IFN-γ production, as well as decreased RORγt expression while causing significant induction of IL-10 in the draining LNs. IL-10 was critical for the AEA-induced mitigation of DTH response inasmuch as neutralization of IL-10 reversed the effects of AEA. We next analyzed miRNA from the LN cells and found that 100 out of 609 miRNA species were differentially regulated in AEA-treated mice when compared to controls. Several of these miRNAs targeted proinflammatory mediators. Interestingly, many of these miRNA were also upregulated upon in vitro treatment of LN cells with IL-10. Together, the current study demonstrates that AEA may suppress Th-17 cell-mediated DTH response by inducing IL-10 which in turn triggers miRNA that target proinflammatory pathways.

  5. Immunization of Mice with a Live Transconjugant Shigella Hybrid Strain Induced Th1 and Th17 Cell-Mediated Immune Responses and Confirmed Passive Protection Against Heterologous Shigellae.

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    Nag, D; Koley, H; Sinha, R; Mukherjee, P; Sarkar, C; Withey, J H; Gachhui, R

    2016-02-01

    An avirulent, live transconjugant Shigella hybrid (LTSHΔstx) strain was constructed in our earlier study by introducing a plasmid vector, pPR1347, into a Shiga toxin gene deleted Shigella dysenteriae 1. Three successive oral administrations of LTSHΔstx to female adult mice produced comprehensive passive heterologous protection in their offspring against challenge with wild-type shigellae. Production of NO and different cytokines such asIL-12p70, IL-1β and IL-23 in peritoneal mice macrophages indicated that LTSHΔstx induced innate and adaptive immunity in mice. Furthermore, production of IFN-γ, IL-10 and IL-17 in LTSH-primed splenic CD4+ T cell suggested that LTSHΔstx may induce Th1 and Th17 cell-mediated immune responses. Exponential increase of the serum IgG and IgA titre against whole shigellae was observed in immunized adult mice during and after the immunization with the highest peak on day 35. Antigen-specific sIgA was also determined from intestinal lavage of immunized mice. The stomach extracts of neonates from immunized mice, mainly containing mother's milk, contained significant levels of anti-LTSHΔstx immunoglobulin. These studies suggest that the LTSHΔstx could be a new live oral vaccine candidate against shigellosis in the near future. © 2015 The Foundation for the Scandinavian Journal of Immunology.

  6. TH1 and TH17 cells promote crescent formation in experimental autoimmune glomerulonephritis.

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    Hünemörder, Stefanie; Treder, Julia; Ahrens, Stefanie; Schumacher, Valéa; Paust, Hans-Joachim; Menter, Thomas; Matthys, Patrick; Kamradt, Thomas; Meyer-Schwesinger, Catherine; Panzer, Ulf; Hopfer, Helmut; Mittrücker, Hans-Willi

    2015-09-01

    Autoimmunity against the Goodpasture antigen α3IV-NC1 results in crescentic glomerulonephritis (GN). Both antibodies and T cells directed against α3IV-NC1 have been implicated in disease development and progression. Using the model of experimental autoimmune glomerulonephritis (EAG) in DBA/1 mice, we aimed to characterize the frequency and function of α3IV-NC1-specific CD4(+) T cells in the kidneys. DBA/1 mice repeatedly immunized with human α3IV-NC1 developed necrotizing/crescentic GN. Kidneys with crescentic GN contained CD4(+) cells responding to α3IV-NC1 with the production of IFN-γ or IL-17A, demonstrating the accumulation of both α3IV-NC1-specific TH1 and TH17 cells. To test the functional relevance of TH1 and TH17 cells, EAG was induced in DBA/1 mice deficient in IFN-γR, IL-17A or IL-23p19. Mice of all knockout groups mounted α3IV-NC1 IgG, developed nephrotic range proteinuria, and IgG deposition to the glomerular basement membranes at levels similar to immunized wild-type mice. However, all knockout groups showed significantly fewer glomerular crescents and attenuated tubulointerstitial damage. Our results suggest that both α3IV-NC1-specific TH1 and TH17 cells accumulate in the kidneys and are crucial for the development of necrotizing/crescentic GN. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  7. Digoxin Attenuates Murine Experimental Colitis by Downregulating Th17-related Cytokines.

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    Tani, Shinya; Takano, Ryosuke; Tamura, Satoshi; Oishi, Shinji; Iwaizumi, Moriya; Hamaya, Yasushi; Takagaki, Kosuke; Nagata, Toshi; Seto, Shintaro; Horii, Toshinobu; Kosugi, Isao; Iwashita, Toshihide; Osawa, Satoshi; Furuta, Takahisa; Miyajima, Hiroaki; Sugimoto, Ken

    2017-05-01

    Digoxin, a cardiac glycoside used for the treatment of heart failure, was reported to inhibit the retinoid-related orphan receptor gamma t (RORγt) and attenuate the severity of experimental autoimmune encephalomyelitis and arthritis in mice. However, the effects of digoxin in a mice model of inflammatory bowel disease have not been elucidated. Colitis was induced in severe combined immunodeficiency mice by adoptive transfer of CD45RB CD4 T cells. Digoxin or a vehicle was injected into mice with colitis intraperitoneally every other day and changes in body weight were evaluated. After 6 to 8 weeks, the treated mice were killed and evaluated for histological score, T-cell subset, and cytokine messenger RNA (mRNA) expression in the colonic tissue. Wasting disease and histological damage were significantly attenuated in digoxin-treated mice with colitis compared with those in the vehicle-treated mice. In addition, the mRNAs of Th17-related cytokines were downregulated, whereas those of interleukin-10 were upregulated in the colonic mucosa of digoxin-treated mice. However, unexpectedly, the mRNA expression level of tumor necrosis factor alpha did not decrease in the colonic mucosa of digoxin-treated mice with colitis. This observation suggests that digoxin may ameliorate colitis by a tumor necrosis factor alpha-independent pathway. This study has shown for the first time that treatment with digoxin can ameliorate murine experimental colitis. This finding suggests that the suppression of Th17 using reagents such as digoxin could be effective in treating Crohn's disease refractory to anti-tumor necrosis factor alpha therapy.

  8. Metformin Attenuates Experimental Autoimmune Arthritis through Reciprocal Regulation of Th17/Treg Balance and Osteoclastogenesis

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    Hye-Jin Son

    2014-01-01

    Full Text Available Metformin is widely used to suppress certain functions of the cells found in diseases including diabetes and obesity. In this study, the effects of metformin on downregulating IL-17-producing T (Th17 cells, activating and upregulating regulatory T (Treg cells, suppressing osteoclastogenesis, and clinically scoring collagen-induced arthritis (CIA were investigated. To evaluate the effect of metformin on CIA, mice were orally fed with either metformin or saline as control three times a week for nine weeks. Histological analysis of the joints was performed using immunohistochemistry and Th17 cells and Treg cells of the spleen tissue were examined by confocal microscopy staining. Metformin mitigated the severity of CIA, reduced serum immunoglobulin concentrations, and reciprocally regulated Th17/Treg axis. Also, metformin treatment of normal cells cultured in Th17 conditions decreased the number of Th17 cells and increased the number of Treg cells. Metformin decreased gene expression and osteoclastogenic activity in CIA and normal mice. These results indicate that metformin had immunomodulatory actions influencing anti-inflammatory action on CIA through the inhibition of Th17 cell differentiation and the upregulation of Treg cell differentiation along with the suppression of osteoclast differentiation. Our results suggest that metformin may be a potential therapeutic for rheumatoid arthritis.

  9. Metformin Attenuates Experimental Autoimmune Arthritis through Reciprocal Regulation of Th17/Treg Balance and Osteoclastogenesis

    Science.gov (United States)

    Son, Hye-Jin; Lee, Seon-Yeong; Kim, Eun-Kyung; Park, Min-Jung; Kim, Kyoung-Woon; Park, Sung-Hwan; Cho, Mi-La

    2014-01-01

    Metformin is widely used to suppress certain functions of the cells found in diseases including diabetes and obesity. In this study, the effects of metformin on downregulating IL-17-producing T (Th17) cells, activating and upregulating regulatory T (Treg) cells, suppressing osteoclastogenesis, and clinically scoring collagen-induced arthritis (CIA) were investigated. To evaluate the effect of metformin on CIA, mice were orally fed with either metformin or saline as control three times a week for nine weeks. Histological analysis of the joints was performed using immunohistochemistry and Th17 cells and Treg cells of the spleen tissue were examined by confocal microscopy staining. Metformin mitigated the severity of CIA, reduced serum immunoglobulin concentrations, and reciprocally regulated Th17/Treg axis. Also, metformin treatment of normal cells cultured in Th17 conditions decreased the number of Th17 cells and increased the number of Treg cells. Metformin decreased gene expression and osteoclastogenic activity in CIA and normal mice. These results indicate that metformin had immunomodulatory actions influencing anti-inflammatory action on CIA through the inhibition of Th17 cell differentiation and the upregulation of Treg cell differentiation along with the suppression of osteoclast differentiation. Our results suggest that metformin may be a potential therapeutic for rheumatoid arthritis. PMID:25214721

  10. Gender-specific effects of genetic variants within Th1 and Th17 cell-mediated immune response genes on the risk of developing rheumatoid arthritis.

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    Rafael Cáliz

    Full Text Available The present study was conducted to explore whether single nucleotide polymorphisms (SNPs in Th1 and Th17 cell-mediated immune response genes differentially influence the risk of rheumatoid arthritis (RA in women and men. In phase one, 27 functional/tagging polymorphisms in C-type lectins and MCP-1/CCR2 axis were genotyped in 458 RA patients and 512 controls. Carriers of Dectin-2 rs4264222T allele had an increased risk of RA (OR = 1.47, 95%CI 1.10-1.96 whereas patients harboring the DC-SIGN rs4804803G, MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of developing the disease (OR = 0.66, 95%CI 0.49-0.88; OR = 0.66, 95%CI 0.50-0.89; OR = 0.73, 95%CI 0.55-0.97 and OR = 0.68, 95%CI 0.51-0.91. Interestingly, significant gender-specific differences were observed for Dectin-2 rs4264222 and Dectin-2 rs7134303: women carrying the Dectin-2 rs4264222T and Dectin-2 rs7134303G alleles had an increased risk of RA (OR = 1.93, 95%CI 1.34-2.79 and OR = 1.90, 95%CI 1.29-2.80. Also five other SNPs showed significant associations only with one gender: women carrying the MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of RA (OR = 0.61, 95%CI 0.43-0.87; OR = 0.67, 95%CI 0.47-0.95 and OR = 0.60, 95%CI 0.42-0.86. In men, carriers of the DC-SIGN rs2287886A allele had an increased risk of RA (OR = 1.70, 95%CI 1.03-2.78, whereas carriers of the DC-SIGN rs4804803G had a decreased risk of developing the disease (OR = 0.53, 95%CI 0.32-0.89. In phase 2, we genotyped these SNPs in 754 RA patients and 519 controls, leading to consistent gender-specific associations for Dectin-2 rs4264222, MCP-1 rs1024611, MCP-1 rs13900 and DC-SIGN rs4804803 polymorphisms in the pooled sample (OR = 1.38, 95%CI 1.08-1.77; OR = 0.74, 95%CI 0.58-0.94; OR = 0.76, 95%CI 0.59-0.97 and OR = 0.56, 95%CI 0.34-0.93. SNP-SNP interaction analysis of significant SNPs also showed a

  11. Gender-specific effects of genetic variants within Th1 and Th17 cell-mediated immune response genes on the risk of developing rheumatoid arthritis.

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    Cáliz, Rafael; Canet, Luz María; Lupiañez, Carmen Belén; Canhão, Helena; Escudero, Alejandro; Filipescu, Ileana; Segura-Catena, Juana; Soto-Pino, María José; Expósito-Ruiz, Manuela; Ferrer, Miguel Ángel; García, Antonio; Romani, Lurdes; González-Utrilla, Alfonso; Vallejo, Teresa; Pérez-Pampin, Eva; Hemminki, Kari; Försti, Asta; Collantes, Eduardo; Fonseca, João Eurico; Sainz, Juan

    2013-01-01

    The present study was conducted to explore whether single nucleotide polymorphisms (SNPs) in Th1 and Th17 cell-mediated immune response genes differentially influence the risk of rheumatoid arthritis (RA) in women and men. In phase one, 27 functional/tagging polymorphisms in C-type lectins and MCP-1/CCR2 axis were genotyped in 458 RA patients and 512 controls. Carriers of Dectin-2 rs4264222T allele had an increased risk of RA (OR = 1.47, 95%CI 1.10-1.96) whereas patients harboring the DC-SIGN rs4804803G, MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of developing the disease (OR = 0.66, 95%CI 0.49-0.88; OR = 0.66, 95%CI 0.50-0.89; OR = 0.73, 95%CI 0.55-0.97 and OR = 0.68, 95%CI 0.51-0.91). Interestingly, significant gender-specific differences were observed for Dectin-2 rs4264222 and Dectin-2 rs7134303: women carrying the Dectin-2 rs4264222T and Dectin-2 rs7134303G alleles had an increased risk of RA (OR = 1.93, 95%CI 1.34-2.79 and OR = 1.90, 95%CI 1.29-2.80). Also five other SNPs showed significant associations only with one gender: women carrying the MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of RA (OR = 0.61, 95%CI 0.43-0.87; OR = 0.67, 95%CI 0.47-0.95 and OR = 0.60, 95%CI 0.42-0.86). In men, carriers of the DC-SIGN rs2287886A allele had an increased risk of RA (OR = 1.70, 95%CI 1.03-2.78), whereas carriers of the DC-SIGN rs4804803G had a decreased risk of developing the disease (OR = 0.53, 95%CI 0.32-0.89). In phase 2, we genotyped these SNPs in 754 RA patients and 519 controls, leading to consistent gender-specific associations for Dectin-2 rs4264222, MCP-1 rs1024611, MCP-1 rs13900 and DC-SIGN rs4804803 polymorphisms in the pooled sample (OR = 1.38, 95%CI 1.08-1.77; OR = 0.74, 95%CI 0.58-0.94; OR = 0.76, 95%CI 0.59-0.97 and OR = 0.56, 95%CI 0.34-0.93). SNP-SNP interaction analysis of significant SNPs also showed a significant

  12. Arctigenin Suppress Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis Through AMPK and PPAR-γ/ROR-γt Signaling.

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    Li, Wen; Zhang, Zhihui; Zhang, Kai; Xue, Zhenyi; Li, Yan; Zhang, Zimu; Zhang, Lijuan; Gu, Chao; Zhang, Qi; Hao, Junwei; Da, Yurong; Yao, Zhi; Kong, Ying; Zhang, Rongxin

    2016-10-01

    Arctigenin is a herb compound extract from Arctium lappa and is reported to exhibit pharmacological properties, including neuronal protection and antidiabetic, antitumor, and antioxidant properties. However, the effects of arctigenin on autoimmune inflammatory diseases of the CNS, multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE) are still unclear. In this study, we demonstrated that arctigenin-treated mice are resistant to EAE; the clinical scores of arctigenin-treated mice are significantly reduced. Histochemical assays of spinal cord sections also showed that arctigenin reduces inflammation and demyelination in mice with EAE. Furthermore, the Th1 and Th17 cells in peripheral immune organs are inhibited by arctigenin in vivo. In addition, the Th1 cytokine IFN-γ and transcription factor T-bet, as well as the Th17 cytokines IL-17A, IL-17F, and transcription factor ROR-γt are significantly suppressed upon arctigenin treatment in vitro and in vivo. Interestedly, Th17 cells are obviously inhibited in CNS of mice with EAE, while Th1 cells do not significantly change. Besides, arctigenin significantly restrains the differentiation of Th17 cells. We further demonstrate that arctigenin activates AMPK and inhibits phosphorylated p38, in addition, upregulates PPAR-γ, and finally suppresses ROR-γt. These findings suggest that arctigenin may have anti-inflammatory and immunosuppressive properties via inhibiting Th17 cells, indicating that it could be a potential therapeutic drug for multiple sclerosis or other autoimmune inflammatory diseases.

  13. Th17-Inducing Cytokines IL-6 and IL-23 Are Crucial for Granuloma Formation during Experimental Paracoccidioidomycosis

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    Fabrine Sales Massafera Tristão

    2017-08-01

    Full Text Available Paracoccidioidomycosis (PCM, a chronic granulomatous disease caused by the thermally dimorphic fungus Paracoccidioides brasiliensis and Paracoccidioides lutzii, has the highest mortality rate among systemic mycosis. The T helper 1-mediated immunity is primarily responsible for acquired resistance during P. brasiliensis infection, while susceptibility is associated with Th2 occurrence. Th17 is a population of T CD4+ cells that, among several chemokines and cytokines, produces IL-17A and requires the presence of IL-1, IL-6, and TGF-β for differentiation in mice and IL-23 for its maintenance. Th17 has been described as an arm of the immune system that enhances host protection against several bacterial and fungal infections, as Pneumocystis carinii and Candida albicans. In this study, we aimed to evaluate the Th17 immune response and the role of Th17-associated cytokines (IL-6, IL-23, and IL-17A during experimental PCM. First, we observed that P. brasiliensis infection [virulent yeast strain 18 of P. brasiliensis (Pb18] increased the IL-17A production in vitro and all the evaluated Th17-associated cytokines in the lung tissue from C57BL/6 wild-type mice. In addition, the deficiency of IL-6, IL-23, or IL-17 receptor A (IL-17RA impaired the compact granuloma formation and conferred susceptibility during infection, associated with reduced tumor necrosis factor-α, IFN-γ, and inducible nitric oxide synthase enzyme expression. Our data suggest that IL-6 production by bone marrow-derived macrophages (BMDMs is important to promote the Th17 differentiation during Pb18 infection. In accordance, the adoptive transfer of BMDMs from C57BL/6 to infected IL-6−/− or IL-17RA−/− mice reduced the fungal burden in the lungs compared to nontransferred mice and reestablished the pulmonary granuloma formation. Taken together, these results suggest that Th17-associated cytokines are involved in the modulation of immune response and granuloma formation during

  14. Tolerogenic Dendritic Cells Generated with Tofacitinib Ameliorate Experimental Autoimmune Encephalomyelitis through Modulation of Th17/Treg Balance

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    Yan Zhou

    2016-01-01

    Full Text Available It is well known that dendritic cells (DCs play a pivotal role in triggering self-specific responses. Conversely, tolerogenic DCs (tolDCs, a specialized subset, induce tolerance and negatively regulate autoreactive responses. Tofacitinib, a Janus kinase inhibitor developed by Pfizer for treatment of rheumatoid arthritis, is probable to be a promising candidate for inducing tolDCs. The aims of this study were to evaluate the effectiveness of tolDCs induced by tofacitinib in a myelin oligodendrocyte glycoprotein- (MOG- specific experimental autoimmune encephalomyelitis (EAE model and to investigate their effects on Th17/Treg balance in the animal model of multiple sclerosis (MS. Our results revealed that tofacitinib-treated DCs maintained a steady semimature phenotype with a low level of proinflammatory cytokines and costimulatory molecules. DCs treated by tofacitinib also induced antigen-specific T cells hyporesponsiveness in a concentration-dependent manner. Upon intravenous injection into EAE mice, MOG pulsed tolDCs significantly dampened disease activity, and adoptive cell therapy (ACT disturbed Th17/Treg balance with a remarkable decrease of Th1/Th17 cells and an increase in regulatory T cells (Tregs. Overall, DCs modified by tofacitinib exhibited a typical tolerogenic phenotype, and the antigen-specific tolDCs may represent a new avenue of research for the development of future clinical treatments for MS.

  15. Periplocoside A prevents experimental autoimmune encephalomyelitis by suppressing IL-17 production and inhibits differentiation of Th17 cells.

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    Zhang, Jing; Ni, Jia; Chen, Zhen-hua; Li, Xin; Zhang, Ru-jun; Tang, Wei; Zhao, Wei-min; Yang, Yi-fu; Zuo, Jian-ping

    2009-08-01

    The aim of this study was to determine the therapeutic effect of Periplocoside A (PSA), a natural product isolated from the traditional Chinese herbal medicine Periploca sepium Bge, in MOG(35-55) (myelin oligodendrocyte glycoprotein 35-55)-induced experimental autoimmune encephalomyelitis (EAE). Female C57BL/6 mice immunized with MOG(35-55) were treated with (50 mg/kg or 25 mg/kg) or without PSA following immunization and continuously throughout the study. The degree of CNS inflammation was evaluated by H&E staining. Anti-MOG-specific recall responses were analyzed by [3H]-Thymidine incorporation, ELISA, and RT-PCR. The proportion of IL-17-producing T cells was measured by flow cytometry. Oral administration of PSA significantly reduced the incidence and severity of EAE, which closely paralleled the inhibition of MOG(35-55)-specific IL-17 production. Importantly, PSA inhibited the transcription of IL-17 mRNA and RORgammat. Further studies examining intracellular staining and adoptive transfer EAE validated the direct suppressive effect of PSA on Th17 cells. In vitro studies also showed that PSA significantly inhibited the differentiation of Th17 cells from murine purified CD4+ T cells in a dose-dependent manner. PSA ameliorated EAE by suppressing IL-17 production and inhibited the differentiation of Th17 cells in vitro. Our results provide new insight into the potential mechanisms underlying the immunosuppressive and anti-inflammatory effects of PSA.

  16. The Glycosylated Rv1860 Protein of Mycobacterium tuberculosis Inhibits Dendritic Cell Mediated TH1 and TH17 Polarization of T Cells and Abrogates Protective Immunity Conferred by BCG

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    Satchidanandam, Vijaya; Kumar, Naveen; Jumani, Rajiv S.; Challu, Vijay; Elangovan, Shobha; Khan, Naseem A.

    2014-01-01

    We previously reported interferon gamma secretion by human CD4+ and CD8+ T cells in response to recombinant E. coli-expressed Rv1860 protein of Mycobacterium tuberculosis (MTB) as well as protection of guinea pigs against a challenge with virulent MTB following prime-boost immunization with DNA vaccine and poxvirus expressing Rv1860. In contrast, a Statens Serum Institute Mycobacterium bovis BCG (BCG-SSI) recombinant expressing MTB Rv1860 (BCG-TB1860) showed loss of protective ability compared to the parent BCG strain expressing the control GFP protein (BCG-GFP). Since Rv1860 is a secreted mannosylated protein of MTB and BCG, we investigated the effect of BCG-TB1860 on innate immunity. Relative to BCG-GFP, BCG-TB1860 effected a significant near total reduction both in secretion of cytokines IL-2, IL-12p40, IL-12p70, TNF-α, IL-6 and IL-10, and up regulation of co-stimulatory molecules MHC-II, CD40, CD54, CD80 and CD86 by infected bone marrow derived dendritic cells (BMDC), while leaving secreted levels of TGF-β unchanged. These effects were mimicked by BCG-TB1860His which carried a 6-Histidine tag at the C-terminus of Rv1860, killed sonicated preparations of BCG-TB1860 and purified H37Rv-derived Rv1860 glycoprotein added to BCG-GFP, but not by E. coli-expressed recombinant Rv1860. Most importantly, BMDC exposed to BCG-TB1860 failed to polarize allogeneic as well as syngeneic T cells to secrete IFN-γ and IL-17 relative to BCG-GFP. Splenocytes from mice infected with BCG-SSI showed significantly less proliferation and secretion of IL-2, IFN-γ and IL-17, but secreted higher levels of IL-10 in response to in vitro restimulation with BCG-TB1860 compared to BCG-GFP. Spleens from mice infected with BCG-TB1860 also harboured significantly fewer DC expressing MHC-II, IL-12, IL-2 and TNF-α compared to mice infected with BCG-GFP. Glycoproteins of MTB, through their deleterious effects on DC may thus contribute to suppress the generation of a TH1- and TH17-dominated

  17. TH17 Cell Induction and Effects of IL-17A and IL-17F Blockade in Experimental Colitis

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    Wedebye Schmidt, Esben Gjerløff; Larsen, Hjalte List; Kristensen, Nanna Ny

    2013-01-01

    T helper (TH) 17 cells are believed to play a pivotal role in development of inflammatory bowel disease, and their contribution to intestinal inflammation has been studied in various models of colitis. TH17 cells produce a range of cytokines, some of which are potential targets for immunotherapy........ However, blockade of IL-17A alone with secukinumab was not effective in Crohn's disease. In this regard, the pathogenic impact of IL-17A versus IL-17F during intestinal inflammation is still unresolved....

  18. The suppressive effect of IL-27 on encephalitogenic Th17 cells induced by multiwalled carbon nanotubes reduces the severity of experimental autoimmune encephalomyelitis.

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    Moraes, Adriel S; Paula, Rosemeire F O; Pradella, Fernando; Santos, Mariana P A; Oliveira, Elaine C; von Glehn, Felipe; Camilo, Daniela S; Ceragioli, Helder; Peterlevitz, Alfredo; Baranauskas, Vitor; Volpini, Walkyria; Farias, Alessandro S; Santos, Leonilda M B

    2013-09-01

    Both Th1 and Th17 cells specific for neuroantigen are described as encephalitogenic in the experimental autoimmune encephalomyelitis (EAE) model. The proposal of this study was to investigate how carbon nanotubes internalized by antigen-presenting cells (APCs) affect the development of encephalitogenic CD4(+) T cells. Therefore, we stimulated encephalitogenic T cells in the presence or not of multiwalled carbon nanotube (MWCNT). After the incubation, we analyzed the expression profile of the encephalitogenic T cells and their capacity to induce EAE. Encephalitogenic CD4(+) T cells cultured with APCs that were previously incubated with MWCNTs do not express IL-17. The adoptive transfer of these cells causes less severe EAE than the transfer of both Th1 and Th17 cells that are not incubated with MWCNTs. These results suggest that the increased IL-27 level produced by the APCs incubated with the carbon nanotubes inhibits the development of Th17 cells. This observation is confirmed by the concomitant reduction in the level of RORγt, which is a transcription factor essential for the development of Th17 cells. Moreover, the incubation of encephalitogenic T cells devoid of Th17 cells with neutralizing anti-IL-27 antibodies restored the production of IL-17. This finding confirms the suppressive effect of IL-27 on encephalitogenic Th17 cells. The results presented suggest that the stimulation of APCs with carbon nanoparticles prior to neuroantigen presentation affects the development of the Th17 subset of encephalitogenic CD4(+) T lymphocytes and results in less severe EAE. © 2013 John Wiley & Sons Ltd.

  19. SLA-PGN-primed dendritic cell-based vaccination induces Th17-mediated protective immunity against experimental visceral leishmaniasis: a crucial role of PKCβ.

    Science.gov (United States)

    Jawed, Junaid Jibran; Majumder, Saikat; Bandyopadhyay, Syamdas; Biswas, Satabdi; Parveen, Shabina; Majumdar, Subrata

    2016-07-01

    Emergence of drug resistance during visceral leishmaniasis (VL) is a major obstacle imposed during successful therapy. An effective vaccine strategy against this disease is therefore necessary. Our present study exploited the SLA (soluble leishmanial antigen) and PGN (peptidoglycan) stimulated bone marrow-derived dendritic cells (DCs) as a suitable vaccine candidate during experimental VL. SLA-PGN-stimulated DCs showed a significant decrease in hepatic and splenic parasite burden, which were associated with increased production of nitric oxide and pro-inflammatory cytokines such as IL-12, IFN-γ and IL-17. Elevated level of IL-17 was accompanied with the generation of more Th17 cells. Further studies on DC provided the evidence that these SLA-PGN-stimulated DCs played an important role in providing necessary cytokines such as IL-6, IL-23 and TGF-β for the generation of Th17 cells. Interestingly, inhibition of protein kinase C-β (PKCβ) in DCs led to decreased production of Th17 polarizing cytokines, causing reduction of the Th17 population size. Altogether, our finding highlighted the important role of DC-based PKCβ in regulation of the function and generation of Th17 cells. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. 1,25-Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H17 cells to protect against experimental autoimmune encephalomyelitis.

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    Jae-Hoon Chang

    Full Text Available BACKGROUND: Vitamin D(3, the most physiologically relevant form of vitamin D, is an essential organic compound that has been shown to have a crucial effect on the immune responses. Vitamin D(3 ameliorates the onset of the experimental autoimmune encephalomyelitis (EAE; however, the direct effect of vitamin D(3 on T cells is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In an in vitro system using cells from mice, the active form of vitamin D(3 (1,25-dihydroxyvitamin D(3 suppresses both interleukin (IL-17-producing T cells (T(H17 and regulatory T cells (Treg differentiation via a vitamin D receptor signal. The ability of 1,25-dihydroxyvitamin D(3 (1,25(OH(2D(3 to reduce the amount of IL-2 regulates the generation of Treg cells, but not T(H17 cells. Under T(H17-polarizing conditions, 1,25(OH(2D(3 helps to increase the numbers of IL-10-producing T cells, but 1,25(OH(2D(3's negative regulation of T(H17 development is still defined in the IL-10(-/- T cells. Although the STAT1 signal reciprocally affects the secretion of IL-10 and IL-17, 1,25(OH(2D(3 inhibits IL-17 production in STAT1(-/- T cells. Most interestingly, 1,25(OH(2D(3 negatively regulates CCR6 expression which might be essential for T(H17 cells to enter the central nervous system and initiate EAE. CONCLUSIONS/SIGNIFICANCE: Our present results in an experimental murine model suggest that 1,25(OH(2D(3 can directly regulate T cell differentiation and could be applied in preventive and therapeutic strategies for T(H17-mediated autoimmune diseases.

  1. Molecular Mechanisms of the Action of Vitamin A in Th17/Treg Axis in Multiple Sclerosis.

    Science.gov (United States)

    Abdolahi, Mina; Yavari, Parvaneh; Honarvar, Niyaz Mohammadzadeh; Bitarafan, Sama; Mahmoudi, Maryam; Saboor-Yaraghi, Ali Akbar

    2015-12-01

    Multiple sclerosis (MS) is an autoinflammatory disease of the central nervous system (CNS). The immunopathogenesis of this disease involves an impaired balance of T helper (Th) 17 cells and regulatory T (Tregs) cells. MS is an autoinflammatory disease characterized by the degeneration of the CNS. For many years, MS has been considered to be an autoreactive Th1 and Th17 cell-dominated disease. The activity and number of Th17 cells are increased in MS; however, the function and number of Treg cells are reduced. Therefore, in MS, the balance between Th17 cells and Treg cells is impaired. Th17 cells produce pro-inflammatory cytokines, which play a role in experimental autoimmune encephalomyelitis (EAE) and MS. However, Treg cell-mediated production of cytokines maintains immune homeostasis and can ameliorate the progression of MS. These observations, therefore, confirm the pathogenic and protective role of Th17 and Treg cells, respectively, and highlight the importance of maintaining the balance of both of these cell types. Evidence suggests that vitamin A and its active metabolites (all-trans-retinoic acid and 9-cis-retinoic acid) modulate the imbalance of Th17 and Treg cells through multiple molecular pathways and can be considered as a promising target in the prevention and treatment of MS.

  2. Dietary Omega-3 Fatty Acids Suppress Experimental Autoimmune Uveitis in Association with Inhibition of Th1 and Th17 Cell Function

    Science.gov (United States)

    Shoda, Hiromi; Yanai, Ryoji; Yoshimura, Takeru; Nagai, Tomohiko; Kimura, Kazuhiro; Sobrin, Lucia; Connor, Kip M.; Sakoda, Yukimi; Tamada, Koji; Ikeda, Tsunehiko; Sonoda, Koh-Hei

    2015-01-01

    Omega (ω)–3 long-chain polyunsaturated fatty acids (LCPUFAs) inhibit the production of inflammatory mediators and thereby contribute to the regulation of inflammation. Experimental autoimmune uveitis (EAU) is a well-established animal model of autoimmune retinal inflammation. To investigate the potential effects of dietary intake of ω-3 LCPUFAs on uveitis, we examined the anti-inflammatory properties of these molecules in comparison with ω-6 LCPUFAs in a mouse EAU model. C57BL/6 mice were fed a diet containing ω-3 LCPUFAs or ω-6 LCPUFAs for 2 weeks before as well as after the induction of EAU by subcutaneous injection of a fragment of human interphotoreceptor retinoid-binding protein emulsified with complete Freund’s adjuvant. Both clinical and histological scores for uveitis were smaller for mice fed ω-3 LCPUFAs than for those fed ω-6 LCPUFAs. The concentrations of the T helper 1 (Th1) cytokine interferon-γ and the Th17 cytokine interleukin-17 in intraocular fluid as well as the production of these cytokines by lymph node cells were reduced for mice fed ω-3 LCPUFAs. Furthermore, the amounts of mRNAs for the Th1- and Th17-related transcription factors T-bet and RORγt, respectively, were reduced both in the retina and in lymph node cells of mice fed ω-3 LCPUFAs. Our results thus show that a diet enriched in ω-3 LCPUFAs suppressed uveitis in mice in association with inhibition of Th1 and Th17 cell function. PMID:26393358

  3. Absence of Notch1 in murine myeloid cells attenuates the development of experimental autoimmune encephalomyelitis by affecting Th1 and Th17 priming.

    Science.gov (United States)

    Fernández, Miriam; Monsalve, Eva M; López-López, Susana; Ruiz-García, Almudena; Mellado, Susana; Caminos, Elena; García-Ramírez, José Javier; Laborda, Jorge; Tranque, Pedro; Díaz-Guerra, María José M

    2017-12-01

    Inhibition of Notch signalling in T cells attenuates the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Growing evidence indicates that myeloid cells are also key players in autoimmune processes. Thus, the present study evaluates the role of the Notch1 receptor in myeloid cells on the progression of myelin oligodendrocyte glycoprotein (MOG) 35-55 -induced EAE, using mice with a myeloid-specific deletion of the Notch1 gene (MyeNotch1KO). We found that EAE progression was less severe in the absence of Notch1 in myeloid cells. Thus, histopathological analysis revealed reduced pathology in the spinal cord of MyeNotch1KO mice, with decreased microglia/astrocyte activation, demyelination and infiltration of CD4 + T cells. Moreover, these mice showed lower Th1 and Th17 cell infiltration and expression of IFN-γ and IL-17 mRNA in the spinal cord. Accordingly, splenocytes from MyeNotch1KO mice reactivated in vitro presented reduced Th1 and Th17 activation, and lower expression of IL-12, IL-23, TNF-α, IL-6, and CD86. Moreover, reactivated wild-type splenocytes showed increased Notch1 expression, arguing for a specific involvement of this receptor in autoimmune T cell activation in secondary lymphoid tissues. In summary, our results reveal a key role of the Notch1 receptor in myeloid cells for the initiation and progression of EAE. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Th17 cytokines and arthritis

    NARCIS (Netherlands)

    E.W. Lubberts (Erik)

    2010-01-01

    textabstractTh17 cells are implicated in human autoimmune diseases, such as rheumatoid arthritis (RA), although it has not been established whether this persistent destructive arthritis is driven by Th1 and/or Th17 cells. Interleukin-17A (IL-17A) contributes to the pathogenesis of arthritis as has

  5. Reversal of paralysis and reduced inflammation from peripheral administration of β-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Grant, Jacqueline L; Ghosn, Eliver Eid Bou; Axtell, Robert C; Herges, Katja; Kuipers, Hedwich F; Woodling, Nathan S; Andreasson, Katrin; Herzenberg, Leonard A; Herzenberg, Leonore A; Steinman, Lawrence

    2012-08-01

    β-Amyloid 42 (Aβ42) and β-amyloid 40 (Aβ40), major components of senile plaque deposits in Alzheimer's disease, are considered neurotoxic and proinflammatory. In multiple sclerosis, Aβ42 is up-regulated in brain lesions and damaged axons. We found, unexpectedly, that treatment with either Aβ42 or Aβ40 peptides reduced motor paralysis and brain inflammation in four different models of experimental autoimmune encephalomyelitis (EAE) with attenuation of motor paralysis, reduction of inflammatory lesions in the central nervous system (CNS), and suppression of lymphocyte activation. Aβ42 and Aβ40 treatments were effective in reducing ongoing paralysis induced with adoptive transfer of either autoreactive T helper 1 (T(H)1) or T(H)17 cells. High-dimensional 14-parameter flow cytometry of peripheral immune cell populations after in vivo Aβ42 and Aβ40 treatment revealed substantial modulations in the percentage of lymphoid and myeloid subsets during EAE. Major proinflammatory cytokines and chemokines were reduced in the blood after Aβ peptide treatment. Protection conferred by Aβ treatment did not require its delivery to the brain: Adoptive transfer with lymphocytes from donors treated with Aβ42 attenuated EAE in wild-type recipient mice, and Aβ deposition in the brain was not detected in treated EAE mice by immunohistochemical analysis. In contrast to the improvement in EAE with Aβ treatment, EAE was worse in mice with genetic deletion of the amyloid precursor protein. Therefore, in the absence of Aβ, there is exacerbated clinical EAE disease progression. Because Aβ42 and Aβ40 ameliorate experimental autoimmune inflammation targeting the CNS, we might now consider its potential anti-inflammatory role in other neuropathological conditions.

  6. ICER is requisite for Th17 differentiation

    Science.gov (United States)

    Yoshida, Nobuya; Comte, Denis; Mizui, Masayuki; Otomo, Kotaro; Rosetti, Florencia; Mayadas, Tanya N.; Crispín, José C.; Bradley, Sean J.; Koga, Tomohiro; Kono, Michihito; Karampetsou, Maria P.; Kyttaris, Vasileios C.; Tenbrock, Klaus; Tsokos, George C.

    2016-01-01

    Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM). Here we report that ICER is predominantly expressed in Th17 cells through the IL-6–STAT3 pathway and binds to the Il17a promoter, where it facilitates the accumulation of the canonical enhancer RORγt. In vitro differentiation from naive ICER/CREM-deficient CD4+ T cells to Th17 cells is impaired but can be rescued by forced overexpression of ICER. Consistent with a role of Th17 cells in autoimmune and inflammatory diseases, ICER/CREM-deficient B6.lpr mice are protected from developing autoimmunity. Similarly, both anti-glomerular basement membrane-induced glomerulonephritis and experimental encephalomyelitis are attenuated in ICER/CREM-deficient mice compared with their ICER/CREM-sufficient littermates. Importantly, we find ICER overexpressed in CD4+ T cells from patients with systemic lupus erythematosus. Collectively, our findings identify a unique role for ICER, which affects both organ-specific and systemic autoimmunity in a Th17-dependent manner. PMID:27680869

  7. Th17 cells in autoimmune demyelinating disease.

    Science.gov (United States)

    Segal, Benjamin Matthew

    2010-03-01

    Recently published studies in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) have demonstrated an association between the development of demyelinating plaques and the accumulation of Th17 cells in the central nervous system and periphery. However, a causal relationship has been difficult to establish. In fact, in reports published thus far, interleukin (IL)-17A deficiency or neutralization in vivo attenuates, but does not completely abrogate, EAE. There is growing evidence that clinically similar forms of autoimmune demyelinating disease can be driven by myelin-specific T cells of distinct lineages with different degrees of dependence on IL-17A production to achieve their pathological effects. While such observations cast doubts about the potential therapeutic efficacy of Th17 blocking agents in MS, the collective data suggest that IL-17A expression in peripheral blood mononuclear cells could serve as a surrogate biomarker of neuroinflammation and plaque formation and be a useful outcome measure for future clinical trials.

  8. Th17 Cells in Autoimmune and Infectious Diseases

    Directory of Open Access Journals (Sweden)

    José Francisco Zambrano-Zaragoza

    2014-01-01

    Full Text Available The view of CD4 T-cell-mediated immunity as a balance between distinct lineages of Th1 and Th2 cells has changed dramatically. Identification of the IL-17 family of cytokines and of the fact that IL-23 mediates the expansion of IL-17-producing T cells uncovered a new subset of Th cells designated Th17 cells, which have emerged as a third independent T-cell subset that may play an essential role in protection against certain extracellular pathogens. Moreover, Th17 cells have been extensively analyzed because of their strong association with inflammatory disorders and autoimmune diseases. Also, they appear to be critical for controlling these disorders. Similar to Th1 and Th2 cells, Th17 cells require specific cytokines and transcription factors for their differentiation. Th17 cells have been characterized as one of the major pathogenic Th cell populations underlying the development of many autoimmune diseases, and they are enhanced and stabilized by IL-23. The characteristics of Th17 cells, cytokines, and their sources, as well as their role in infectious and autoimmune diseases, are discussed in this review.

  9. TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease.

    Science.gov (United States)

    Pappu, Bhanu P; Borodovsky, Anna; Zheng, Timothy S; Yang, Xuexian; Wu, Ping; Dong, Xingwen; Weng, Shawn; Browning, Beth; Scott, Martin L; Ma, Li; Su, Lihe; Tian, Qiang; Schneider, Pascal; Flavell, Richard A; Dong, Chen; Burkly, Linda C

    2008-05-12

    T helper type 17 (Th17) cells play an important pathogenic function in autoimmune diseases; their regulation, however, is not well understood. We show that the expression of a tumor necrosis factor receptor family member, death receptor 3 (DR3; also known as TNFRSF25), is selectively elevated in Th17 cells, and that TL1A, its cognate ligand, can promote the proliferation of effector Th17 cells. To further investigate the role of the TL1A-DR3 pathway in Th17 regulation, we generated a TL1A-deficient mouse and found that TL1A(-/-) dendritic cells exhibited a reduced capacity in supporting Th17 differentiation and proliferation. Consistent with these data, TL1A(-/-) animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE). Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells. These observations thus establish an important role of the TL1A-DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease.

  10. TL1A–DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease

    Science.gov (United States)

    Pappu, Bhanu P.; Borodovsky, Anna; Zheng, Timothy S.; Yang, Xuexian; Wu, Ping; Dong, Xingwen; Weng, Shawn; Browning, Beth; Scott, Martin L.; Ma, Li; Su, Lihe; Tian, Qiang; Schneider, Pascal; Flavell, Richard A.; Dong, Chen; Burkly, Linda C.

    2008-01-01

    T helper type 17 (Th17) cells play an important pathogenic function in autoimmune diseases; their regulation, however, is not well understood. We show that the expression of a tumor necrosis factor receptor family member, death receptor 3 (DR3; also known as TNFRSF25), is selectively elevated in Th17 cells, and that TL1A, its cognate ligand, can promote the proliferation of effector Th17 cells. To further investigate the role of the TL1A–DR3 pathway in Th17 regulation, we generated a TL1A-deficient mouse and found that TL1A−/− dendritic cells exhibited a reduced capacity in supporting Th17 differentiation and proliferation. Consistent with these data, TL1A−/− animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE). Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells. These observations thus establish an important role of the TL1A–DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease. PMID:18411337

  11. Induction and regulation of pathogenic Th17 cell responses in schistosomiasis.

    Science.gov (United States)

    Larkin, Bridget M; Smith, Patrick M; Ponichtera, Holly E; Shainheit, Mara G; Rutitzky, Laura I; Stadecker, Miguel J

    2012-11-01

    Schistosomiasis is a major tropical disease caused by trematode helminths in which the host mounts a pathogenic immune response against tissue-trapped parasite eggs. The immunopathology consists of egg antigen-specific CD4 T cell-mediated granulomatous inflammation that varies greatly in magnitude in humans and among mouse strains in an experimental model. New evidence, covered in this review, intimately ties the development of severe pathology to IL-17-producing CD4 T helper (Th17) cells, a finding that adds a new dimension to the traditional CD4 Th1 vs. Th2 cell paradigm. Most examined mouse strains, in fact, develop severe immunopathology with substantial Th17 as well as Th1 and Th2 cell responses; a solely Th2-polarized response is an exception that is only observed in low-pathology strains such as the C57BL/6. The ability to mount pathogenic Th17 cell responses is genetically determined and depends on the production of IL-23 and IL-1β by antigen presenting cells following recognition of egg antigens; analyses of several F2 progenies of (high × low)-pathology strain crosses demonstrated that quantitative trait loci governing IL-17 levels and disease severity vary substantially from cross to cross. Low pathology is dominant, which may explain the low incidence of severe disease in humans; however, coinfection with intestinal nematodes can also dampen pathogenic Th17 cell responses by promoting regulatory mechanisms such as those afforded by alternatively activated macrophages and T regulatory cells. A better understanding of the pathways conducive to severe forms of schistosomiasis and their regulation should lead to interventions similar to those presently used to manage other immune-mediated diseases.

  12. Plasticity of Th17 Cells in Autoimmune Kidney Diseases.

    Science.gov (United States)

    Krebs, Christian F; Turner, Jan-Eric; Paust, Hans-Joachim; Kapffer, Sonja; Koyro, Tobias; Krohn, Sonja; Ufer, Friederike; Friese, Manuel A; Flavell, Richard A; Stockinger, Brigitta; Steinmetz, Oliver M; Stahl, Rolf A K; Huber, Samuel; Panzer, Ulf

    2016-07-15

    The ability of CD4(+) T cells to differentiate into pathogenic Th1 and Th17 or protective T regulatory cells plays a pivotal role in the pathogenesis of autoimmune diseases. Recent data suggest that CD4(+) T cell subsets display a considerable plasticity. This plasticity seems to be a critical factor for their pathogenicity, but also for the potential transition of pathogenic effector T cells toward a more tolerogenic phenotype. The aim of the current study was to analyze the plasticity of Th17 cells in a mouse model of acute crescentic glomerulonephritis and in a mouse chronic model of lupus nephritis. By transferring in vitro generated, highly purified Th17 cells and by using IL-17A fate reporter mice, we demonstrate that Th17 cells fail to acquire substantial expression of the Th1 and Th2 signature cytokines IFN-γ and IL-13, respectively, or the T regulatory transcription factor Foxp3 throughout the course of renal inflammation. In an attempt to therapeutically break the stability of the Th17 phenotype in acute glomerulonephritis, we subjected nephritic mice to CD3-specific Ab treatment. Indeed, this treatment induced an immunoregulatory phenotype in Th17 cells, which was marked by high expression of IL-10 and attenuated renal tissue damage in acute glomerulonephritis. In summary, we show that Th17 cells display a minimum of plasticity in acute and chronic experimental glomerulonephritis and introduce anti-CD3 treatment as a tool to induce a regulatory phenotype in Th17 cells in the kidney that may be therapeutically exploited. Copyright © 2016 by The American Association of Immunologists, Inc.

  13. A validated regulatory network for Th17 cell specification

    Science.gov (United States)

    Ciofani, Maria; Madar, Aviv; Galan, Carolina; Sellars, Maclean; Mace, Kieran; Pauli, Florencia; Agarwal, Ashish; Huang, Wendy; Parkhurst, Christopher N.; Muratet, Michael; Newberry, Kim M.; Meadows, Sarah; Greenfield, Alex; Yang, Yi; Jain, Preti; Kirigin, Francis F.; Birchmeier, Carmen; Wagner, Erwin F.; Murphy, Kenneth M.; Myers, Richard M.; Bonneau, Richard; Littman, Dan R.

    2012-01-01

    Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively-bound BATF and IRF4 contribute to initial chromatin accessibility, and with STAT3 initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple datasets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease. PMID:23021777

  14. Are Th17 Cells Playing a Role in Immunity to Dermatophytosis?

    Science.gov (United States)

    Heinen, Marie-Pierre; Cambier, Ludivine; Fievez, Laurence; Mignon, Bernard

    2017-02-01

    Despite their superficial localization in the skin, pathogenic dermatophytes can induce a complex but still misunderstood immune response in their hosts. The cell-mediated immunity (CMI) is correlated with both clinical recovery and protection against reinfection, and CD4+ T lymphocytes have been recognized as a crucial component of the immune defense against dermatophytes. Before the discovery of the Th17 pathway, CMI was considered to be only dependent of Th1 cells, and thus most studies on the immunology of dermatophytosis have focused on the Th1 pathway. Nevertheless, the fine comparative analysis of available scientific data on immunology of dermatophytosis in one hand and on the Th17 pathway mechanisms involved in opportunistic mucosal fungal infections in the other hand reveals that some key elements of the Th17 pathway can be activated by dermatophytes. Stimulation of the Th17 pathway could occur through the activation of some C-type lectin-like receptors and inflammasome in antigen-presenting cells. The Th17 cells could go back to the affected skin and by the production of signature cytokines could induce the effector mechanisms like the recruitment of polymorphonuclear neutrophils and the synthesis of antimicrobial peptides. In conclusion, besides the Th1 pathway, which is important to the immune response against dermatophytes, there are also growing evidences for the involvement of the Th17 pathway.

  15. The Th17 cell population and the immune homeostasis of the gastrointestinal tract.

    Science.gov (United States)

    Rossi, Mauro; Bot, Adrian

    2013-01-01

    Th17 cells are a recently discovered subset of CD4(+) T lymphocytes filling a hole in the repertoire of effector T cells. Th17 cells produce multiple cytokines, with pivotal impact on immune homeostasis, inflammation, and influencing a wide range of intestinal cell targets. The current issue of the International Reviews of Immunology is entirely dedicated to the various roles of Th17 T cells in the immune homeostasis and inflammation occurring in the gut. In addition to describing diverse Th17-mediated molecular pathways, a specific focus is being given to Th17 cell plasticity. This enables the Th17 cells to shift towards a Th1 profile, or to express IL-22, a protective cytokine in experimental colitis. Participation of microbiota-specific Th17 cells to normal immune homeostasis, and their role in the pathogenesis of inflammatory bowel disease (IBD), or of gluten specific-Th17 cells in celiac disease, are also being discussed. Neutralizing antibodies against IL-17A and IL-17F have commenced clinical testing in IBD. In conclusion, Th17 cells emerge as a key immune cell population and further elucidation of their roles and functional plasticity are warranted to support the discovery of novel therapies against IBD and other intestinal disorders.

  16. Aldosterone promotes autoimmune damage by enhancing Th17-mediated immunity.

    Science.gov (United States)

    Herrada, Andrés A; Contreras, Francisco J; Marini, Natacha P; Amador, Cristian A; González, Pablo A; Cortés, Claudia M; Riedel, Claudia A; Carvajal, Cristián A; Figueroa, Fernando; Michea, Luis F; Fardella, Carlos E; Kalergis, Alexis M

    2010-01-01

    Excessive production of aldosterone leads to the development of hypertension and cardiovascular disease by generating an inflammatory state that can be promoted by T cell immunity. Because nature and intensity of T cell responses is controlled by dendritic cells (DCs), it is important to evaluate whether the function of these cells can be modulated by aldosterone. In this study we show that aldosterone augmented the activation of CD8(+) T cells in a DC-dependent fashion. Consistently, the mineralocorticoid receptor was expressed by DCs, which showed activation of MAPK pathway and secreted IL-6 and TGF-beta in response to aldosterone. In addition, DCs stimulated with aldosterone impose a Th17 phenotype to CD4(+) T cells, which have recently been associated with the promotion of inflammatory and autoimmune diseases. Accordingly, we observed that aldosterone enhances the progression of experimental autoimmune encephalomyelitis, an autoimmune disease promoted by Th17 cells. In addition, blockade of the mineralocorticoid receptor prevented all aldosterone effects on DCs and attenuated experimental autoimmune encephalomyelitis development in aldosterone-treated mice. Our data suggest that modulation of DC function by aldosterone enhances CD8(+) T cell activation and promotes Th17-polarized immune responses, which might contribute to the inflammatory damage leading to hypertension and cardiovascular disease.

  17. Tregs promote the differentiation of Th17 cells in silica-induced lung fibrosis in mice.

    Directory of Open Access Journals (Sweden)

    Laiyu Song

    Full Text Available BACKGROUND: Silicosis is an occupational lung disease caused by inhalation of silica dust and characterized by lung inflammation and fibrosis. Previous study showed that Tregs regulate the process of silicosis by modulating the maintenance of immune homeostasis in the lung. Th17 cells share reciprocal developmental pathway with Tregs and play a pivotal role in the immunopathogenesis of many lung diseases by recruiting and activating neutrophils, but the regulatory function of Tregs on Th17 response in silica induced lung fibrosis remains to be explored. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the role of Th17 and IL-17 in the development of silicosis and their interaction with Tregs, Treg-depleted mice model was generated and exposed to silica to establish experimental model of silica-induced lung fibrosis. Here we showed that silica increased Th17 response in lung fibrosis. Tregs depletion enhanced the neutrophils accumulation and attenuated Th17 response in silica induced lung fibrosis. Both mRNA and protein results showed that Tregs exerted its modulatory function on Th17 cells and IL-17 by regulating TGF-β1 and IL-1β. CONCLUSION/SIGNIFICANCE: Our study suggested that Tregs could promote Th17 cells differentiation by regulating TGF-β1 and IL-1β in silica induced lung fibrosis of mice, which further the understanding of the progress of silicosis and provide a new insight in the regulatory mechanism of Th17 by Tregs in lung inflammation.

  18. T cell–derived inducible nitric oxide synthase switches off TH17 cell differentiation

    Science.gov (United States)

    Yang, Jianjun; Zhang, Ruihua; Lu, Geming; Shen, Yu; Peng, Liang; Zhu, Chen; Cui, Miao; Wang, Weidong; Arnaboldi, Paul; Tang, Meng; Gupta, Monica; Qi, Chen-Feng; Jayaraman, Padmini; Zhu, Hongfa; Jiang, Bo; Chen, Shu-hsia; He, John Cijiang; Ting, Adrian T.; Zhou, Ming-Ming; Kuchroo, Vijay K.; Morse, Herbert C.; Ozato, Keiko; Sikora, Andrew G.

    2013-01-01

    RORγt is necessary for the generation of TH17 cells but the molecular mechanisms for the regulation of TH17 cells are still not fully understood. We show that activation of CD4+ T cells results in the expression of inducible nitric oxide synthase (iNOS). iNOS-deficient mice displayed enhanced TH17 cell differentiation but without major effects on either TH1 or TH2 cell lineages, whereas endothelial NOS (eNOS) or neuronal NOS (nNOS) mutant mice showed comparable TH17 cell differentiation compared with wild-type control mice. The addition of N6-(1-iminoethyl)-l-lysine dihydrochloride (L-NIL), the iNOS inhibitor, significantly enhanced TH17 cell differentiation, and S-nitroso-N-acetylpenicillamine (SNAP), the NO donor, dose-dependently reduced the percentage of IL-17–producing CD4+ T cells. NO mediates nitration of tyrosine residues in RORγt, leading to the suppression of RORγt-induced IL-17 promoter activation, indicating that NO regulates IL-17 expression at the transcriptional level. Finally, studies of an experimental model of colitis showed that iNOS deficiency results in more severe inflammation with an enhanced TH17 phenotype. These results suggest that NO derived from iNOS in activated T cells plays a negative role in the regulation of TH17 cell differentiation and highlight the importance of intrinsic programs for the control of TH17 immune responses. PMID:23797094

  19. Autoimmune diseases in the TH17 era

    Directory of Open Access Journals (Sweden)

    D. Mesquita Jr.

    2009-06-01

    Full Text Available A new subtype of CD4+ T lymphocytes characterized by the production of interleukin 17, i.e., TH17 cells, has been recently described. This novel T cell subset is distinct from type 1 and type 2 T helper cells. The major feature of this subpopulation is to generate significant amounts of pro-inflammatory cytokines, therefore appearing to be critically involved in protection against infection caused by extracellular microorganisms, and in the pathogenesis of autoimmune diseases and allergy. The dynamic balance among subsets of T cells is important for the modulation of several steps of the immune response. Disturbances in this balance may cause a shift from normal immunologic physiology to the development of immune-mediated disorders. In autoimmune diseases, the fine balance between the proportion and degree of activation of the various T lymphocyte subsets can contribute to persistent undesirable inflammatory responses and tissue replacement by fibrosis. This review highlights the importance of TH17 cells in this process by providing an update on the biology of these cells and focusing on their biology and differentiation processes in the context of immune-mediated chronic inflammatory diseases.

  20. Immunization with Leishmania donovani protein disulfide isomerase DNA construct induces Th1 and Th17 dependent immune response and protection against experimental visceral leishmaniasis in Balb/c mice.

    Science.gov (United States)

    Amit, Ajay; Vijayamahantesh; Dikhit, Manas R; Singh, Ashish Kumar; Kumar, Vikash; Suman, Shashi S; Singh, Ashu; Kumar, Akhilesh; Thakur, Ajit Kumar; Das, Vidyanand Ravi; Das, Pradeep; Bimal, Sanjiva

    2017-02-01

    In the present study, the efficacy of Leishmania donovani protein disulfide isomerase (LdPDI) as a DNA vaccine was evaluated in BALB/C mice. Mice immunized with the LdPDI-DNA construct were found to be the most immuno-reactive, as the construct induced higher T-cell proliferation. The increased T-cell proliferation was associated with a substantial rise in Th1 and Th17+ CD4 cell response and triggered a higher proportion of CD8+ T cells for the release of interferon-gamma along with a reduced splenic parasite load on Days20 and 60 post challenge (PC). Furthermore, the vaccine construct triggered increased interferon (IFN)-γ, interleukin(IL)-17A, and IL-22 release accompanied by decreased extracellular signal-regulated kinases (ERK) 1/2 signaling and increased mitogen-activated protein kinase (MAPK) signaling coinciding with an increase in the amount of nitrite and reactive oxygen species (ROS)in vaccinating the splenocyts. We summarize from our data that the PDI-DNA construct of Leishmania donovani has the potential to elicit protective immunity through the pro-inflammatory cytokines of CD8+ and CD4+(Th1 and Th17) following an intervention in the downstream signaling event of ERK1/2 (probably through p38MAPK signaling). Therefore, the study suggests a new control against visceral leishmaniasis in the future. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Suppression of Th17-polarized airway inflammation by rapamycin.

    Science.gov (United States)

    Joean, Oana; Hueber, Anja; Feller, Felix; Jirmo, Adan Chari; Lochner, Matthias; Dittrich, Anna-Maria; Albrecht, Melanie

    2017-11-10

    Because Th17-polarized airway inflammation correlates with poor control in bronchial asthma and is a feature of numerous other difficult-to-treat inflammatory lung diseases, new therapeutic approaches for this type of airway inflammation are necessary. We assessed different licensed anti-inflammatory agents with known or expected efficacy against Th17-polarization in mouse models of Th17-dependent airway inflammation. Upon intravenous transfer of in vitro derived Th17 cells and intranasal challenge with the corresponding antigen, we established acute and chronic murine models of Th17-polarised airway inflammation. Consecutively, we assessed the efficacy of methylprednisolone, roflumilast, azithromycin, AM80 and rapamycin against acute or chronic Th17-dependent airway inflammation. Quantifiers for Th17-associated inflammation comprised: bronchoalveolar lavage (BAL) differential cell counts, allergen-specific cytokine and immunoglobulin secretion, as well as flow cytometric phenotyping of pulmonary inflammatory cells. Only rapamycin proved effective against acute Th17-dependent airway inflammation, accompanied by increased plasmacytoid dendritic cells (pDCs) and reduced neutrophils as well as reduced CXCL-1 levels in BAL. Chronic Th17-dependent airway inflammation was unaltered by rapamycin treatment. None of the other agents showed efficacy in our models. Our results demonstrate that Th17-dependent airway inflammation is difficult to treat with known agents. However, we identify rapamycin as an agent with inhibitory potential against acute Th17-polarized airway inflammation.

  2. Salt-responsive gut commensal modulates TH17 axis and disease.

    Science.gov (United States)

    Wilck, Nicola; Matus, Mariana G; Kearney, Sean M; Olesen, Scott W; Forslund, Kristoffer; Bartolomaeus, Hendrik; Haase, Stefanie; Mähler, Anja; Balogh, András; Markó, Lajos; Vvedenskaya, Olga; Kleiner, Friedrich H; Tsvetkov, Dmitry; Klug, Lars; Costea, Paul I; Sunagawa, Shinichi; Maier, Lisa; Rakova, Natalia; Schatz, Valentin; Neubert, Patrick; Frätzer, Christian; Krannich, Alexander; Gollasch, Maik; Grohme, Diana A; Côrte-Real, Beatriz F; Gerlach, Roman G; Basic, Marijana; Typas, Athanasios; Wu, Chuan; Titze, Jens M; Jantsch, Jonathan; Boschmann, Michael; Dechend, Ralf; Kleinewietfeld, Markus; Kempa, Stefan; Bork, Peer; Linker, Ralf A; Alm, Eric J; Müller, Dominik N

    2017-11-30

    A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.

  3. CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells.

    Science.gov (United States)

    Kara, Ervin E; McKenzie, Duncan R; Bastow, Cameron R; Gregor, Carly E; Fenix, Kevin A; Ogunniyi, Abiodun D; Paton, James C; Mack, Matthias; Pombal, Diana R; Seillet, Cyrill; Dubois, Bénédicte; Liston, Adrian; MacDonald, Kelli P A; Belz, Gabrielle T; Smyth, Mark J; Hill, Geoffrey R; Comerford, Iain; McColl, Shaun R

    2015-10-29

    IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens but also drive numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10-producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFNγ-producing Th17 cells. However, their distinct developmental requirements, functions and trafficking mechanisms in vivo remain poorly understood. Here we identify a temporally regulated IL-23-dependent switch from CCR6 to CCR2 usage by developing Th17 cells that is critical for pathogenic Th17 cell-driven inflammation in experimental autoimmune encephalomyelitis (EAE). This switch defines a unique in vivo cell surface signature (CCR6(-)CCR2(+)) of GM-CSF/IFNγ-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, we identify an IL-23/IL-1/IFNγ/TNFα/T-bet/Eomesodermin-driven circuit driving GM-CSF/IFNγ-producing Th17 cell formation in vivo. Thus, our data identify a unique cell surface signature, trafficking mechanism and T-cell intrinsic regulators of GM-CSF/IFNγ-producing Th17 cells.

  4. Plasticity and heterogeneity of Th17 in immune-mediated kidney diseases.

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    Krebs, Christian F; Panzer, Ulf

    2017-12-21

    Anti-neutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis, anti-glomerular basement membrane (GBM) glomerulonephritis and lupus nephritis are the most common causes of rapid progressive glomerulonephritis (RPGN) in the Western world. These aggressive forms of autoimmune kidney diseases significantly contribute to end-stage renal disease and are associated with high morbidity and mortality. Moreover, patients show significant heterogeneity with respect to clinical outcome and response to therapy. T cell infiltration is a morphological hallmark of RPGN and it is a critical driver of kidney injury. Different CD4+ T cell subsets that are endowed with distinct regulatory and effector functions are involved in this detrimental inflammatory process. In particular, the identification and functional characterization of IL-17-expressing CD4+ Th17 cells have substantially advanced our understanding of organ-specific autoimmunity. In experimental models of crescentic and proliferative GN, including ANCA-associated GN, anti-GBM-GN and lupus nephritis, the Th17/IL-17 axis significantly contributes to renal tissue damage. In patients with ANCA-associated GN or lupus nephritis, IL-17 serum levels correlated with disease activity. Moreover, Th17 cells are present in the kidneys of these patients and represents a topic of intense ongoing clinical and basic research. Importantly, recent studies have challenged the view of CD4+ T cells subsets as terminally differentiated homogenous cells, showing that T cells, in particular Th17 cells, are much more flexible and heterogeneous than previously thought. However, analysis of Th17 cell fate in mouse models of autoimmune kidney disease revealed a high degree of stability within these cells, an observation that is in contrast to Th17 cells in other models of autoimmune diseases including experimental autoimmune encephalomyelitis. Interestingly, anti-CD3 treatment interferes with stable Th17 cells and induces a potential

  5. Role of Th17 cells in common liver diseases

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    WEI Linlin

    2013-06-01

    Full Text Available In recent years, it has been found that T helper type 17 (Th17 cells are a new subset of CD4+ Th cells. Th17 cells play an important role in the onset and development of many liver diseases and have become the research focus in immunology. This paper summarizes the studies on the relationship between Th17 cells and various liver diseases in order to provide a new idea for the study and treatment of liver diseases.

  6. Humoral and cell-mediated immune response to crude antigens of Dermatophilus congolensis during experimental infection of rabbits.

    Science.gov (United States)

    Makinde, A A; Wilkie, B N

    1979-01-01

    Rabbits were infected with Dermatophilus congolensis and tested for humoral immune response by indirect haemagglutination and for cell-mediated immune response to crude antigens of D. congolensis. Lymphocyte transformation and macrophage migration inhibition assays were used as in vitro correlates of cell-mediated immune response while cutaneous delayed hypersensitivity was used in vivo. Endo-antigen and whole cell antigen were found to significantly induce cell-mediated immune response. In contrast, humoral responses were found to be more significantly induced by exo-antigen. A biphasic immune response was revealed by the lymphocyte transformation test.

  7. Th17 in Animal Models of Rheumatoid Arthritis

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    Motomu Hashimoto

    2017-07-01

    Full Text Available IL-17-secreting helper CD4 T cells (Th17 cells constitute a newly identified subset of helper CD4 T cells that play a key role in the development of rheumatoid arthritis (RA in its animal models. Recently, several models of spontaneous RA, which elucidate the mechanism of RA onset, have been discovered. These animal models shed new light on the role of Th17 in the development of autoimmune arthritis. Th17 cells coordinate inflammation and promote joint destruction, acting on various cells, including neutrophils, macrophages, synovial fibroblasts, and osteoclasts. Regulatory T cells cannot control Th17 cells under conditions of inflammation. In this review, the pathogenic role of Th17 cells in arthritis development, which was revealed by the recent animal models of RA, is discussed.

  8. Microbial-induced Th17: superhero or supervillain?

    Science.gov (United States)

    McGeachy, Mandy J; McSorley, Stephen J

    2012-10-01

    Th17 cells are an effector lineage of CD4 T cells that can contribute to protection against microbial pathogens and to the development of harmful autoimmune and inflammatory conditions. An increasing number of studies suggests that Th17 cells play an important protective role in mobilizing host immunity to extracellular and intracellular microbial pathogens, such as Candida and Salmonella. Furthermore, the generation of Th17 cells is heavily influenced by the normal microbial flora, highlighting the complex interplay among harmless microbes, pathogens, and host immunity in the regulation of pathogen-specific Th17 responses. In this article, we review the current understanding of microbe-induced Th17 cells in the context of infectious and inflammatory disease.

  9. Th17 in Animal Models of Rheumatoid Arthritis.

    Science.gov (United States)

    Hashimoto, Motomu

    2017-07-21

    IL-17-secreting helper CD4 T cells (Th17 cells) constitute a newly identified subset of helper CD4 T cells that play a key role in the development of rheumatoid arthritis (RA) in its animal models. Recently, several models of spontaneous RA, which elucidate the mechanism of RA onset, have been discovered. These animal models shed new light on the role of Th17 in the development of autoimmune arthritis. Th17 cells coordinate inflammation and promote joint destruction, acting on various cells, including neutrophils, macrophages, synovial fibroblasts, and osteoclasts. Regulatory T cells cannot control Th17 cells under conditions of inflammation. In this review, the pathogenic role of Th17 cells in arthritis development, which was revealed by the recent animal models of RA, is discussed.

  10. Th17 cells in the pathogenesis of multiple sclerosis

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    Marek Juszczak

    2009-10-01

    Full Text Available Th17 cells are a recently described subset of T helper lymphocytes characterized by the production of IL-17 (IL-17A. Since their discovery in 2003, studies on Th17 cells have become increasingly popular among immunologists and they have emerged as key players in the pathogenesis of multiple sclerosis (MS and other autoimmune disorders traditionally attributed to Th1 cells. Murine Th17 lymphocytes differentiate from naive CD4 cells in a specific cytokine environment, which includes TGF- and IL-6 or IL-21, whereas human Th17 cell development requires TGF-, IL-1, and IL-2 in combination with IL-6, IL-21, or IL-23. Th17-related response is additionally enhanced by osteopontin, TNF, and PGE2 and suppressed by IL-25, IL-27, IL-35, and IL-10. Apart from their main cytokine, Th17 cells can also express IL-17F, IL-21, IL-22, TNF, CCL20, and, in humans, IL-26. All of these mediators may contribute to the proinflammatory action of Th17 .cells both in the clearance of various pathogens and in autoimmunity. At least some of these functions are exerted through the induction of neutrophil-recruiting chemokines (CXCL1, CXCL2, CXCL8 by IL-17. Accumulating evidence from studies on mice and humans indicates an important role of Th17 cells in mediating autoimmune neuroinflammation. This has led some immunologists to question the previously exhibited importance of Th1 cells in MS pathology. However, more recent data suggest that both these T-cell subsets are capable of inducing and promoting the disease. Further investigation is required to clarify the role of Th17 cells in the pathogenesis of MS since some of the Th17-related molecules appear as attractive targets for future therapeutic strategies

  11. Harnessing the Therapeutic Potential of Th17 Cells

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    Jonas Bystrom

    2015-01-01

    Full Text Available Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon γ (IFNγ. In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases.

  12. Cytokine crowdsourcing: multicellular production of TH17-associated cytokines.

    Science.gov (United States)

    Busman-Sahay, Kathleen O; Walrath, Travis; Huber, Samuel; O'Connor, William

    2015-03-01

    In the 2 decades since its discovery, IL-17A has become appreciated for mounting robust, protective responses against bacterial and fungal pathogens. When improperly regulated, however, IL-17A can play a profoundly pathogenic role in perpetuating inflammation and has been linked to a wide variety of debilitating diseases. IL-17A is often present in a composite milieu that includes cytokines produced by TH17 cells (i.e., IL-17F, IL-21, IL-22, and IL-26) or associated with other T cell lineages (e.g., IFN-γ). These combinatorial effects add mechanistic complexity and more importantly, contribute differentially to disease outcome. Whereas TH17 cells are among the best-understood cell types that secrete IL-17A, they are frequently neither the earliest nor dominant producers. Indeed, non-TH17 cell sources of IL-17A can dramatically alter the course and severity of inflammatory episodes. The dissection of the temporal regulation of TH17-associated cytokines and the resulting net signaling outcomes will be critical toward understanding the increasingly intricate role of IL-17A and TH17-associated cytokines in disease, informing our therapeutic decisions. Herein, we discuss important non-TH17 cell sources of IL-17A and other TH17-associated cytokines relevant to inflammatory events in mucosal tissues. © Society for Leukocyte Biology.

  13. Loss and Dysregulation of Th17 Cells during HIV Infection

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    Sandra L. Bixler

    2013-01-01

    Full Text Available Bacterial translocation across the damaged mucosal epithelium has emerged as a major paradigm for chronic immune activation observed during HIV infection. T helper 17 (Th17 cells are a unique lineage of T helper cells that are enriched in mucosal tissues and are thought to play a central role in protecting the integrity of the mucosal barrier and maintaining immune homeostasis at mucosal sites. Th17 cells are lost very early during the course of HIV infection, and their loss has been shown to correlate with bacterial translocation. Interestingly, Th17 cells are unable to completely recover from the early destruction even after successful antiretroviral therapy (ART. Here, we review some of the potential mechanisms for the loss and dysregulation of Th17 cells during HIV infection.

  14. The Th17/Treg balance is disturbed during aging.

    Science.gov (United States)

    Schmitt, Vanessa; Rink, Lothar; Uciechowski, Peter

    2013-12-01

    Aging is associated with multiple changes in the proliferative and functional abilities of the immune system which are not related to any pathology but consequences in immunosenescence and inflammaging. T helper (TH) 17 cells have been implicated in the development of autoimmune and chronic inflammatory diseases in humans. Additionally, a reciprocal relationship between these pro-inflammatory TH17 and the anti-inflammatory regulatory T cells (Tregs) has been described. Recent studies reported an increase of TH17 cells in aged humans and aged mice, but the role of TH17 cells and their relation to Tregs is poorly understood in human aging. This study investigated the proportion of TH17 (CD4+ IL23 receptor(R)+) cells and Tregs (CD4+ Foxp3+) as well as Interleukin (IL)-17 and IL-10 production in four different age groups from human healthy donors. The data revealed a continual increase of basal CD4+ IL23R+ cell amounts in the different age groups. By analyzing the balance of both T-cell subsets it was observed that, on a basal resting level, TH17 cells were significantly increased in older individuals whereas Tregs were reduced. However, the TH17/Treg ratio decreased age-dependently after stimulation and was accompanied by elevated Foxp3 mRNA and IL-10 protein expressions. In conclusion, changes of the TH17/Treg ratios in combination with altered cytokine expression during aging may contribute to an imbalance between the pro-inflammatory and the anti-inflammatory immune response. This indicates a higher susceptibility to develop inflammatory diseases with increasing age. © 2013.

  15. Blockade of CD47 ameliorates autoimmune inflammation in CNS by suppressing IL-1-triggered infiltration of pathogenic Th17 cells.

    Science.gov (United States)

    Gao, Qiangguo; Zhang, Yi; Han, Chaofeng; Hu, Xiang; Zhang, Hua; Xu, Xiongfei; Tian, Jun; Liu, Yiqi; Ding, Yuanyuan; Liu, Juan; Wang, Chunmei; Guo, Zhenhong; Yang, Yongguang; Cao, Xuetao

    2016-05-01

    The migration of Th17 cells into central nervous system (CNS) tissue is the key pathogenic step in experimental autoimmune encephalomyelitis (EAE) model. However, the mechanism underlying the pathogenic Th17 cell migration remains elusive. Here we report that blockade of CD47 with CD47-Fc fusion protein is effective in preventing and curing EAE by impairing infiltration of Th17 cells into CNS. However, CD47 deficiency does not directly impair the migration of Th17 cells. Mechanistic studies showed that CD47 deficiency inhibited degradation of inducible nitric oxide synthase (iNOS) in proteasome of macrophages by Src activation and led to the increased nitric oxide (NO) production. Then NO suppressed inflammasome activation-induced IL-1β production. This lower IL-1β reduces the expression of IL-1R1 and migration-related chemokine receptors on CD47(-/-) Th17 cells, inhibiting the ability of Th17 cells to infiltrate into the CNS of CD47(-/-) mice and therefore suppressing EAE development. In vivo administration of exogenous IL-1β indeed promoted the infiltration CD47(-/-) Th17 cells into CNS and antagonized the protective role of CD47 deficiency in EAE pathogenesis. Our results demonstrate a potential preventive and therapeutic application of CD47 blockade in controlling EAE development. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. TH17 cells in autoimmunity and immunodeficiency: protective or pathogenic?

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    Ashish eMarwaha

    2012-06-01

    Full Text Available In 2005 a newly discovered T helper cell subset that secreted interleukin (IL-17 became the center of attention in immunology. Initial studies painted Th17 cells as the culprit for destruction caused in many different autoimmune and auto-inflammatory diseases. Subsequently, the discovery of patients with primary immunodeficiencies in the IL-17 pathway taught us that Th17 cells have a critical role in defense against certain fungal and bacterial infections. Moreover, the paradoxical exacerbation of Crohn’s disease in the clinical trials of a Secukiumab (AIN457, a fully human neutralizing antibody to IL-17A, has cast into doubt a universal pro-inflammatory and harmful role for Th17 cells. Evidence now suggests that depending on the environment Th17 cell can alter their differentiation program, ultimately giving rise to either protective or pro-inflammatory cells. In this review will summarize the evidence from patients with immunodeficiencies, autoimmune, or auto-inflammatory disease that teaches us how the pro-inflammatory versus protective function of Th17 cells varies within the context of different human diseases.

  17. Increased Th17/Treg Ratio in Poststroke Fatigue

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    Xinjing Liu

    2015-01-01

    Full Text Available Fatigue is a major debilitating symptom after stroke. The biological mechanisms underlying poststroke fatigue (PFS are unknown. We hypothesized that PSF is associated with an alteration in the balance between Th17 and Treg cells. To test this hypothesis we assessed fatigue in 30 stroke survivors using the Fatigue Scale for Motor and Cognitive Functions (FSMC. Peripheral blood was collected for assessment of Th17 and Treg cell populations and measurement of interleukin-10 (IL-10. Participants were dichotomized into severe fatigue n=14 and low-moderate fatigue n=16 groups by K-mean cluster analysis of FSMC scores. There were no group differences in age, gender, stroke type, stroke severity, or time since stroke. Stroke survivors in the severe fatigue group reported greater anxiety p=0.004 and depression p=0.001 than in the low-moderate fatigue group. The ratio of Th17 to Treg cells was significantly increased in the severe fatigue group relative to the mild-moderate fatigue group p=0.035. Serum levels of IL-10 negatively correlated withTh17/Treg ratio (r=-0.408,  p=0.025. Our preliminary findings suggest that an imbalance in the Th17/Treg ratio is associated with the severity of PSF.

  18. Transmembrane TNF-TNFR2 Impairs Th17 Differentiation by Promoting Il2 Expression.

    Science.gov (United States)

    Miller, Patrick G; Bonn, Michael B; McKarns, Susan C

    2015-09-15

    The double-edged sword nature by which IL-2 regulates autoimmunity and the unpredictable outcomes of anti-TNF therapy in autoimmunity highlight the importance for understanding how TNF regulates IL-2. Transmembrane TNF (tmTNF) preferentially binds TNFR2, whereas soluble TNF (sTNF) binds TNFR1. We previously showed reduced IL-2 production in TNFR1(-/-) TNFR2(-/-) CD4(+) T cells. In this study, we generated TNFR1(-/-), TNFR2(-/-), or TNFR1(-/-) TNFR2(-/-) 5C.C7 TCR Il2-GFP mice and report that CD4(+) T cell-intrinsic tmTNF/TNFR2 stimulates Il2 promoter activity and Il2 mRNA stability. We further used tmTNF Foxp3 gfp reporter mice and pharmacological TNF blockade in wild-type mice to report a tmTNF/TNFR2 interaction for Il2 expression. IL-17 is critical for host defense, but its overabundance promotes autoimmunity. IL-2 represses Th17 differentiation, but the role for TNFR2 in this process is not well understood. We report elevated expression of TNFR2 under Th17-polarization conditions. Genetic loss-of-function experimental models, as well as selective TNF blockade by etanercept and XPro1595 in wild-type mice, demonstrate that impaired tmTNF/TNFR2, but not sTNF/TNFR1, promotes Th17 differentiation in vivo and in vitro. Under Th17-polarizing conditions, elevated IL-17 production by TNFR2-knockout CD4(+) T cells was associated with increased STAT3 activity and decreased STAT5 activity. Increased IL-17 production in TNFR2-knockout T cells was prevented by adding exogenous IL-2. We conclude that CD4(+) T cell-intrinsic tmTNF/TNFR2 promotes IL-2 production that inhibits the generation of Th17 cells in a Foxp3-independent manner. Moreover, under Th17-polarizing conditions, selective blockade of CD4(+) T cell-intrinsic TNFR2 appears to be sufficient to promote Th17 differentiation. Copyright © 2015 by The American Association of Immunologists, Inc.

  19. Limfocyty Th17 w patogenezie doświadczalnego modelu stwardnienia rozsianego

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    Dagmara Wójkowska

    2011-07-01

    Full Text Available Limfocyty Th17 są stosunkowo niedawno opisaną subpopulacją limfocytów pomocniczych T (Th, charakteryzującą się wytwarzaniem cytokiny IL-17 (IL-17. Badania nad tymi limfocytami rzuciły nowe światło na patogenezę stwardnienia rozsianego (SM i jego doświadczalnego modelu – eksperymentalnego autoimmunizacyjnego zapalenia mózgu i rdzenia kręgowego (experimental autoimmune encephalomyelitis, EAE. Limfocyty te wykazują znaczne podobieństwo do limfocytów Th1, a dziewicze limfocyty CD4+ różnicują się w kierunku fenotypu Th17 pod wpływem stymulacji ściśle określonego zestawu cytokin. Powstawanie mysich limfocytów Th17 indukują cytokiny TGF-β oraz IL-6 lub IL-21. Komórki Th17 produkują różne chemokiny, m.in. IL-17A/F, IL-21 i IL-22. Udokumentowano, że neutralizacja IL-17 zmniejsza objawy choroby EAE. Głównym mediatorem stanu patologicznego w ośrodkowym układzie nerwowym (OUN indukowanego przez limfocyty Th17 jest cytokina IL-17A. Do najlepiej scharakteryzowanych funkcji IL-17A należy indukcja wytwarzania neutrofilowych chemokin ELR+ CXC, tj. CXCL1 i CXCL2. Ponadto limfocyty Th17 mogą sprzyjać rozwojowi EAE poprzez aktywację neutrofili wewnątrz szpiku kostnego, co w konsekwencji prowadzi do mobilizacji niedojrzałych monocytów do krwiobiegu i rozwoju zapalenia w ośrodkowym układzie nerwowym. Rosnąca liczba danych płynących z badań nad SM i EAE potwierdza istotny udział limfocytów Th17 w patogenezie tej choroby, a poznanie dokładnej roli tych limfocytów wymaga dalszych badań – ich wyniki mogą być użyteczne w opracowywaniu nowych metod terapii SM.

  20. RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells

    Science.gov (United States)

    Park, Tae-Yoon; Park, Sung-Dong; Cho, Jen-Young; Moon, Jae-Seung; Kim, Na-Yeon; Park, Kyungsoo; Seong, Rho Hyun; Lee, Sang-Won; Morio, Tomohiro; Bothwell, Alfred L. M.; Lee, Sang-Kyou

    2014-01-01

    The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (RORγt) is a transcription factor (TF) specific to TH17 cells that produce interleukin (IL)-17 and have been implicated in a wide range of autoimmunity. Here, we developed a novel therapeutic strategy to modulate the functions of RORγt using cell-transducible form of transcription modulation domain of RORγt (tRORγt-TMD), which can be delivered effectively into the nucleus of cells and into the central nerve system (CNS). tRORγt-TMD specifically inhibited TH17-related cytokines induced by RORγt, thereby suppressing the differentiation of naïve T cells into TH17, but not into TH1, TH2, or Treg cells. tRORγt-TMD injected into experimental autoimmune encephalomyelitis (EAE) animal model can be delivered effectively in the splenic CD4+ T cells and spinal cord-infiltrating CD4+ T cells, and suppress the functions of TH17 cells. The clinical severity and incidence of EAE were ameliorated by tRORγt-TMD in preventive and therapeutic manner, and significant reduction of both infiltrating CD4+ IL-17+ T cells and inflammatory cells into the CNS was observed. As a result, the number of spinal cord demyelination was also reduced after tRORγt-TMD treatment. With the same proof of concept, tTbet-TMD specifically blocking TH1 differentiation improved the clinical incidence of rheumatoid arthritis (RA). Therefore, tRORγt-TMD and tTbet-TMD can be novel therapeutic reagents with the natural specificity for the treatment of inflammatory diseases associated with TH17 or TH1. This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis. PMID:25527718

  1. Role of Th17 Cells in Skin Inflammation of Allergic Contact Dermatits

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    Matthias Peiser

    2013-01-01

    Full Text Available Extending the classical concept considering an imbalance exclusively of T helper(h 1 and Th2 cells on the bottom of many inflammatory diseases, Th17 cells were recently described. Today, there is sufficient experimental evidence to classify psoriasis and allergic contact dermatitis (ACD amongst other inflammatory skin disorders as IL-17 associated diseases. In several human studies, T-cell-clones could be isolated from eczema biopsies, and high IL-17 levels were observed after challenge with allergen. In the last years, the phenotype of these IL-17 releasing T cells was in the focus of discussion. It has been suggested that Th17 could be identified by expression of retinoic acid receptor-related orphan receptor (RORC (humans or RORγt (mice and IL-17, accompanied by the absence of IFN-γ and IL-22. In cells from skin biopsies, contact allergens elevate IL-17A, IL-23, and RORC within the subset of Th cells. The indications for a participation of Th17 in the development of ACD are supported by data from IL-17 deficient mice with reduced contact hypersensitivity (CHS reactions that could be restored after transplantation of wild type CD4+ T cells. In addition to Th17 cells, subpopulations of CD8+ T cells and regulatory T cells are further sources of IL-17 that play important roles in ACD as well. Finally, the results from Th17 cell research allow today identification of different skin diseases by a specific profile of signature cytokines from Th cells that can be used as a future diagnostic tool.

  2. Circulating Th17, Th22, and Th1 Cells Are Elevated in the Guillain-Barré Syndrome and Downregulated by IVIg Treatments

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    Shujuan Li

    2014-01-01

    Full Text Available The Guillain-Barré syndrome (GBS is considered a T helper 1 (Th1 cells-mediated acute inflammatory peripheral neuropathy. However, some changes in GBS could not be explained completely by Th1 cells pathogenic role. Recently, Th17 cells have been identified and can mediate tissue inflammation and autoimmune response. Therefore, a study on the role of Th17 and Th22 cells and their cytokines in GBS is necessary for exploring the pathogenesis of GBS. Here, we detected the frequency of Th1, Th17, and Th22 cells by using 4-color flow cytometry and we detected the plasma levels of IL-17 and IL-22 by ELISA in GBS patients, relapsing-remitting multiple sclerosis patients at the acute phase of relapse, viral encephalitis or meningitis patients and healthy controls. Our data showed that the frequency of circulating Th1, Th17, and Th22 cells was significantly increased in GBS patients. The plasma levels of IL-17 and IL-22 in GBS and relapsing-remitting multiple sclerosis at the acute phase of relapse were also markedly elevated. Enhanced circulating Th22 cells were correlated with GBS severity. Intravenous immunoglobulin therapy downregulated Th17, and Th22 cells and the plasma levels of IL-17 and IL-22 in GBS patients. Th17 and Th22 cells may be involved in the pathogenesis of GBS, and intravenous immunoglobulin mediates therapeutic effects by downregulating these cells and their cytokines.

  3. Th17 responses and host defense against microorganisms: an overview.

    NARCIS (Netherlands)

    Veerdonk, F.L. van de; Gresnigt, M.S.; Kullberg, B.J.; Meer, J.W.M. van der; Joosten, L.A.B.; Netea, M.G.

    2009-01-01

    T helper (Th) 17 cells have recently been described as a third subset of T helper cells, and have provided new insights into the mechanisms that are important in the development of autoimmune diseases and the immune responses that are essential for effective antimicrobial host defense. Both

  4. Increased expression of Th17 cytokines in patients with psoriasis ...

    African Journals Online (AJOL)

    Psoriasis is a chronic inflammatory skin disease that is thought to be mediated by a new distinct type of T helper cell, called Th17 cells that play an essential pathogenic role in psoriasis. In this study, we measured serum levels of IL-17A and IL-23P19 in 43 psoriatic patients and 30 healthy control using nested real time ...

  5. Th17-related genes and celiac disease susceptibility.

    Directory of Open Access Journals (Sweden)

    Luz María Medrano

    Full Text Available Th17 cells are known to be involved in several autoimmune or inflammatory diseases. In celiac disease (CD, recent studies suggest an implication of those cells in disease pathogenesis. We aimed at studying the role of genes relevant for the Th17 immune response in CD susceptibility. A total of 101 single nucleotide polymorphisms (SNPs, mainly selected to cover most of the variability present in 16 Th17-related genes (IL23R, RORC, IL6R, IL17A, IL17F, CCR6, IL6, JAK2, TNFSF15, IL23A, IL22, STAT3, TBX21, SOCS3, IL12RB1 and IL17RA, were genotyped in 735 CD patients and 549 ethnically matched healthy controls. Case-control comparisons for each SNP and for the haplotypes resulting from the SNPs studied in each gene were performed using chi-square tests. Gene-gene interactions were also evaluated following different methodological approaches. No significant results emerged after performing the appropriate statistical corrections. Our results seem to discard a relevant role of Th17 cells on CD risk.

  6. Role of Th17 lymphocytes in pathogenesis of colorectal cancer

    Directory of Open Access Journals (Sweden)

    Jacek Karczewski

    2014-01-01

    Full Text Available Colorectal cancer (CRC is estimated to be the first leading cause of death from cancer among men and women in the EU. Every year in Poland, 15,254 cases of CRC are diagnosed, and 10,501 patients die of the disease, making it the second leading cause of death from cancer. In more than 90% of cases, the disease begins as adenomatous polyps with epithelial dysplasia as a common feature. Inflammatory bowel diseases (IBD, a group of chronic inflammatory diseases of the gastrointestinal tract characterized by remissions and relapses, constitute an independent risk factor of CRC development. CRC developing in IBD patients, however, has features distinct from sporadic cancer, suggesting the influence of unique factors. The high risk of CRC in IBD patients probably results from chronic inflammation. In most cases, neoplastic lesions arise within the inflamed gastrointestinal mucosa during the process of re-epithelization, which is a healing response to ulceration. The recently discovered Th17 lymphocytes, which demonstrate strong pro-inflammatory capabilities, might link the two diseases. Th17 lymphocytes produce a number of pro-inflammatory cytokines, such as interleukin (IL-17A, IL-17F, IL-21, IL-22 and tumor necrosis factor (TNF-a, and play a key role in mucosal defense against various pathogens. Numerous observations suggest that Th17 lymphocytes are involved in pathogenesis of different autoimmune diseases and pathologic inflammatory states. Mounting evidence suggests that Th17 cells contribute to the pathogenesis of IBD and CRC. However, their precise role in both diseases is unknown.

  7. IL-17/Th17 Pathway Is Activated in Acne Lesions

    Science.gov (United States)

    Kelhälä, Hanna-Leena; Palatsi, Riitta; Fyhrquist, Nanna; Lehtimäki, Sari; Väyrynen, Juha P.; Kallioinen, Matti; Kubin, Minna E.; Greco, Dario; Tasanen, Kaisa; Alenius, Harri; Bertino, Beatrice; Carlavan, Isabelle; Mehul, Bruno; Déret, Sophie; Reiniche, Pascale; Martel, Philippe; Marty, Carine; Blume-Peytavi, Ulrike; Voegel, Johannes J.; Lauerma, Antti

    2014-01-01

    The mechanisms of inflammation in acne are currently subject of intense investigation. This study focused on the activation of adaptive and innate immunity in clinically early visible inflamed acne lesions and was performed in two independent patient populations. Biopsies were collected from lesional and non-lesional skin of acne patients. Using Affymetrix Genechips, we observed significant elevation of the signature cytokines of the Th17 lineage in acne lesions compared to non-lesional skin. The increased expression of IL-17 was confirmed at the RNA and also protein level with real-time PCR (RT-PCR) and Luminex technology. Cytokines involved in Th17 lineage differentiation (IL-1β, IL-6, TGF-β, IL23p19) were remarkably induced at the RNA level. In addition, proinflammatory cytokines and chemokines (TNF-α, IL-8, CSF2 and CCL20), Th1 markers (IL12p40, CXCR3, T-bet, IFN-γ), T regulatory cell markers (Foxp3, IL-10, TGF-β) and IL-17 related antimicrobial peptides (S100A7, S100A9, lipocalin, hBD2, hBD3, hCAP18) were induced. Importantly, immunohistochemistry revealed significantly increased numbers of IL-17A positive T cells and CD83 dendritic cells in the acne lesions. In summary our results demonstrate the presence of IL-17A positive T cells and the activation of Th17-related cytokines in acne lesions, indicating that the Th17 pathway is activated and may play a pivotal role in the disease process, possibly offering new targets of therapy. PMID:25153527

  8. Sodium butyrate regulates Th17/Treg cell balance to ameliorate uveitis via the Nrf2/HO-1 pathway.

    Science.gov (United States)

    Chen, Xiaoqing; Su, Wenru; Wan, Taoshang; Yu, Jianfeng; Zhu, Wenjie; Tang, Fen; Liu, Guangming; Olsen, Nancy; Liang, Dan; Zheng, Song Guo

    2017-10-15

    Autoimmune uveitis, a group of potentially blinding intraocular inflammatory diseases, remains a therapeutic challenge for ophthalmologists. Butyrates, which belong to the short-chain fatty acid family, possess immunomodulatory properties and therapeutic potential in several inflammatory disorders. However, the roles of butyrates in uveitis and their underlying immunomodulatory mechanisms remain elusive. Here, we report that treatment with sodium butyrate (NaB) significantly attenuated the ocular inflammatory response in mice with experimental autoimmune uveitis (EAU) at 14days after immunization, with significant decreases in inflammatory cell infiltration and inflammatory cytokine production in the retinas. Furthermore, NaB treatment decreased the frequency and number of Th17 cells and increased the frequency and number of T regulatory (Treg) cells in both draining lymph nodes and spleens of EAU mice. In vitro, NaB treatment directly converted the differentiation of naive T cells from Th17 cells toward Treg cells. Mechanistically, the NaB-mediated inhibition of Th17 cell differentiation may occur via inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/interleukin-6 receptor pathway. Moreover, the NaB-mediated inhibition on Th17 cell differentiation and uveitis were abrogated when an HO-1 inhibitor, SnPP, was used. These findings suggest that NaB inverts the differentiation of Th17 cells toward Treg cells and attenuates experimental autoimmune uveitis by modulating the Nrf2/HO-1 pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Inorganic arsenic represses interleukin-17A expression in human activated Th17 lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Morzadec, Claudie; Macoch, Mélinda; Robineau, Marc; Sparfel, Lydie [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes (France); Fardel, Olivier [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes (France); Pôle Biologie, Centre Hospitalier Universitaire (CHU) Rennes, 2 rue Henri Le Guilloux, 35033 Rennes (France); Vernhet, Laurent, E-mail: laurent.vernhet@univ-rennes1.fr [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes (France)

    2012-08-01

    Trivalent inorganic arsenic [As(III)] is an efficient anticancer agent used to treat patients suffering from acute promyelocytic leukemia. Recently, experimental studies have clearly demonstrated that this metalloid can also cure lymphoproliferative and/or pro-inflammatory syndromes in different murine models of chronic immune-mediated diseases. T helper (Th) 1 and Th17 lymphocytes play a central role in development of these diseases, in mice and humans, especially by secreting the potent pro-inflammatory cytokine interferon-γ and IL-17A, respectively. As(III) impairs basic functions of human T cells but its ability to modulate secretion of pro-inflammatory cytokines by differentiated Th lymphocytes is unknown. In the present study, we demonstrate that As(III), used at concentrations clinically achievable in plasma of patients, has no effect on the secretion of interferon-γ from Th1 cells but almost totally blocks the expression and the release of IL-17A from human Th17 lymphocytes co-stimulated for five days with anti-CD3 and anti-CD28 antibodies, in the presence of differentiating cytokines. In addition, As(III) specifically reduces mRNA levels of the retinoic-related orphan receptor (ROR)C gene which encodes RORγt, a key transcription factor controlling optimal IL-17 expression in fully differentiated Th17 cells. The metalloid also blocks initial expression of IL-17 gene induced by the co-stimulation, probably in part by impairing activation of the JNK/c-Jun pathway. In conclusion, our results demonstrate that As(III) represses expression of the major pro-inflammatory cytokine IL-17A produced by human Th17 lymphocytes, thus strengthening the idea that As(III) may be useful to treat inflammatory immune-mediated diseases in humans. -- Highlights: ► Arsenic inhibits secretion of IL-17A from human naïve and memory Th17 lymphocytes. ► Arsenic represses early expression of IL-17A gene in human activated T lymphocytes. ► Arsenic interferes with activation of

  10. TLR4 Expression by Liver Resident Cells Mediates the Development of Glucose Intolerance and Insulin Resistance in Experimental Periodontitis

    Science.gov (United States)

    Ilievski, Vladimir; Cho, Yale; Katwala, Priya; Rodriguez, Heriberto; Tulowiecka, Margaret; Kurian, David; Leoni, Lara; Christman, John W.; Unterman, Terry G.; Watanabe, Keiko

    2015-01-01

    Background Results from epidemiological studies indicate a close association between periodontitis and type 2 diabetes mellitus. However, the mechanism linking periodontitis to glucose intolerance (GI) and insulin resistance (IR) is unknown. We therefore tested the hypothesis that periodontitis induces the development of GI/IR through a liver Toll-like receptor 4 (TLR4) dependent mechanism. Methods TLR4 chimeric mice were developed by bone marrow transplantation using green fluorescent protein expressing TLR4WT mouse (GFPWT) as donor and TLR4 WT or TLR4-/- as recipient mice (GFPWT:WT and GFPWT:KO chimeras respectively). These chimeras were subjected to experimental chronic periodontitis induced by repeated applications of LPS to the gingival sulci for 18 weeks. The levels of GI/IR were monitored and plasma cytokines and LPS were determined at 18 weeks when differences in glucose tolerance were most apparent. Cytokine gene expression was measured in liver tissue by qPCR. Results Alveolar bone loss was significantly greater in GFPWT:WT chimeras treated with LPS compared with chimeras treated with PBS or GFPWT:KO chimeras. However, the degree of gingival inflammation was similar between GFPWT:WT and GFPWT:KO mice with LPS application. Severe GI/IR occurred in GFPWT:WT chimeras but not in the GFPWT:KO chimeras that were subjected to 18 weeks of LPS. Serum LPS was detected only in animals to which LPS was applied and the level was similar in GFPWT:WT and GFPWT:KO mice at the 18 week time point. Surprisingly, there was no significant difference in the plasma levels of IL1β, IL6 and TNFα at 18 weeks in spite of the severe GI/IR in the GFPWT:WT chimeras with LPS application. Also, no difference in the expression of TNFα or IL6 mRNA was detected in the liver of GFPWT:WT vs GFPWT:KO mice. In contrast, liver IL1β expression was significantly greater in GFPWT:WT chimeras compared to GFPWT:KO chimeras treated with LPS. Conclusion We observed that GFPWT:WT, but not GFPWT

  11. Changes in the expression of Th17 cell-associated cytokines in the development of rheumatic heart disease.

    Science.gov (United States)

    Wen, Yun; Zeng, Zhiyu; Gui, Chun; Li, Lang; Li, Wenting

    2015-01-01

    Autoimmunity plays a critical role in the development of rheumatic heart disease (RHD). Recent studies have linked Th17 cells to the autoimmune mechanism associated with RHD. This study aimed to investigate changes in Th17 cell-related cytokine expression in acute and chronic RHD. We established a Lewis rat model of experimental RHD, which was induced by inactivated Group A streptococci and complete Freund's adjuvant. After 7- and 24-week intervention treatments, we measured serum levels of interleukin-17 (IL-17) and IL-6, key cytokines associated with Th17 cells, using a Luminex liquichip method, and levels of IL-17 and IL-6 in heart tissues using immunohistochemical assays. Moreover, expression levels of IL-17, IL-21, IL-6, and IL-23 in mitral valve tissues of human RHD patients were also measured using immunohistochemistry. Compared with the normal control group, serum IL-17 and IL-6 concentrations were significantly increased, and the expression levels of IL-17 and IL-6 in the mitral valve were also significantly increased in 7- or 24-week RHD rats (P<.017). Compared with the control group, expression of IL-17, IL-21, IL-6, and IL-23 in mitral valve tissues was significantly increased in RHD patients (P<.05). Our study suggested that the increased expression of Th17 cell-associated cytokines might play an important role in the pathogenesis and development of RHD. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway.

    Directory of Open Access Journals (Sweden)

    Varun C Anipindi

    2016-05-01

    Full Text Available Clinical and experimental studies have shown that estradiol (E2 confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway.

  13. CD103+ Dendritic Cells Control Th17 Cell Function in the Lung

    Directory of Open Access Journals (Sweden)

    Teresa Zelante

    2015-09-01

    Full Text Available Th17 cells express diverse functional programs while retaining their Th17 identity, in some cases exhibiting a stem-cell-like phenotype. Whereas the importance of Th17 cell regulation in autoimmune and infectious diseases is firmly established, the signaling pathways controlling their plasticity are undefined. Using a mouse model of invasive pulmonary aspergillosis, we found that lung CD103+ dendritic cells (DCs would produce IL-2, dependent on NFAT signaling, leading to an optimally protective Th17 response. The absence of IL-2 in DCs caused unrestrained production of IL-23 and fatal hyperinflammation, which was characterized by strong Th17 polarization and the emergence of a Th17 stem-cell-like population. Although several cell types may be affected by deficient IL-2 production in DCs, our findings identify the balance between IL-2 and IL-23 productions by lung DCs as an important regulator of the local inflammatory response to infection.

  14. Aiolos promotes TH17 differentiation by directly silencing Il2 expression

    Science.gov (United States)

    Quintana, Francisco J; Jin, Hulin; Burns, Evan J; Nadeau, Meghan; Yeste, Ada; Kumar, Deepak; Rangachari, Manu; Zhu, Chen; Xiao, Sheng; Seavitt, John; Georgopoulos, Katia; Kuchroo, Vijay K

    2013-01-01

    CD4+ interleukin 17 (IL-17)-producing helper T cells (TH17 cells) are instrumental in the immune response to pathogens. However, an overactive TH17 response results in tissue inflammation and autoimmunity, and therefore it is important to identify the molecular mechanisms that control the development of TH17 cells. IL-2 suppresses such development, but how IL-2 production is actively suppressed during TH7 differentiation is not understood. Here we report that under TH17-polarizing conditions, the transcription factors STAT3 and AhR upregulated the expression of Aiolos, a member of the Ikaros family of transcription factors. Using Aiolos-deficient mice, we demonstrated that Aiolos silenced the Il2 locus, promoting TH17 differentiation in vitro and in vivo. Thus, we have identified a module in the transcriptional program of TH17 cells that actively limits IL-2 production and promotes their differentiation. PMID:22751139

  15. Unique Tailoring of Th17 at the Gingival Oral Mucosal Barrier.

    Science.gov (United States)

    Konkel, J E; Moutsopoulos, N M

    2017-10-01

    Our recent work highlights unique requirements for the induction of Th17 cells at the oral/gingival mucosal barrier. Unlike other barrier sites, such as the skin and gastrointestinal tract, we found that Th17 cells can develop at the gingiva independently of commensal microbiota colonization. Instead, we identified that damage, which occurs physiologically due to mastication, promotes induction of Th17 cells and tones homeostatic immunity at the gingiva.

  16. Th17 cells correlate positively to the structural and functional integrity of the brain in bipolar depression and healthy controls.

    Science.gov (United States)

    Poletti, Sara; de Wit, Harm; Mazza, Elena; Wijkhuijs, Annemarie J M; Locatelli, Clara; Aggio, Veronica; Colombo, Cristina; Benedetti, Francesco; Drexhage, Hemmo A

    2017-03-01

    Abnormalities of T cell-mediated immune activation, in the absence of active somatic immune diseases, have consistently been reported in mood disorders. Apart from being important players in the regulation of cells of the immune system, T cells are essential for normal brain development. We here report studies on the relationship between circulating levels of T helper cells and structural and functional brain imaging in depressed bipolar patients. Since the CCL20-CCR6 axis is an important entry to the brain we differentiated the various T helper cell subpopulations on the basis of their chemokine receptor expression. FACS staining was performed for Th1, Th2, Th17, Th22 and T regulatory cells on frozen leukocytes of 25 consecutively admitted inpatients affected by a major depressive episode, without psychotic features, in the course of Bipolar Disorder I and 21 healthy controls. The frequency of the T helper populations was associated with DTI and fMRI data acquired on a Philips 3.0 Tesla scanner. Tract based spatial statistic was used to obtain measures of white matter integrity (fractional anisotropy, axial, radial and mean diffusivity) from a standard DTI sequence with 35 directions. Patients were also studied for fMRI through a moral valence decision task were subjects had to decide whether morally tuned stimuli were positive or negative. The percentage of circulating Th17 (CCR6(+)CXCR3(neg)CCR4(+)CCR10(neg)) cells correlated positively with higher fractional anisotropy in fiber tracts contributing to the functional integrity of the brain both in patients and healthy controls, while the frequency of circulating T regulatory (CD4(+)CD25(+)FOXP3(+)) cells correlated positively with higher radial and mean diffusivity in patients. The frequency of circulating T regulatory cells also correlated to lower neuronal responses to negative versus positive morally tuned stimuli in the right dorsolateral prefrontal cortex of patients. Th1 cells correlated negatively with

  17. Propionibacterium acnes and the Th1/Th17 Axis, implications in acne pathogenesis and treatment

    Directory of Open Access Journals (Sweden)

    Kabir Sardana

    2017-01-01

    Full Text Available Acne vulgaris is one of the most commonly seen conditions and the immunological link is a topic of active research. Recently, the Th17 pathway has been found to play a pivotal role in acne. The adaptive immune response toward Propionibacterium acnes leads to activation of Th17 axis. Consequently, the Th17 cytokines (IL-17, IL-1 β, IL-6, and tumor growth factor, in turn, activate the various pathogenic steps in acne. Drugs such as Vitamin D3 and isotretinoin which target the Th17 pathway may offer an additional pathway for their therapeutic response.

  18. IL-23 and T(H)17-mediated inflammation in human allergic contact dermatitis

    DEFF Research Database (Denmark)

    Larsen, Jeppe Madura; Bonefeld, Charlotte Menné; Poulsen, Steen Seier

    2009-01-01

    . OBJECTIVE: To investigate T(H)17-mediated inflammation in human beings with allergic contact dermatitis; in particular, the innate response of keratinocytes to contact allergen, the induction of allergen-specific T(H)17 cells, and the presence of T(H)17-related effector cells in inflamed skin. METHODS...... peripheral blood of individuals with nickel allergy, but not healthy controls, contained T(H)17 and T(H)1 cells proliferating in response to nickel-pulsed DCs. Inflamed skin of nickel-challenged allergic individuals contained infiltrating neutrophils and cells expressing IL-17, IL-22, CCR6, and IL-22R...

  19. The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis

    Directory of Open Access Journals (Sweden)

    Vanessa Sue Wacleche

    2017-10-01

    Full Text Available The T helper 17 (Th17 cells represent a subset of CD4+ T-cells with unique effector functions, developmental plasticity, and stem-cell features. Th17 cells bridge innate and adaptive immunity against fungal and bacterial infections at skin and mucosal barrier surfaces. Although Th17 cells have been extensively studied in the context of autoimmunity, their role in various other pathologies is underexplored and remains an area of open investigation. This review summarizes the history of Th17 cell discovery and the current knowledge relative to the beneficial role of Th17 cells in maintaining mucosal immunity homeostasis. We further discuss the concept of Th17 pathogenicity in the context of autoimmunity, cancer, and HIV infection, and we review the most recent discoveries on molecular mechanisms regulating HIV replication/persistence in pathogenic Th17 cells. Finally, we stress the need for novel fundamental research discovery-based Th17-specific therapeutic interventions to treat pathogenic conditions associated with Th17 abnormalities, including HIV infection.

  20. RORγt and RORα signature genes in human Th17 cells.

    Directory of Open Access Journals (Sweden)

    Glenda Castro

    Full Text Available RORγt and RORα are transcription factors of the RAR-related orphan nuclear receptor (ROR family. They are expressed in Th17 cells and have been suggested to play a role in Th17 differentiation. Although RORγt signature genes have been characterized in mouse Th17 cells, detailed information on its transcriptional control in human Th17 cells is limited and even less is known about RORα signature genes which have not been reported in either human or mouse T cells. In this study, global gene expression of human CD4 T cells activated under Th17 skewing conditions was profiled by RNA sequencing. RORγt and RORα signature genes were identified in these Th17 cells treated with specific siRNAs to knock down RORγt or RORα expression. We have generated selective small molecule RORγt modulators and they were also utilized as pharmacological tools in RORγt signature gene identification. Our results showed that RORγt controlled the expression of a very selective number of genes in Th17 cells and most of them were regulated by RORα as well albeit a weaker influence. Key Th17 genes including IL-17A, IL-17F, IL-23R, CCL20 and CCR6 were shown to be regulated by both RORγt and RORα. Our results demonstrated an overlapping role of RORγt and RORα in human Th17 cell differentiation through regulation of a defined common set of Th17 genes. RORγt as a drug target for treatment of Th17 mediated autoimmune diseases such as psoriasis has been demonstrated recently in clinical trials. Our results suggest that RORα could be involved in same disease mechanisms and gene signatures identified in this report could be valuable biomarkers for tracking the pharmacodynamic effects of compounds that modulate RORγt or RORα activities in patients.

  1. Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties

    DEFF Research Database (Denmark)

    Prajeeth, Chittappen K; Kronisch, Julius; Khorooshi, Reza M. H.

    2017-01-01

    , cytokines and chemokines using real-time PCR. Data obtained was analysed using Kruskal- Wallis test. Results: We observed in α4-deficient mice weak microglial activation but comparable astrogliosis to that of wild-type mice in the regions of the brain populated with Th17 infiltrates suggesting that Th17...

  2. Identity crisis of Th17 cells: many forms, many functions, many questions.

    Science.gov (United States)

    Sundrud, Mark S; Trivigno, Catherine

    2013-11-15

    Th17 cells are a subset of CD4(+) effector T cells characterized by expression of the IL-17-family cytokines, IL-17A and IL-17F. Since their discovery nearly a decade ago, Th17 cells have been implicated in the regulation of dozens of immune-mediated inflammatory diseases and cancer. However, attempts to clarify the development and function of Th17 cells in human health and disease have generated as many questions as answers. On one hand, cytokine expression in Th17 cells appears to be remarkably dynamic and is subject to extensive regulation (both positive and negative) in tissue microenvironments. On the other hand, accumulating evidence suggests that the human Th17 subset is a heterogeneous population composed of several distinct pro- and anti-inflammatory subsets. Clearly, Th17 cells as originally conceived no longer neatly fit the long-standing paradigm of stable and irrepressible effector T cell function. Here we review current concepts surrounding human Th17 cells, with an emphasis on their plasticity, heterogeneity, and their many, tissue-specific functions. In spite of the challenges ahead, a comprehensive understanding of Th17 cells and their relationship to human disease is key to ongoing efforts to develop safer and more selective anti-inflammatory medicines. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. The Th17 immune response is controlled by the Rel-RORγ-RORγ T transcriptional axis

    National Research Council Canada - National Science Library

    Ruan, Qingguo; Kameswaran, Vasumathi; Zhang, Yan; Zheng, Shijun; Sun, Jing; Wang, Junmei; DeVirgiliis, Jennifer; Liou, Hsiou-Chi; Beg, Amer A; Chen, Youhai H

    2011-01-01

    .... However, how Rorg is switched on during Th17 differentiation is unknown. We report here that c-Rel and RelA/p65 transcription factors drive Th17 differentiation by binding to and activating two distinct Rorg promoters that control RORγT and RORγ...

  4. Host response signature to Staphylococcus aureus alpha-hemolysin implicates pulmonary Th17 response.

    Science.gov (United States)

    Frank, Karen M; Zhou, Tong; Moreno-Vinasco, Liliana; Hollett, Brian; Garcia, Joe G N; Bubeck Wardenburg, Juliane

    2012-09-01

    Staphylococcus aureus pneumonia causes significant morbidity and mortality. Alpha-hemolysin (Hla), a pore-forming cytotoxin of S. aureus, has been identified through animal models of pneumonia as a critical virulence factor that induces lung injury. In spite of considerable molecular knowledge of how this cytotoxin injures the host, the precise host response to Hla in the context of infection remains poorly understood. We employed whole-genome expression profiling of infected lungs to define the host response to wild-type S. aureus compared with the response to an Hla-deficient isogenic mutant in experimental pneumonia. These data provide a complete expression profile at 4 and at 24 h postinfection, revealing a unique response to the toxin-expressing strain. Gene ontogeny analysis revealed significant differences in the extracellular matrix and cardiomyopathy pathways, both of which govern cellular interactions in the tissue microenvironment. Evaluation of individual transcript responses to Hla-secreting staphylococci was notable for upregulation of host cytokine and chemokine genes, including the p19 subunit of interleukin-23. Consistent with this observation, the cellular immune response to infection was characterized by a prominent Th17 response to the wild-type pathogen. These findings define specific host mRNA responses to Hla-producing S. aureus, coupling the pulmonary Th17 response to the secretion of this cytotoxin. Expression profiling to define the host response to a single virulence factor proved to be a valuable tool in identifying pathways for further investigation in S. aureus pneumonia. This approach may be broadly applicable to the study of bacterial toxins, defining host pathways that can be targeted to mitigate toxin-induced disease.

  5. Sarcoidosis Th17 Cells are ESAT-6 Antigen Specific but Demonstrate Reduced IFN-γ Expression

    Science.gov (United States)

    Richmond, Bradley W.; Ploetze, Kristen; Isom, Joan; Chambers-Harris, Isfahan; Braun, Nicole A.; Taylor, Thyneice; Abraham, Susamma; Mageto, Yolanda; Culver, Dan A.; Oswald-Richter, Kyra A.; Drake, Wonder P.

    2013-01-01

    Rationale Sarcoidosis is a granulomatous disease of unknown etiology. Many patients with sarcoidosis demonstrate antigen-specific immunity to mycobacterial virulence factors. Th-17 cells are crucial to the immune response in granulomatous inflammation, and have recently been shown to be present in greater numbers in the peripheral blood and bronchoalveolar lavage (BAL) fluid (BALF) of sarcoidosis patients than healthy controls. It is unclear whether Th-17 cells in sarcoidosis are specific for mycobacterial antigens, or whether they have similar functionality to control Th-17 cells. Methods Flow cytometry was used to determine the numbers of Th-17 cells present in the peripheral blood and BALF of patients with sarcoidosis, the percentage of Th-17 cells that were specific to the mycobacterial virulence factor ESAT-6, and as well as to assess IFN-γ expression in Th-17 cells following polyclonal stimulation. Results Patients with sarcoidosis had greater numbers of Th-17 cells in the peripheral blood and BALF than controls and produced significantly more extracellular IL-17A (p=0.03 and p=0.02, respectively). ESAT-6 specific Th-17 cells were present in both peripheral blood and BALF of sarcoidosis patients (psarcoidosis patients produced less IFN-γ than healthy controls. Conclusions Patients with sarcoidosis have mycobacterial antigen-specific Th-17 cells peripherally and in sites of active sarcoidosis involvement. Despite the Th1 immunophenotype of sarcoidosis immunology, the Th-17 cells have reduced IFN-γ expression, compared to healthy controls. This reduction in immunity may contribute to sarcoidosis pathogenesis. PMID:23073617

  6. Targeting Th17 Cells with Small Molecules and Small Interference RNA

    Directory of Open Access Journals (Sweden)

    Hui Lin

    2015-01-01

    Full Text Available T helper 17 (Th17 cells play a central role in inflammatory and autoimmune diseases via the production of proinflammatory cytokines interleukin- (IL- 17, IL-17F, and IL-22. Anti-IL-17 monoclonal antibodies show potent efficacy in psoriasis but poor effect in rheumatoid arthritis (RA and Crohn’s disease. Alternative agents targeting Th17 cells may be a better way to inhibit the development and function of Th17 cells than antibodies of blocking a single effector cytokine. Retinoic acid-related orphan receptor gamma t (RORγt which acts as the master transcription factor of Th17 differentiation has been an attractive pharmacologic target for the treatment of Th17-mediated autoimmune disease. Recent progress in technology of chemical screen and engineering nucleic acid enable two new classes of therapeutics targeting RORγt. Chemical screen technology identified several small molecule specific inhibitors of RORγt from a small molecule library. Systematic evolution of ligands by exponential enrichment (SELEX technology enabled target specific aptamers to be isolated from a random sequence oligonucleotide library. In this review, we highlight the development and therapeutic potential of small molecules inhibiting Th17 cells by targeting RORγt and aptamer mediated CD4+ T cell specific delivery of small interference RNA against RORγt gene expression to inhibit pathogenic effector functions of Th17 lineage.

  7. Sex-Based Selectivity of PPARγ Regulation in Th1, Th2, and Th17 Differentiation

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    Hong-Jai Park

    2016-08-01

    Full Text Available Peroxisome proliferator-activated receptor gamma (PPARγ has recently been recognized to regulate adaptive immunity through Th17 differentiation, Treg functions, and TFH responses. However, its role in adaptive immunity and autoimmune disease is still not clear, possibly due to sexual differences. Here, we investigated in vitro treatment study with the PPARγ agonist pioglitazone to compare Th1, Th2, and Th17 differentiation in male and female mouse splenic T cells. Pioglitazone treatment significantly inhibited various effector T cell differentiations including Th1, Th2, and Th17 cells from female naïve T cells, but it selectively reduced IL-17 production in male Th17 differentiation. Interestingly, pioglitazone and estradiol (E2 co-treatment of T cells in males inhibited differentiation of Th1, Th2, and Th17 cells, suggesting a mechanism for the greater sensitivity of PPARγ to ligand treatment in the regulation of effector T cell differentiation in females. Collectively, these results demonstrate that PPARγ selectively inhibits Th17 differentiation only in male T cells and modulates Th1, Th2, and Th17 differentiation in female T cells based on different level of estrogen exposure. Accordingly, PPARγ could be an important immune regulator of sexual differences in adaptive immunity.

  8. Th17/IL-17A might play a protective role in chronic lymphocytic leukemia immunity.

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    Iwona Hus

    Full Text Available Th17 cells, a recently discovered subset of T helper cells that secrete IL-17A, can affect the inflammation process autoimmune and cancer diseases development. The purpose of this study was to evaluate the role of Th17 cells and IL17A in biology of CLL. The study group included 294 untreated CLL patients in different clinical stages. Here, we show that higher Th17 and IL-17A values were associated with less advanced clinical stage of CLL. Th17 cells' percentages in PB were lower in patients who died due to CLL during follow-up due to CLL (as compared to surviving patients and in patients responding to first-line therapy with fludarabine-based regimens (as compared to non-responders. IL-17A inversely correlated with the time from CLL diagnosis to the start of therapy and was lower in patients who required treatment during follow-up. Th-17 and IL-17A values were lower in patients with adverse prognostic factors (17p and 11q deletion, CD38 and ZAP-70 expression. CLL patients with detectable IL-17A mRNA in T cells were in Rai Stage 0 and negative for both ZAP-70 and CD38 expression. Th17 percentages positively correlated with iNKT and adversely with Treg cells. The results of this study suggest that Th17 may play a beneficial role in CLL immunity.

  9. Cigarette smoke induction of Interleukin-27/WSX-1 regulates the differentiation of Th1 and Th17 cells in a smoking mouse model of emphysema

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    Shi-Lin Qiu

    2016-12-01

    Full Text Available IFN-γ-producing CD4+T (Th1 cells and IL-17-producing CD4+T (Th17 cells play a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD. However, the immune regulation between Th1 and Th17 cells remains unclear. Previous studies have demonstrated that IL-27/WSX-1 exerted pro- or anti-inflammatory effects in many acute inflammatory diseases by modulating T cell-mediated immune response, but little was known about its role in chronic inflammatory disease, especially in smoking-related lung diseases. Considering IL-27 is an important regulator in T lymphocytes immune responses and was markedly increased in patients with COPD, we hypothesize that IL-27/WSX-1 may exert immuno-regulatory effects on the differentiation of Th1 and Th17 cells in smoking-related COPD. In this study, we aimed to evaluate the expression of IL-27 in patients with COPD and explore the role of IL-27/WSX-1 on Th1 and Th17 cells differentiation in a smoking mouse model of emphysema. We found that elevated expression of IL-27 was associated with increased proportion of Th1 cells and Th17 cells in patients with COPD and demonstrated parallel findings in cigarette smoke exposed mice. In addition, cigarette smoke exposure up-regulated the expression of IL-27R (WSX-1 by naive CD4+T cells in mice. In vitro, IL-27 significantly augmented the secretion of IFN-γ by naive CD4+ T cells via a T-bet, p-STAT1 and p-STAT3-dependent manner, but inhibited the production of IL-17 by a ROR-γt and p-STAT1-dependent way. Furthermore, anti-IL27 treatment dramatically decreased the expression of IFN-γ-producing CD+4 T cells in cigarette smoke exposed mice. These findings proposed that IL-27 has functions for promoting the expression of Th1 cells but inhibiting the expression of Th17 cells in vitro and IL-27 neutralization attenuated Th1-mediated inflammation in vivo, suggesting targeting IL-27/WSX-1 may provide a new therapeutic approach for smoking-related COPD.

  10. Regulation of TH17 Cells and Associated Cytokines in Wound Healing, Tissue Regeneration, and Carcinogenesis

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    Leonie Brockmann

    2017-05-01

    Full Text Available Wound healing is a crucial process which protects our body against permanent damage and invasive infectious agents. Upon tissue damage, inflammation is an early event which is orchestrated by a multitude of innate and adaptive immune cell subsets including TH17 cells. TH17 cells and TH17 cell associated cytokines can impact wound healing positively by clearing pathogens and modulating mucosal surfaces and epithelial cells. Injury of the gut mucosa can cause fast expansion of TH17 cells and their induction from naïve T cells through Interleukin (IL-6, TGF-β, and IL-1β signaling. TH17 cells produce various cytokines, such as tumor necrosis factor (TNF-α, IL-17, and IL-22, which can promote cell survival and proliferation and thus tissue regeneration in several organs including the skin, the intestine, and the liver. However, TH17 cells are also potentially pathogenic if not tightly controlled. Failure of these control mechanisms can result in chronic inflammatory conditions, such as Inflammatory Bowel Disease (IBD, and can ultimately promote carcinogenesis. Therefore, there are several mechanisms which control TH17 cells. One control mechanism is the regulation of TH17 cells via regulatory T cells and IL-10. This mechanism is especially important in the intestine to terminate immune responses and maintain homeostasis. Furthermore, TH17 cells have the potential to convert from a pro-inflammatory phenotype to an anti-inflammatory phenotype by changing their cytokine profile and acquiring IL-10 production, thereby limiting their own pathological potential. Finally, IL-22, a signature cytokine of TH17 cells, can be controlled by an endogenous soluble inhibitory receptor, Interleukin 22 binding protein (IL-22BP. During tissue injury, the production of IL-22 by TH17 cells is upregulated in order to promote tissue regeneration. To limit the regenerative program, which could promote carcinogenesis, IL-22BP is upregulated during the later phase of

  11. Inflammasome activation by adenylate cyclase toxin directs Th17 responses and protection against Bordetella pertussis

    National Research Council Canada - National Science Library

    Dunne, Aisling; Ross, Pádraig J; Pospisilova, Eva; Masin, Jiri; Meaney, Aoife; Sutton, Caroline E; Iwakura, Yoichiro; Tschopp, Jurg; Sebo, Peter; Mills, Kingston H G

    2010-01-01

    .... In this article, we demonstrate that inflammasome-mediated IL-1beta plays a critical role in promoting Ag-specific Th17 cells and in generating protective immunity against Bordetella pertussis infection...

  12. TH17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26

    KAUST Repository

    Meller, Stephan

    2015-07-13

    Interleukin 17-producing helper T cells (TH 17 cells) have a major role in protection against infections and in mediating autoimmune diseases, yet the mechanisms involved are incompletely understood. We found that interleukin 26 (IL-26), a human TH17 cell-derived cytokine, is a cationic amphipathic protein that kills extracellular bacteria via membrane-pore formation. Furthermore, TH17 cell-derived IL-26 formed complexes with bacterial DNA and self-DNA released by dying bacteria and host cells. The resulting IL-26-DNA complexes triggered the production of type I interferon by plasmacytoid dendritic cells via activation of Toll-like receptor 9, but independently of the IL-26 receptor. These findings provide insights into the potent antimicrobial and proinflammatory function of TH17 cells by showing that IL-26 is a natural human antimicrobial that promotes immune sensing of bacterial and host cell death. © 2015 Nature America, Inc.

  13. Interleukin-23 and Th17 Cells in the Control of Gut Inflammation

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    Ivan Monteleone

    2009-01-01

    Full Text Available Crohn's Disease and Ulcerative Colitis, the major forms of inflammatory bowel diseases (IBDs in humans, have been traditionally associated with exaggerated and poorly controlled T helper (Th type 1 or Th2 cell response, respectively. More recent studies have, however, shown that IBDs are also characterized by a sustained production of cytokines made by a distinct lineage of Th cells, termed Th17 cells. The demonstration that Th17-related cytokines cause pathology in many organs, including the gut, and that expansion and maintenance of Th17 cell responses require the activity of IL-23, a cytokine made in excess in the gut of IBD patients has contributed to elucidate new pathways of intestinal tissue damage as well as to design new therapeutic strategies. In this review, we discuss the available data supporting the role of the IL-23/Th17 axis in the modulation of intestinal tissue inflammation.

  14. Photo(chemotherapy reduces circulating Th17 cells and restores circulating regulatory T cells in psoriasis.

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    Takuya Furuhashi

    Full Text Available BACKGROUND: Photo(chemotherapy is widely used to treat psoriasis, the pathogenesis of which might be caused by an imbalance of Th17 cells/regulatory T cells (Treg. In the present study, we evaluated the effects of photo(chemotherapy on the Th17/Treg balance and Treg function. METHODS: Peripheral blood was obtained from psoriasis patients treated with bath-psoralen ultraviolet A (UVA, n = 50 or narrowband ultraviolet B (UVB, n = 18, and age-matched healthy volunteers (n = 20. CD3(+CD4(+IL-17A(+ or CD4(+CD25(+Foxp3(+cells were analyzed to estimate Th17 or Treg number by fluorescence-activated cell sorting. Moreover, CD4(+ CD25(- T cells from patients treated with PUVA(n = 14 were incubated in CFSE and activated with or without CD4(+ CD25(+T cells, and the suppressive function of CD4(+ CD25(+T cells were analyzed. RESULTS: Photo(chemotherapy significantly reduced Th17 levels from 5.66 ± 3.15% to 2.96 ± 2.89% in patients with increased Th17 (Th17/CD4>3.01% [mean+SD of controls]. In contrast, photo(chemotherapy significantly increased Treg levels from 2.77 ± 0.75 to 3.40 ± 1.88% in patients with less than 4.07% Treg level, defined as the mean of controls. Furthermore, while Treg suppressed the CD4(+CD25(- T cell proliferation to a greater extent in controls (Treg Functional Ratio 94.4 ± 4.28% than in patients (70.3±25.1%, PUVA significantly increased Treg Functional Ratio to 88.1 ± 6.47%. Th17 levels in severe patients (>30 PASI were significantly higher as compared to controls. Th17 levels that were left after treatment in the patients not achieving PASI 50 (3.78 ± 4.18% were significantly higher than those in the patients achieving PASI 75 (1.83±1.87%. Treg levels in patients achieving PASI 90 (4.89 ± 1.70% were significantly higher than those in the patients not achieving PASI 90 (3.90 ± 1.66%. Treg levels prior to treatment with Th17 high decreased group (5.16 ± 2.20% was significantly higher than that with Th17 high increased group

  15. Intranasal delivery of cholera toxin induces th17-dominated T-cell response to bystander antigens.

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    Jee-Boong Lee

    Full Text Available Cholera toxin (CT is a potent vaccine adjuvant, which promotes mucosal immunity to protein antigen given by nasal route. It has been suggested that CT promotes T helper type 2 (Th2 response and suppresses Th1 response. We here report the induction of Th17-dominated responses in mice by intranasal delivery of CT. This dramatic Th17-driving effect of CT, which was dependent on the B subunit, was observed even in Th1 or Th2-favored conditions of respiratory virus infection. These dominating Th17 responses resulted in the significant neutrophil accumulation in the lungs of mice given CT. Both in vitro and in vivo treatment of CT induced strongly augmented IL-6 production, and Th17-driving ability of CT was completely abolished in IL-6 knockout mice, indicating a role of this cytokine in the Th17-dominated T-cell responses by CT. These data demonstrate a novel Th17-driving activity of CT, and help understand the mechanisms of CT adjuvanticity to demarcate T helper responses.

  16. Alterations in Th17 and the Respective Cytokine Levels in Helicobacter pylori-Induced Stomach Diseases.

    Science.gov (United States)

    Shamsdin, Seyedeh Azra; Alborzi, Abdolvahab; Rasouli, Manoochehr; Hosseini, Mohamad Kazem; Bagheri Lankrani, Kamran; Kalani, Mehdi

    2015-12-01

    Infections by Helicobacter can cause the stimulation of sophisticated immune response in mucosal immunity. Among the different lymphocytes, Th17 plays an important role in the defense against H. pylori and may cause gastritis and peptic ulcer due to the increased activation of Th17 and cytokine changes. To find a relationship between Th17 and IL-17A, IL-21, IL-22, IL-23, TGF-β in the patients with H. pylori infection having signs including gastritis and peptic ulcer. A total of 36 samples from the patients [24 Hp+ and 12 Hp- cases] with dyspepsia symptoms were collected. The percentage of Th17 was measured by flow cytometry. The levels of Th17-associated cytokines in the sera and supernatants of peripheral blood mononuclear cells (PBMCs) which were stimulated with the H. pylori antigen, phytohemagglutinin (PHA), or Dynabeads were measured by ELISA. Patients were divided into two groups of having either H. pylori infected (peptic ulcer, gastritis (mild, moderate)) or being uninfected. The percentage of Th17 in the patients with peptic ulcer and gastritis was significantly higher than their uninfected counterparts (p ≤ .001). The serum levels of IL-17A, IL-23, and TGF-β in the peptic ulcer and gastritis groups were significantly higher compared with the corresponding levels in the uninfected population (p pylori. Furthermore, inflammation varies depending on the type of the cytokine and its secreted level. © 2015 John Wiley & Sons Ltd.

  17. Th17 Cells as Potential Probiotic Therapeutic Targets in Inflammatory Bowel Diseases.

    Science.gov (United States)

    Owaga, Eddy; Hsieh, Rong-Hong; Mugendi, Beatrice; Masuku, Sakhile; Shih, Chun-Kuang; Chang, Jung-Su

    2015-09-01

    Inflammatory bowel diseases (IBD) are characterized by wasting and chronic intestinal inflammation triggered by various cytokine-mediated pathways. In recent years, it was shown that T helper 17 (Th17) cells are involved in the pathogenesis of IBD, which makes them an attractive therapeutic target. Th17 cells preferentially produce interleukin (IL)-17A-F as signature cytokines. The role of the interplay between host genetics and intestinal microbiota in the pathogenesis of IBD was demonstrated. Probiotics are live microorganisms that when orally ingested in adequate amounts, confer a health benefit to the host by modulating the enteric flora or by stimulating the local immune system. Several studies indicated the effectiveness of probiotics in preventing and treating IBD (ulcerative colitis, and Crohn's disease). Furthermore, there is mounting evidence of probiotics selectively targeting the Th17 lineage in the prevention and management of inflammatory and autoimmune diseases such as IBD. This review highlights critical roles of Th17 cells in the pathogenesis of IBD and the rationale for using probiotics as a novel therapeutic approach for IBD through manipulation of Th17 cells. The potential molecular mechanisms by which probiotics modulate Th17 cells differentiation and production are also discussed.

  18. Identification of protective pneumococcal T(H17 antigens from the soluble fraction of a killed whole cell vaccine.

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    Kristin L Moffitt

    Full Text Available Mucosal or parenteral immunization with a killed unencapsulated pneumococcal whole cell antigen (WCA with an adjuvant protects mice from colonization by a T(H17 CD4+ cell-mediated mechanism. Using preparative SDS gels, we separated the soluble proteins that compose the WCA in order to identify fractions that were immunogenic and protective. We screened these fractions for their ability to stimulate IL-17A secretion from splenocytes obtained from mice immunized with WCA and adjuvant. We identified 12 proteins within the stimulatory fractions by mass spectrometry; these proteins were then cloned, recombinantly expressed and purified using an Escherichia coli expression system. The ability of these proteins to induce IL-17A secretion was then evaluated by stimulation of mouse splenocytes. Of the four most stimulatory proteins, three were protective in a mouse pneumococcal serotype 6B colonization model. This work thus describes a method for identifying immunogenic proteins from the soluble fraction of pneumococcus and shows that several of the proteins identified protect mice from colonization when used as mucosal vaccines. We propose that, by providing protection against pneumococcal colonization, one or more of these proteins may serve as components of a multivalent pneumococcal vaccine.

  19. Immune Response to Bifidobacterium bifidum Strains Support Treg/Th17 Plasticity

    Science.gov (United States)

    López, Patricia; González-Rodríguez, Irene; Gueimonde, Miguel; Margolles, Abelardo; Suárez, Ana

    2011-01-01

    In this work we analyzed the immune activation properties of different Bifidobacterium strains in order to establish their ability as inductors of specific effector (Th) or regulatory (Treg) responses. First, we determined the cytokine pattern induced by 21 Bifidobacterium strains in peripheral blood mononuclear cells (PBMCs). Results showed that four Bifidobacterium bifidum strains showed the highest production of IL-17 as well as a poor secretion of IFNγ and TNFα, suggesting a Th17 profile whereas other Bifidobacterium strains exhibited a Th1-suggestive profile. Given the key role of Th17 subsets in mucosal defence, strains suggestive of Th17 responses and the putative Th1 Bifidobacterium breve BM12/11 were selected to stimulate dendritic cells (DC) to further determine their capability to induce the differentiation of naïve CD4+ lymphocytes toward different Th or Treg cells. All selected strains were able to induce phenotypic DC maturation, but showed differences in cytokine stimulation, DC treated with the putative Th17 strains displaying high IL-1β/IL-12 and low IL-12/IL-10 index, whereas BM12/11-DC exhibited the highest IL-12/IL-10 ratio. Differentiation of naïve lymphocytes confirmed Th1 polarization by BM12/11. Unexpectedly, any B. bifidum strain showed significant capability for Th17 generation, and they were able to generate functional Treg, thus suggesting differences between in vivo and vitro responses. In fact, activation of memory lymphocytes present in PBMCS with these bacteria, point out the presence in vivo of specific Th17 cells, supporting the plasticity of Treg/Th17 populations and the key role of commensal bacteria in mucosal tolerance and T cell reprogramming when needed. PMID:21966367

  20. Reasons for rarity of Th17 cells in inflammatory sites of human disorders.

    Science.gov (United States)

    Annunziato, Francesco; Santarlasci, Veronica; Maggi, Laura; Cosmi, Lorenzo; Liotta, Francesco; Romagnani, Sergio

    2013-11-15

    T helper 17 (Th17) cells have been reported to be responsible for several chronic inflammatory diseases. However, a peculiar feature of human Th17 cells is that they are very rare in the inflammatory sites in comparison with Th1 cells. The first reason for this rarity is the existence of some self-regulatory mechanisms that limit their expansion. The limited expansion of human Th17 cells is related to the retinoic acid orphan (ROR)C-dependent up-regulation of the interleukin (IL)-4 induced gene 1 (IL4I1), which encodes for a l-phenylalanine oxidase, that has been shown to down-regulate CD3ζ expression in T cells. This results in abnormalities of the molecular pathway which is responsible for the impairment of IL-2 production and therefore for the lack of cell proliferation in response to T-cell receptor (TCR) signalling. IL4I1 up-regulation also associates with the increased expression of Tob1, a member of the Tob/BTG anti-proliferative protein family, which is involved in cell cycle arrest. A second reason for the rarity of human Th17 cells in the inflammatory sites is their rapid shifting into the Th1 phenotype, which is mainly related to the activity of IL-12 and TNF-α. We have named these Th17-derived Th1 cells as non-classic because they differ from classic Th1 cells for the expression of molecules specific for Th17 cells, such as RORC, CD161, CCR6, IL4I1, and IL-17 receptor E. This distinction may be important for defining the respective pathogenic role of Th17, non-classic Th1 and classic Th1 cells in many human inflammatory disorders. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Disruption of Tumor Necrosis Factor Receptor-Associated Factor 5 Exacerbates Murine Experimental Colitis via Regulating T Helper Cell-Mediated Inflammation.

    Science.gov (United States)

    Shang, Jian; Li, Lixia; Wang, Xiaobing; Pan, Huaqin; Liu, Shi; He, Ruohang; Li, Jin; Zhao, Qiu

    2016-01-01

    Tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) is a key mediator of TNF receptor superfamily members and is important in both T helper (Th) cell immunity and the regulation of multiple signaling pathways. To clarify TRAF5's influence on inflammatory bowel diseases (IBDs), we investigated TRAF5 deficiency's effect on dextran sulfate sodium- (DSS-) induced colitis. Colitis was induced in TRAF5 knockout (KO) mice and their wild-type (WT) littermates by administering 3% DSS orally for 7 days. The mice were then sacrificed, and their colons were removed. Our data suggested that KO mice were more susceptible to DSS-induced colitis. TRAF5 deficiency significantly enhanced IFN-γ, IL-4, and IL-17a mRNA and protein levels in the colons of DSS-fed mice, and the mRNA expression of T-bet and GATA-3 was also markedly elevated. However, ROR-α and ROR-γt mRNA levels did not differ between DSS-induced KO and WT mice. Flow cytometry showed increased frequencies of Th2 and IFN-γ/IL-17a-coproducing CD4(+) T cells in the colons of DSS-induced KO mice. Additionally, TRAF5 deficiency significantly enhanced the activation of NF-κB in CD4(+) T cells after DSS administration. These results indicated that TRAF5 deficiency significantly aggravated DSS-induced colitis, most likely by regulating Th cell-mediated inflammation.

  2. Th17 cytokines differentiate obesity from obesity-associated type 2 diabetes and promote TNFα production.

    Science.gov (United States)

    Ip, Blanche; Cilfone, Nicholas A; Belkina, Anna C; DeFuria, Jason; Jagannathan-Bogdan, Madhumita; Zhu, Min; Kuchibhatla, Ramya; McDonnell, Marie E; Xiao, Qiang; Kepler, Thomas B; Apovian, Caroline M; Lauffenburger, Douglas A; Nikolajczyk, Barbara S

    2016-01-01

    T cell inflammation plays pivotal roles in obesity-associated type 2 diabetes (T2DM). The identification of dominant sources of T cell inflammation in humans remains a significant gap in understanding disease pathogenesis. It was hypothesized that cytokine profiles from circulating T cells identify T cell subsets and T cell cytokines that define T2DM-associated inflammation. Multiplex analyses were used to quantify T cell-associated cytokines in αCD3/αCD28-stimulated PBMCs, or B cell-depleted PBMCs, from subjects with T2DM or BMI-matched controls. Cytokine measurements were subjected to multivariate (principal component and partial least squares) analyses. Flow cytometry detected intracellular TNFα in multiple immune cell subsets in the presence/absence of antibodies that neutralize T cell cytokines. T cell cytokines were generally higher in T2DM samples, but Th17 cytokines are specifically important for classifying individuals correctly as T2DM. Multivariate analyses indicated that B cells support Th17 inflammation in T2DM but not control samples, while monocytes supported Th17 inflammation regardless of T2DM status. Partial least squares regression analysis indicated that both Th17 and Th1 cytokines impact %HbA1c. Among various T cell subsets, Th17 cells are major contributors to inflammation and hyperglycemia and are uniquely supported by B cells in obesity-associated T2DM. © 2015 The Obesity Society.

  3. 5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation.

    Science.gov (United States)

    Wang, Juan; Peng, Liang; Zhang, Ruihua; Zheng, Zihan; Chen, Chun; Cheung, Ka Lung; Cui, Miao; Bian, Guanglin; Xu, Feihong; Chiang, David; Hu, Yuan; Chen, Ye; Lu, Geming; Yang, Jianjun; Zhang, Hui; Yang, Jianfei; Zhu, Hongfa; Chen, Shu-Hsia; Liu, Kebin; Zhou, Ming-Ming; Sikora, Andrew G; Li, Liwu; Jiang, Bo; Xiong, Huabao

    2016-04-12

    While it is well established that treatment of cancer patients with 5-Fluorouracil (5-FU) can result in immune suppression, the exact function of 5-FU in the modulation of immune cells has not been fully established. We found that low dose 5-FU selectively suppresses TH17 and TH1 cell differentiation without apparent effect on Treg, TH2, and significantly suppresses thymidylate synthase (TS) expression in TH17 and TH1 cells but has a lesser effect in tumor cells and macrophages. Interestingly, the basal expression of TS varies significantly between T helper phenotypes and knockdown of TS significantly impairs TH17 and TH1 cell differentiation without affecting the differentiation of either Treg or TH2 cells. Finally, low dose 5-FU is effective in ameliorating colitis development by suppressing TH17 and TH1 cell development in a T cell transfer colitis model. Taken together, the results highlight the importance of the anti-inflammatory functions of low dose 5-FU by selectively suppressing TH17 and TH1 immune responses.

  4. Human memory Th17 cells express a functional histamine H4 receptor.

    Science.gov (United States)

    Mommert, Susanne; Gschwandtner, Maria; Koether, Brigitta; Gutzmer, Ralf; Werfel, Thomas

    2012-01-01

    The histamine H4 receptor is functionally expressed on CD4(+) T cells and in particular on human CD4(+) Th2-polarized T cells. Interleukin (IL)-17-producing T cells (Th17 cells) represent a newly defined major CD4(+) T-cell subset, having been identified in psoriatic plaques and in acute skin lesions of atopic dermatitis where histamine is also present in high concentrations. To elucidate the role of the histamine H4 receptor (H4R) on these effector T cells, we polarized human memory T cells into Th17 cells. Further, we investigated H4R expression and assessed its function by real-time PCR, by a cytokine secretion assay of IL-17, and by electrophoretic mobility shift assay of activating protein-1 (AP-1). We show that Th17 cells polarized by IL-1β together with IL-23 express the H4R on mRNA and protein level. Additionally, we identified IL-17-positive cells in psoriatic skin lesions. The IL-17-positive lymphocytes were all positive also for functional H4R. Stimulation with histamine or a H4R agonist increased the production of IL-17 and induced activating protein-1 in Th17 cells. In inflammatory skin diseases with enhanced histamine release, such as psoriasis and atopic dermatitis, histamine might foster the immunomodulatory potency of skin-infiltrating Th17 cells. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  5. Delayed Activation Kinetics of Th2- and Th17 Cells Compared to Th1 Cells.

    Science.gov (United States)

    Duechting, Andrea; Przybyla, Anna; Kuerten, Stefanie; Lehmann, Paul V

    2017-09-12

    During immune responses, different classes of T cells arise: Th1, Th2, and Th17. Mobilizing the right class plays a critical role in successful host defense and therefore defining the ratios of Th1/Th2/Th17 cells within the antigen-specific T cell repertoire is critical for immune monitoring purposes. Antigen-specific Th1, Th2, and Th17 cells can be detected by challenging peripheral blood mononuclear cells (PBMC) with antigen, and establishing the numbers of T cells producing the respective lead cytokine, IFN-γ and IL-2 for Th1 cells, IL-4 and IL-5 for Th2, and IL-17 for Th-17 cells, respectively. Traditionally, these cytokines are measured within 6 h in flow cytometry. We show here that 6 h of stimulation is sufficient to detect peptide-induced production of IFN-γ, but 24 h are required to reveal the full frequency of protein antigen-specific Th1 cells. Also the detection of IL-2 producing Th1 cells requires 24 h stimulation cultures. Measurements of IL-4 producing Th2 cells requires 48-h cultures and 96 h are required for frequency measurements of IL-5 and IL-17 secreting T cells. Therefore, accounting for the differential secretion kinetics of these cytokines is critical for the accurate determination of the frequencies and ratios of antigen-specific Th1, Th2, and Th17 cells.

  6. Imbalance of Th17/Treg in Different Subtypes of Autoimmune Thyroid Diseases

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    Cui Li

    2016-11-01

    Full Text Available Aims: To clarify the imbalance of Th17/Treg in different subtypes of autoimmune thyroid diseases (AITDs including Graves' disease(GD, Hashimoto's thyroiditis(HT and Graves' ophthalmopathy (GO. Methods: 47 patients with AITD (including 16 GD, 15 HT, and 16 GO and 12 healthy controls were enrolled in this study. The percentages of Th17 and Treg cells, the ratio of Th17/Treg, as well as their related transcription factors RORγt and Foxp3 mRNA in peripheral blood mononuclear cells (PBMCs were measured by flow cytometry and real-time quantitative PCR Results: Compared with those in control group, the percentage of CD4+IL-17+T cell(Th17 and the mRNA expression of its transcription factor RORγt were higher in PBMCs of AITDs (P+Foxp3+T (Treg cells and its transcription factor Foxp3 mRNA were significantly decreased in PBMCs of GD (PConclusion: Increased Th17 lymphocytes may play a more important role in the pathogenesis of HT and GO while decreased Treg may be greatly involved in GD.

  7. Imbalance between Th17 and Regulatory T-Cells in Sarcoidosis

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    Hui Huang

    2013-10-01

    Full Text Available Sarcoidosis is a systemic granulomatous disease, which is thought to result from an aberrant immune response. CD4+ T lymphocytes play an important role in the development of granulomas. Previously, the immunopathogenesis of sarcoidosis was focused on Th1/Th2 disturbances. The aim of this study was to evaluate the balance between newer CD4+ T lymphocytes, i.e., Treg and Th17 cells. In our studies, a decrease in Treg cells and an increase in Th17 cells were observed in the peripheral blood and BALF of sarcoidosis patients. A significant increase in the Th17/Treg cell ratio was observed in sarcoidosis patients. After treatment with prednisone, the expression of Foxp3 mRNA was elevated in the peripheral blood, and expression of (RORγt mRNA showed a downward trend. These findings suggest that sarcoidosis is associated with an imbalance between Th17 and Treg cells in peripheral blood and BALF. Therefore, targeting the cytokines that affect the Th17/Treg ratio could provide a new promising therapy for pulmonary sarcoidosis.

  8. Balancing Inflammation: The Link between Th17 and Regulatory T Cells

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    Maggie L. Diller

    2016-01-01

    Full Text Available CD4+ T cell compartments in mouse and man are composed of multiple distinct subsets each possessing unique phenotypic and functional characteristics. IL-17-producing CD4+ T cells (Th17 cells represent a distinct subset of the CD4+ T cell lineage. Recent evidence suggests that Th17 cells carry out effector functions similar to cytotoxic CD8+ T cells and play an important role in the clearance of extracellular pathogens and fungi. Th17 cell differentiation and function are closely related to the development and function of regulatory T cells (TREG. The balance between these two cell populations is essential for immune homeostasis and dysregulation of this balance has been implicated in a variety of inflammatory conditions including autoimmunity, allograft rejection, and tumorigenesis. Emerging evidence reports a significant amount of plasticity between the Th17 and regulatory T cell compartments, and the mechanisms by which these cells communicate and influence each other are just beginning to be understood. In this review, we highlight recent findings detailing the mechanisms driving Th17 and TREG plasticity and discuss the biologic consequences of their unique relationship.

  9. Changes of Treg and Th17 cells as well as cytokines in children with acute bronchitis.

    Science.gov (United States)

    Tu, Zhiqiang; Xue, Haiyan; Chen, Wei; Cao, Lanfang; Zhang, Weiqi

    2017-10-01

    The present study aimed to investigate changes of T-regulatory (Treg) and T-helper (Th)17 cells as well as cytokines in peripheral blood of children with acute bronchitis, and to explore the roles of these cells in the pathogenesis of acute bronchitis. A total of 126 children who had presented at Renji Hospital (Shanghai, China) with acute bronchitis were selected as the observation group and 30 healthy children were selected as the control group. Th17/Tregs in the peripheral blood of the children of the observation group and the control group was detected by flow cytometry. The levels of cytokines interleukin (IL)-17, IL-22, IL-10 and transforming growth factor (TGF)-β in peripheral blood serum were detected by ELISA. Compared with those in the control group, Treg cells, the Treg/Th17 ratio as well as serum IL-10 and TGF-β levels were significantly decreased in the observation group (Pacute bronchitis, suggesting that Treg and Th17 cells as well as their cytokines may be involved in the pathogenesis of acute bronchitis. It may be of certain guiding significance to detect Treg/Th17 and levels of serum cytokines in peripheral blood for clinical treatment.

  10. Tissue inhibitor of metalloproteinase 1 is preferentially expressed in Th1 and Th17 T-helper cell subsets and is a direct STAT target gene.

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    Adewole Adamson

    Full Text Available CD4(+ T helper (Th cells differentiate into distinct effector subsets that are critical for host defense, but are also implicated in the pathogenesis of autoimmune disorders. Thelper17 (Th17 cells in particular are emerging as important drivers of multiple diseases including psoriasis, spondyloarthropathy and multiple sclerosis. To gain insight into the function of Th17 cells, we performed transcriptional profiling in hopes of elucidating products not previously recognized as being functionally relevant in these T cells. Herein, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP1, a secreted protein with pleiotropic effects on cellular growth, survival and integrity of the extracellular matrix, is preferentially produced by Th17 and Th1 cells. We further show that Th1 and Th17 cell TIMP1 regulation follows separate mechanisms with a requirement for STAT4 in the former and STAT3 in the latter. Finally, we demonstrate that when restricted to T cells, expression of TIMP1 promotes neuropathology in experimental allergic encephalomyelitis.

  11. Intestinal Monocyte-Derived Macrophages Control Commensal-Specific Th17 Responses

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    Casandra Panea

    2015-08-01

    Full Text Available Generation of different CD4 T cell responses to commensal and pathogenic bacteria is crucial for maintaining a healthy gut environment, but the associated cellular mechanisms are poorly understood. Dendritic cells (DCs and macrophages (Mfs integrate microbial signals and direct adaptive immunity. Although the role of DCs in initiating T cell responses is well appreciated, how Mfs contribute to the generation of CD4 T cell responses to intestinal microbes is unclear. Th17 cells are critical for mucosal immune protection and at steady state are induced by commensal bacteria, such as segmented filamentous bacteria (SFB. Here, we examined the roles of mucosal DCs and Mfs in Th17 induction by SFB in vivo. We show that Mfs, and not conventional CD103+ DCs, are essential for the generation of SFB-specific Th17 responses. Thus, Mfs drive mucosal T cell responses to certain commensal bacteria.

  12. Dendritic cell-mediated-immunization with xenogenic PrP and adenoviral vectors breaks tolerance and prolongs mice survival against experimental scrapie.

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    Martine Bruley Rosset

    Full Text Available In prion diseases, PrP(c, a widely expressed protein, is transformed into a pathogenic form called PrP(Sc, which is in itself infectious. Antibodies directed against PrP(c have been shown to inhibit PrP(c to PrP(Sc conversion in vitro and protect in vivo from disease. Other effectors with potential to eliminate PrPSc-producing cells are cytotoxic T cells directed against PrP-derived peptides but their ability to protect or to induce deleterious autoimmune reactions is not known. The natural tolerance to PrP(c makes difficult to raise efficient adaptive responses. To break tolerance, adenovirus (Ad encoding human PrP (hPrP or control Ad were administered to wild-type mice by direct injection or by transfer of Ad-transduced dendritic cells (DCs. Control Ad-transduced DCs from Tg650 mice overexpressing hPrP were also used for immunization. DC-mediated but not direct administration of AdhPrP elicited antibodies that bound to murine native PrP(c. Frequencies of PrP-specific IFNgamma-secreting T cells were low and in vivo lytic activity only targeted cells strongly expressing hPrP. Immunohistochemical analysis revealed that CD3(+ T cell infiltration was similar in the brain of vaccinated and unvaccinated 139A-infected mice suggesting the absence of autoimmune reactions. Early splenic PrP(Sc replication was strongly inhibited ten weeks post infection and mean survival time prolonged from 209 days in untreated 139A-infected mice to 246 days in mice vaccinated with DCs expressing the hPrP. The efficacy appeared to be associated with antibody but not with cytotoxic cell-mediated PrP-specific responses.

  13. Disruption of Tumor Necrosis Factor Receptor-Associated Factor 5 Exacerbates Murine Experimental Colitis via Regulating T Helper Cell-Mediated Inflammation

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    Jian Shang

    2016-01-01

    Full Text Available Tumor necrosis factor (TNF receptor-associated factor 5 (TRAF5 is a key mediator of TNF receptor superfamily members and is important in both T helper (Th cell immunity and the regulation of multiple signaling pathways. To clarify TRAF5’s influence on inflammatory bowel diseases (IBDs, we investigated TRAF5 deficiency’s effect on dextran sulfate sodium- (DSS- induced colitis. Colitis was induced in TRAF5 knockout (KO mice and their wild-type (WT littermates by administering 3% DSS orally for 7 days. The mice were then sacrificed, and their colons were removed. Our data suggested that KO mice were more susceptible to DSS-induced colitis. TRAF5 deficiency significantly enhanced IFN-γ, IL-4, and IL-17a mRNA and protein levels in the colons of DSS-fed mice, and the mRNA expression of T-bet and GATA-3 was also markedly elevated. However, ROR-α and ROR-γt mRNA levels did not differ between DSS-induced KO and WT mice. Flow cytometry showed increased frequencies of Th2 and IFN-γ/IL-17a-coproducing CD4+ T cells in the colons of DSS-induced KO mice. Additionally, TRAF5 deficiency significantly enhanced the activation of NF-κB in CD4+ T cells after DSS administration. These results indicated that TRAF5 deficiency significantly aggravated DSS-induced colitis, most likely by regulating Th cell-mediated inflammation.

  14. ESAT-6- and CFP-10-specific Th1, Th22 and Th17 cells in tuberculous pleurisy may contribute to the local immune response against Mycobacterium tuberculosis infection.

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    Qiao, D; Yang, B Y; Li, L; Ma, J J; Zhang, X L; Lao, S H; Wu, C Y

    2011-04-01

    Th1 cell-mediated adaptive immune response is very important but may not be sufficient to control Mycobacterium tuberculosis (M. tuberculosis) infection. The roles of the various T cell subsets and cytokines in the inflammatory processes are not clearly elucidated. We investigated whether Th1, Th22 and Th17 cells mediated cellular immunity at the local site of M. tuberculosis infection in patients with tuberculous pleurisy (TBP). The results showed that the cytokines IFN-γ and IL-22 but not IL-17 were elevated in tubercular pleural fluid. Following stimulation with immune-dominant peptides of early secreted antigenic target-6 (ESAT-6), culture filtrate protein-10 (CFP-10) or Bacille Calmette-Guerin, pleural fluid mononuclear cells expressed high levels of cytokines IFN-γ, IL-22 and IL-17 as revealed by mRNA and protein measurements. In addition, we showed that cytokines IFN-γ, IL-22 and IL-17 were produced in M. tuberculosis-specific immune response by distinct subsets of CD4+ T cells with the phenotype of CD45RA-CD62L-CCR7+CD27+ . Our results demonstrated for the first time that ESAT-6- and CFP-10-specific Th1, Th22 and Th17 cells existed in the patients with TBP and might play an essential role against M. tuberculosis infection. The findings of this study raised the possibility of unravelling the critical targets for therapeutic intervention in chronic inflammatory diseases such as TBP. © 2011 The Authors. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.

  15. Peripheral blood Th17/Treg imbalance in patients with low-active systemic lupus erythematosus

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    Magdalena Szmyrka-Kaczmarek

    2014-01-01

    Full Text Available Introduction: The balance between proinflammatory Th17 cells and regulatory T cells plays an important role in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE. In particular, an increased ratio of Th17/Treg cells has been shown to correlate with active SLE and specific organ involvement. The aim of our study was to assess Th17 and Treg cell populations in peripheral blood (PB of patients with clinically quiescent SLE, and to evaluate their correlation with organ involvement.Material/Methods: We performed flow cytometric analysis of studied T CD4+ cell subpopulations in PB from 21 patients with SLE and 13 healthy controls. Disease activity was measured with the SELENA-SLEDAI index; organ involvement was divided into renal, neurological and hematological.Results: A statistically significant difference (p<0.01 between the mean percentages of CD4+CD25highFoxP3+ Treg cells in SLE patients (18.57% and healthy controls (32.08% was observed. Similarly, proportions of functional CTLA-4+ Treg cells were markedly lower in SLE patients than in healthy controls – 19.3% vs. 23.82% (p=0.03. In contrast, SLE patients exhibited a significantly increased frequency of circulating Th17 cells with the phenotype CD4+IL-17+ compared to controls – 1.36 % vs 0.19% (p<0.01. Also the ratio of Th17 cells to Th1 cells was markedly higher in SLE patients than in the control group (p<0.01. We did not find any correlation of PB Th cell distribution with organ involvement in SLE patients examined.Conclusions: Our report showed for the first time that systemic Th17/Treg imbalance occurred also in patients with low disease activity and in remission. We suggest that immunological alterations may precede clinical and laboratory symptoms of the disease activity.

  16. Transfer of tolerance to collagen type V suppresses Th-17 lymphocyte mediated acute lung transplant rejection

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    Braun, Ruedi K.; Molitor-Dart, Melanie; Wigfield, Christopher; Xiang, Zhuzai; Fain, Sean B.; Jankowska-Gan, Ewa; Seroogy, Christine M.; Burlingham, William J.; Wilkes, David S.; Brand, David D.; Torrealba, Jose; Love, Robert B.

    2009-01-01

    Background Rat lung allograft rejection is mediated by collagen type V (col(V)) specific Th17 cells. Adoptive transfer of these cells is sufficient to induce rejection pathology in isografts, whereas tolerance to col(V) suppresses allograft rejection. We therefore tested if regulatory T cells from tolerant rats could suppress the Th17 mediated rejection in the syngeneic model of lung transplantation. Methods Rats were subjected to syngeneic left lung transplantation and acute rejection was induced by adoptive transfer of lymph node cells from col(V)-immunized rats. Tolerance was induced by intravenous (iv) injection of col(V) and spleen lymphocytes were used for adoptive transfer. CD4+ T cells were depleted using magnetic beads. Lung isografts were analyzed using micro-PET imaging and histochemistry. The transvivo delayed type hypersensitivity (TV-DTH) assay was used to analyze the Th17 response. Results Adoptive co-transfer of col(V)-specific effector cells with cells from col(V) tolerized rats suppressed severe vasculitis and bronchiolitis with parenchymal inflammation, and the expression of IL-17 transcripts in mediastinal lymph nodes induced by effector cells alone. Analysis by TV-DTH showed that the reactivity to col(V) was dependent on the presence of TNF-α and IL-17, but not IFN-γ. Depletion of CD4+ T cells from the suppressor cell population abrogated the col(V)-specific protection. Conclusion Th17 mediated acute rejection after lung transplantation is ameliorated by CD4+ col(V)-specific regulatory T cells. The mechanism for this Th17 suppression is consistent with tolerance induction to col(V). The goal of transplantation treatment therefore should target Th17 development and not suppression of T cell activation by suppressing IL-2. PMID:20029330

  17. HCV infection enhances Th17 commitment, which could affect the pathogenesis of autoimmune diseases.

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    Yasuteru Kondo

    Full Text Available Various kinds of autoimmune diseases have been reported to have a significant relationship with persistent hepatitis c virus (HCV infection and Th17 cells. Previously, our group reported that the existence of HCV in T lymphocytes could affect the development of CD4+ helper T cells and their proliferation, in addition to the induction of immunoglobulin hyper-mutation.Therefore, we analyzed the relationship between persistent infection of HCV and the mechanism of Th17 cell induction ex vivo and in vitro.The prevalence of autoimmune-related diseases in chronic hepatitis c patients (CH-C was significantly higher than in other types of chronic hepatitis (hepatitis B and NASH. A significantly higher frequency of IL6 and TGF-β double-high patients was detected in CH-C than in other liver diseases. Moreover, these double-high patients had significantly higher positivity of anti-nuclear antibody, cryoglobulinemia, and lymphotropic HCV and higher amounts of IL1-β, IL21, IL23. In addition to the previously reported lymphotropic SB-HCV strain, we found a novel, genotype 1b lymphotropic HCV (Ly-HCV, by deep sequencing analysis. Lymphotropic-HCV replication could be detected in the lymphoid cells with various kinds of cytokine-conditions including IL1β, IL23, IL6 and TGF-β in vitro. Infection by HCV could significantly enhance the development of Th17 cells. The HCV protein responsible for inducing the Th17 cells was HCV-Core protein, which could enhance the STAT-3 signaling and up-regulate the expression of RORγt as a Th17 master gene.Infection by lymphotropic HCV might enhance the Th17 development and contribute to understanding the pathogenesis of autoimmune-related diseases.

  18. HCV infection enhances Th17 commitment, which could affect the pathogenesis of autoimmune diseases.

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    Kondo, Yasuteru; Ninomiya, Masashi; Kimura, Osamu; Machida, Keigo; Funayama, Ryo; Nagashima, Takeshi; Kobayashi, Koju; Kakazu, Eiji; Kato, Takanobu; Nakayama, Keiko; Lai, Michael M C; Shimosegawa, Tooru

    2014-01-01

    Various kinds of autoimmune diseases have been reported to have a significant relationship with persistent hepatitis c virus (HCV) infection and Th17 cells. Previously, our group reported that the existence of HCV in T lymphocytes could affect the development of CD4+ helper T cells and their proliferation, in addition to the induction of immunoglobulin hyper-mutation. Therefore, we analyzed the relationship between persistent infection of HCV and the mechanism of Th17 cell induction ex vivo and in vitro. The prevalence of autoimmune-related diseases in chronic hepatitis c patients (CH-C) was significantly higher than in other types of chronic hepatitis (hepatitis B and NASH). A significantly higher frequency of IL6 and TGF-β double-high patients was detected in CH-C than in other liver diseases. Moreover, these double-high patients had significantly higher positivity of anti-nuclear antibody, cryoglobulinemia, and lymphotropic HCV and higher amounts of IL1-β, IL21, IL23. In addition to the previously reported lymphotropic SB-HCV strain, we found a novel, genotype 1b lymphotropic HCV (Ly-HCV), by deep sequencing analysis. Lymphotropic-HCV replication could be detected in the lymphoid cells with various kinds of cytokine-conditions including IL1β, IL23, IL6 and TGF-β in vitro. Infection by HCV could significantly enhance the development of Th17 cells. The HCV protein responsible for inducing the Th17 cells was HCV-Core protein, which could enhance the STAT-3 signaling and up-regulate the expression of RORγt as a Th17 master gene. Infection by lymphotropic HCV might enhance the Th17 development and contribute to understanding the pathogenesis of autoimmune-related diseases.

  19. Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

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    Schewitz-Bowers, Lauren P.; Lait, Philippa J. P.; Copland, David A.; Chen, Ping; Wu, Wenting; Dhanda, Ashwin D.; Vistica, Barbara P.; Williams, Emily L.; Liu, Baoying; Jawad, Shayma; Li, Zhiyu; Tucker, William; Hirani, Sima; Wakabayashi, Yoshiyuki; Zhu, Jun; Sen, Nida; Conway-Campbell, Becky L.; Gery, Igal; Dick, Andrew D.; Wei, Lai; Nussenblatt, Robert B.; Lee, Richard W. J.

    2015-01-01

    Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients’ glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual’s disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation. PMID:25775512

  20. CTLA4 blockade increases Th17 cells in patients with metastatic melanoma

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    Comin-Anduix Begonya

    2009-05-01

    Full Text Available Abstract Background Th17 cells are CD4+ cells that produce interleukin 17 (IL-17 and are potent inducers of tissue inflammation and autoimmunity. We studied the levels of this T cell subset in peripheral blood of patients treated with the anti-CTLA4 antibody tremelimumab since its major dose limiting toxicities are inflammatory and autoimmune in nature. Methods Peripheral blood mononuclear cells (PBMC were collected before and after receiving tremelimumab within two clinical trials, one with tremelimumab alone (21 patients and another together with autologous dendritic cells (DC pulsed with the melanoma epitope MART-126–35 (6 patients. Cytokines were quantified directly in plasma from patients and after in vitro stimulation of PBMC. We also quantified IL-17 cytokine-producing cells by intracellular cytokine staining (ICS. Results There were no significant changes in 13 assayed cytokines, including IL-17, when analyzing plasma samples obtained from patients before and after administration of tremelimumab. However, when PBMC were activated in vitro, IL-17 cytokine in cell culture supernatant and Th17 cells, detected as IL-17-producing CD4 cells by ICS, significantly increased in post-dosing samples. There were no differences in the levels of Th17 cells between patients with or without an objective tumor response, but samples from patients with inflammatory and autoimmune toxicities during the first cycle of therapy had a significant increase in Th17 cells. Conclusion The anti-CTLA4 blocking antibody tremelimumab increases Th17 cells in peripheral blood of patients with metastatic melanoma. The relation between increases in Th17 cells and severe autoimmune toxicity after CTLA4 blockade may provide insights into the pathogenesis of anti-CTLA4-induced toxicities. Trial Registration Clinical trial registration numbers: NCT0090896 and NCT00471887

  1. Antigen-Specific Th17 Cells Are Primed by Distinct and Complementary Dendritic Cell Subsets in Oropharyngeal Candidiasis.

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    Kerstin Trautwein-Weidner

    2015-10-01

    Full Text Available Candida spp. can cause severe and chronic mucocutaneous and systemic infections in immunocompromised individuals. Protection from mucocutaneous candidiasis depends on T helper cells, in particular those secreting IL-17. The events regulating T cell activation and differentiation toward effector fates in response to fungal invasion in different tissues are poorly understood. Here we generated a Candida-specific TCR transgenic mouse reactive to a novel endogenous antigen that is conserved in multiple distant species of Candida, including the clinically highly relevant C. albicans and C. glabrata. Using TCR transgenic T cells in combination with an experimental model of oropharyngeal candidiasis (OPC we investigated antigen presentation and Th17 priming by different subsets of dendritic cells (DCs present in the infected oral mucosa. Candida-derived endogenous antigen accesses the draining lymph nodes and is directly presented by migratory DCs. Tissue-resident Flt3L-dependent DCs and CCR2-dependent monocyte-derived DCs collaborate in antigen presentation and T cell priming during OPC. In contrast, Langerhans cells, which are also present in the oral mucosa and have been shown to prime Th17 cells in the skin, are not required for induction of the Candida-specific T cell response upon oral challenge. This highlights the functional compartmentalization of specific DC subsets in different tissues. These data provide important new insights to our understanding of tissue-specific antifungal immunity.

  2. β-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses.

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    Zhang, Zhonghua; Biagini Myers, Jocelyn M; Brandt, Eric B; Ryan, Patrick H; Lindsey, Mark; Mintz-Cole, Rachael A; Reponen, Tiina; Vesper, Stephen J; Forde, Frank; Ruff, Brandy; Bass, Stacey A; LeMasters, Grace K; Bernstein, David I; Lockey, James; Budelsky, Alison L; Khurana Hershey, Gurjit K

    2017-01-01

    Allergic sensitization to fungi has been associated with asthma severity. As a result, it has been largely assumed that the contribution of fungi to allergic disease is mediated through their potent antigenicity. We sought to determine the mechanism by which fungi affect asthma development and severity. We integrated epidemiologic and experimental asthma models to explore the effect of fungal exposure on asthma development and severity. We report that fungal exposure enhances allergen-driven TH2 responses, promoting severe allergic asthma. This effect is independent of fungal sensitization and can be reconstituted with β-glucan and abrogated by neutralization of IL-17A. Furthermore, this severe asthma is resistant to steroids and characterized by mixed TH2 and TH17 responses, including IL-13(+)IL-17(+)CD4(+) double-producing effector T cells. Steroid resistance is dependent on fungus-induced TH17 responses because steroid sensitivity was restored in IL-17rc(-/-) mice. Similarly, in children with asthma, fungal exposure was associated with increased serum IL-17A levels and asthma severity. Our data demonstrate that fungi are potent immunomodulators and have powerful effects on asthma independent of their potential to act as antigens. Furthermore, our results provide a strong rationale for combination treatment strategies targeting IL-17A for this subgroup of fungus-exposed patients with difficult-to-treat asthma. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  3. Host responses to Candida albicans: Th17 cells and mucosal candidiasis

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    Conti, Heather R.; Gaffen, Sarah L.

    2010-01-01

    Candida albicans causes mucosal and disseminated candidiasis, which represent serious problems for the rapidly expanding immunocompromised population. Until recently, Th1-mediated immunity was thought to confer the primary protection, particularly for oral candidiasis. However, emerging data indicate that the newly-defined Th17 compartment appears to play the predominant role in mucosal candidiasis. PMID:20381638

  4. Role of interleukin (IL)-17 and T-helper (Th)17 cells in cancer.

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    Song, Yang; Yang, Jian Ming

    2017-11-04

    Interleukin-17 (IL-17), a pleiotropic proinflammatory cytokine, is reported to be significantly generated by a distinct subset of CD4 + T-cells, upgrading cancer-elicited inflammation and preventing cancer cells from immune surveillance. T-helper (Th)17 cells produced from naive CD4 + T cells have recently been renowned and generally accepted, gaining eminence in cancer studies and playing the effective role in context of cancer. Th17 cells are the main source of IL-17-secreting cells, It was found that other cell types produced this cytokine as well, including Group 3 innate lymphoid cells (ILC3), δγT cells, invariant natural killer T (iNKT) cells, lymphoid-tissue inducer (LTi)-like cells and Natural killer (NK) cells. Th17-associated cytokines give impetus to tumor progression, or inducing angiogenesis and metastasis. This review demonstrates an understanding on how the pro- or antitumor function of Th17 cells and IL-17 may change cancer progression, leading to the appearance of complex and pivotal biologic activities in tumor. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. The Role of Th17 in Neuroimmune Disorders: Target for CAM Therapy. Part II

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    Aristo Vojdani

    2011-01-01

    Full Text Available Decades of research went into understanding the role that Th1 autoreactive T-cells play in neuroinflammation. Here we describe another effector population, the IL-17-producing T-helper lineage (Th17, which drives the inflammatory process. Through the recruitment of inflammatory infiltration neutrophils and the activation of matrix metalloproteinases, IL-17, a cytokine secreted by Th17 cells, contributes to blood-brain barrier breakdown and the subsequent attraction of macrophages and monocytes into the nervous system. The entry of cells along with the local production of inflammatory cytokines leads to myelin and axonal damage. This activation of the inflammatory response system is induced by different pathogenic factors, such as gut bacterial endotoxins resulting in progressive neurodegeneration by Th17 cells. Through the understanding of the role of bacterial endotoxins and other pathogenic factors in the induction of autoimmune diseases by Th17 cells, CAM practitioners will be able to design CAM therapies targeting IL-17 activity. Targeted therapy can restore the integrity of the intestinal and blood-brain barriers using probiotics, N-acetyl-cysteine, α-lipoic acid, resveratrol and others for their patients with autoimmunities, in particular those with neuroinflammation and neurodegeneration.

  6. Th17 involvement in nonalcoholic fatty liver disease progression to non-alcoholic steatohepatitis.

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    Chackelevicius, Carla Melisa; Gambaro, Sabrina Eliana; Tiribelli, Claudio; Rosso, Natalia

    2016-11-07

    The nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a wide histological spectrum ranging from benign simple steatosis to non-alcoholic steatohepatitis (NASH). Sustained inflammation in the liver is critical in this process. Hepatic macrophages, including liver resident macropaghes (Kupffer cells), monocytes infiltrating the injured liver, as well as specific lymphocytes subsets play a pivotal role in the initiation and perpetuation of the inflammatory response, with a major deleterious impact on the progression of fatty liver to fibrosis. During the last years, Th17 cells have been involved in the development of inflammation not only in liver but also in other organs, such as adipose tissue or lung. Differentiation of a naïve T cell into a Th17 cell leads to pro-inflammatory cytokine and chemokine production with subsequent myeloid cell recruitment to the inflamed tissue. Th17 response can be mitigated by T regulatory cells that secrete anti-inflammatory cytokines. Both T cell subsets need TGF-β for their differentiation and a characteristic plasticity in their phenotype may render them new therapeutic targets. In this review, we discuss the role of the Th17 pathway in NAFLD progression to NASH and to liver fibrosis analyzing different animal models of liver injury and human studies.

  7. DDX5 and its associated lncRNA Rmrp modulate Th17 cell effector functions

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    Huang, Wendy; Thomas, Benjamin; Flynn, Ryan A.; Gavzy, Samuel J.; Wu, Lin; Kim, Sangwon V.; Hall, Jason A.; Miraldi, Emily R.; Ng, Charles P.; Rigo, Frank; Meadows, Sarah; Montoya, Nina R.; Herrera, Natalia G.; Domingos, Ana I.; Rastinejad, Fraydoon; Myers, Richard M.; Fuller-Pace, Frances V.; Bonneau, Richard; Chang, Howard Y.; Acuto, Oreste; Littman, Dan R.

    2016-01-01

    Th17 lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORγt, a ligand-regulated nuclear receptor. We identified the DEAD-box RNA helicase DDX5 as a RORγt partner that coordinates transcription of selective Th17 genes and is required for Th17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORγt and co-activate its targets depends on its intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in Cartilage-Hair Hypoplasia (CHH) patients. A targeted Rmrp mutation in mice, corresponding to one in CHH patients, abrogated the lncRNA’s chromatin recruitment, ability to potentiate DDX5-RORγt interaction and RORγt target gene transcription. Elucidation of the link between Rmrp and the DDX5-RORγt complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation and promises new opportunities for therapeutic intervention in Th17-dependent diseases. PMID:26675721

  8. The Role of Regulatory T Cells and TH17 Cells in Multiple Myeloma

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    Walter M. T. Braga

    2012-01-01

    Full Text Available The development of multiple myeloma (MM involves a series of genetic alterations and changes in the bone marrow microenvironment, favoring the growth of the tumor and failure of local immune control. Quantitative and functional alterations in CD4+ and CD8+ T cells have been described in MM. The balance between T regulatory cells (Treg and T helper (Th 17 cells represents one essential prerequisite for maintaining anti-tumor immunity in MM. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against infections and tumor cells. In MM patients, Tregs seem to contribute to myeloma-related immune dysfunction and targeting them could, therefore, help to restore and enhance vital immune responses. Th17 cells protect against fungal and parasitic infections and participate in inflammatory reactions and autoimmunity. The interplay of TGF-β and IL-6, expressed at high levels in the bone marrow of myeloma patients, may affect generation of Th17 cells both directly or via other pro-inflammatory cytokines and thereby modulate antitumor immune responses. A detailed analysis of the balance between Tregs and Th17 cells seems necessary in order to design more effective and less toxic modes of immunotherapy myeloma which still is an uncurable malignancy.

  9. The inflammasome drives protective Th1 and Th17 cellular responses in disseminated candidiasis

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    van de Veerdonk, Frank L.; Joosten, Leo A.B.; Shaw, Patrick J.; Smeekens, Sanne P.; Malireddi, Subbarao; van der Meer, Jos W.M.; Kullberg, Bart-Jan; Netea, Mihai G.; Kanneganti, Thirumala-Devi

    2014-01-01

    The Nlrp3 inflammasome has been proposed to play an important role in antifungal host defense. However, studies exploring the role of the inflammasome in antifungal host defense have been limited to the direct effects on IL-1β processing. Although IL-1β has important direct effects on the innate immune response, important effects of the caspase-1-dependent cytokines IL-1β and IL-18 are exerted on the initiation of adaptive cellular responses Th1 and Th17. No studies have been employed to assess the impact of the inflammasome on the Th1/Th17 defense mechanisms in-vivo during candidiasis. In the present study we demonstrate an essential role for caspase-1 and ASC in disseminated candidiasis through regulating antifungal Th1 and Th17 responses. Caspase-1−/− and ASC−/− mice display diminished Th1/Th17 responses, followed by increased fungal outgrowth and lower survival. These observations identify a critical role for the inflammasome in controlling protective adaptive immune responses during invasive fungal infection. PMID:21681738

  10. Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1

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    Yusuke Endo

    2015-08-01

    Full Text Available Chronic inflammation due to obesity contributes to the development of metabolic diseases, autoimmune diseases, and cancer. Reciprocal interactions between metabolic systems and immune cells have pivotal roles in the pathogenesis of obesity-associated diseases, although the mechanisms regulating obesity-associated inflammatory diseases are still unclear. In the present study, we performed transcriptional profiling of memory phenotype CD4 T cells in high-fat-fed mice and identified acetyl-CoA carboxylase 1 (ACC1, the gene product of Acaca as an essential regulator of Th17 cell differentiation in vitro and of the pathogenicity of Th17 cells in vivo. ACC1 modulates the DNA binding of RORγt to target genes in differentiating Th17 cells. In addition, we found a strong correlation between IL-17A-producing CD45RO+CD4 T cells and the expression of ACACA in obese subjects. Thus, ACC1 confers the appropriate function of RORγt through fatty acid synthesis and regulates the obesity-related pathology of Th17 cells.

  11. Th17 Immune Cells in vivo: Friend or Foe? | Center for Cancer Research

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    Upon encountering an antigen, T cells bearing CD4+ (a helper marker) proliferate and become polarized. During this process, the cells produce specific signaling molecules called cytokines.  This signaling stimulates the T cells to become more specialized.  What results is the production of T cell subsets such as Th1, Th17, or others.

  12. Baicalin attenuates TNBS-induced colitis in rats by modulating the Th17/Treg paradigm.

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    Zou, Ying; Dai, Shi-Xue; Chi, Hong-Gang; Li, Tao; He, Zhi-Wei; Wang, Jian; Ye, Cai-Guo; Huang, Guo-Liang; Zhao, Bing; Li, Wen-Yang; Wan, Zheng; Feng, Jin-Shan; Zheng, Xue-Bao

    2015-10-01

    Baicalin, a flavonoid, has a wide range of pharmacological properties, including immunomodulation. The objective of this study was to investigate the effect of baicalin on the balance of T helper 17 (Th17) and regulatory T (Treg) cells in a colitis model. The rat colitis model was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Baicalin (10 ml/kg, each) or mesalazine (positive control) was then administered orally for 7 days. Inflammatory and immunological responses were evaluated by pathology, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, western blot analysis, and flow cytometry. Our study showed that baicalin not only significantly attenuated TNBS-induced colitis by reducing the disease activity index as well as macroscopic and microscopic scores, but it also improved the weight loss and shortening of the colon. Baicalin treatment also induced a significant decrease in the levels of inflammatory mediators, including the myeloperoxidase activity, the levels of tumor necrosis factor α, IL-1β, and Th1-related cytokines IL-12 and IFN-γ. Furthermore, the beneficial effects of baicalin seem to be associated with regulation of the Th17 and Treg paradigm. We found that administration of baicalin significantly downregulated the number of Th17 cells and the levels of Th17-related cytokines (IL-17 and IL-6) and retinoic acid receptor-related orphan receptor γt. In contrast, there was an increase in Treg cells numbers, Treg-related cytokines transforming growth factor-β and IL-10, and forkhead box P3. Our results suggest that the anti-inflammatory effect of baicalin may be linked to modulation of the balance between Th17 and Treg cells in TNBS-induced ulcerative colitis.

  13. Effect of Th17 and Treg Axis Disorder on Outcomes of Pulmonary Arterial Hypertension in Connective Tissue Diseases

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    Saren Gaowa

    2014-01-01

    Full Text Available This prospective cohort study is to verify the hypothesis that the balance of Th17 and Treg cells frequencies in the peripheral circulation is disturbed in patients with varying degrees of connective tissue diseases-associated pulmonary arterial hypertension (CTD-aPAH and to prove the influence of Th17/Treg imbalance on prognosis. We detected the frequencies and absolute counts of Th17 and Treg cells and related serum cytokines secretion and expressions of key transcription factors in 117 patients with connective tissue diseases (CTD, 53 patients with CTD-aPAH, and 48 healthy volunteers. Moreover, the median value according to levels of Th17/Treg ratios in patients with CTD-aPAH was chosen as basis of group division for survival analysis. CTD-aPAH patients revealed significant increase in peripheral Th17 cells, Th17-related cytokines, and ROR γt mRNA levels. They also presented a significant decrease in Treg cells, Treg-related cytokines, and Foxp3 mRNA levels as compared with CTD patients and healthy controls. More importantly, the Th17/Treg ratio was significantly related to the severity and prognosis of CTD-aPAH. This study indicated that the Th17/Treg axis disorder plays a critical role in CTD-aPAH. Furthermore, the dynamic balance between Th17 and Treg cells was likely to influence prognosis of patients with CTD-aPAH.

  14. Murine AIDS Protects Mice Against Experimental Cerebral Malaria: Down-Regulation by Interleukin 10 a T-Helper Type 1 CD4^+ Cell-Mediated Pathology

    Science.gov (United States)

    Eckwalanga, Michel; Marussig, Myriam; Dias Tavares, Marisa; Bouanga, Jean Claude; Hulier, Elisabeth; Henriette Pavlovitch, Jana; Minoprio, Paola; Portnoi, Denis; Renia, Laurent; Mazier, Dominique

    1994-08-01

    The retrovirus LP-BM5 murine leukemia virus induces murine AIDS in C57BL/6 mice that has many similarities with human AIDS; Plasmodium berghei ANKA causes experimental cerebral malaria in the same strain of mice. The outcome of malaria infection was studied in mice concurrently infected with the two pathogens. The retrovirus significantly reduced the gravity of the neurological manifestations associated with Plasmodium berghei ANKA infection. The protection against experimental cerebral malaria induced by murine AIDS increased with duration of viral infection and, hence, with the severity of the immunodeficiency. Interleukin 10, principally from splenic T cells, was shown to play a crucial role in this protection.

  15. IL-18 potentiated whole blood IFN-γ assay can identify cell-mediated immune responses towards Lawsonia intracellularis in experimentally infected pigs

    DEFF Research Database (Denmark)

    Riber, Ulla; Jakobsen, Jeanne Toft; Hvass, Henriette Cordes

    Lawsonia intracellularis is an obligate intracellular bacteria causing proliferative enteropathy (PE) in pigs. The infection causes diarrhoea, retarded growth and sudden death, and is one of the major causes of antibiotics usage in modern pig production. In experimental L. intracellularis infection...

  16. Gene network inference using continuous time Bayesian networks: a comparative study and application to Th17 cell differentiation.

    Science.gov (United States)

    Acerbi, Enzo; Zelante, Teresa; Narang, Vipin; Stella, Fabio

    2014-12-11

    Dynamic aspects of gene regulatory networks are typically investigated by measuring system variables at multiple time points. Current state-of-the-art computational approaches for reconstructing gene networks directly build on such data, making a strong assumption that the system evolves in a synchronous fashion at fixed points in time. However, nowadays omics data are being generated with increasing time course granularity. Thus, modellers now have the possibility to represent the system as evolving in continuous time and to improve the models' expressiveness. Continuous time Bayesian networks are proposed as a new approach for gene network reconstruction from time course expression data. Their performance was compared to two state-of-the-art methods: dynamic Bayesian networks and Granger causality analysis. On simulated data, the methods comparison was carried out for networks of increasing size, for measurements taken at different time granularity densities and for measurements unevenly spaced over time. Continuous time Bayesian networks outperformed the other methods in terms of the accuracy of regulatory interactions learnt from data for all network sizes. Furthermore, their performance degraded smoothly as the size of the network increased. Continuous time Bayesian networks were significantly better than dynamic Bayesian networks for all time granularities tested and better than Granger causality for dense time series. Both continuous time Bayesian networks and Granger causality performed robustly for unevenly spaced time series, with no significant loss of performance compared to the evenly spaced case, while the same did not hold true for dynamic Bayesian networks. The comparison included the IRMA experimental datasets which confirmed the effectiveness of the proposed method. Continuous time Bayesian networks were then applied to elucidate the regulatory mechanisms controlling murine T helper 17 (Th17) cell differentiation and were found to be effective in

  17. Th17 cytokines induce pro-fibrotic cytokines release from human eosinophils

    Science.gov (United States)

    2013-01-01

    Background Subepithelial fibrosis is one of the most critical structural changes affecting bronchial airway function during asthma. Eosinophils have been shown to contribute to the production of pro-fibrotic cytokines, TGF-β and IL-11, however, the mechanism regulating this process is not fully understood. Objective In this report, we investigated whether cytokines associated with inflammation during asthma may induce eosinophils to produce pro-fibrotic cytokines. Methods Eosinophils were isolated from peripheral blood of 10 asthmatics and 10 normal control subjects. Eosinophils were stimulated with Th1, Th2 and Th17 cytokines and the production of TGF-β and IL-11 was determined using real time PCR and ELISA assays. Results The basal expression levels of eosinophil derived TGF-β and IL-11 cytokines were comparable between asthmatic and healthy individuals. Stimulating eosinophils with Th1 and Th2 cytokines did not induce expression of pro-fibrotic cytokines. However, stimulating eosinophils with Th17 cytokines resulted in the enhancement of TGF-β and IL-11 expression in asthmatic but not healthy individuals. This effect of IL-17 on eosinophils was dependent on p38 MAPK activation as inhibiting the phosphorylation of p38 MAPK, but not other kinases, inhibited IL-17 induced pro-fibrotic cytokine release. Conclusions Th17 cytokines might contribute to airway fibrosis during asthma by enhancing production of eosinophil derived pro-fibrotic cytokines. Preventing the release of pro-fibrotic cytokines by blocking the effect of Th17 cytokines on eosinophils may prove to be beneficial in controlling fibrosis for disorders with IL-17 driven inflammation such as allergic and autoimmune diseases. PMID:23496774

  18. Disrupted TH17/Treg balance in patients with chronic low back pain.

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    Benjamin Luchting

    Full Text Available Chronic low back pain (CLBP is a leading cause of disability and costs in health care systems worldwide. Despite extensive research, the exact pathogenesis of CLBP, particularly the individual risk of chronification remains unclear. To investigate a possible role of the adaptive immune system in the pathophysiology of CLBP, we analyzed T cell related cytokine profiles, T cell related mRNA expression patterns and the distribution of T cell subsets in 37 patients suffering from nonspecific CLBP before and after multimodal therapy in comparison to 25 healthy controls. Serum patterns of marker cytokines were analyzed by Luminex technology, mRNA expression of cytokines and specific transcription factors was measured by real-time PCR, and distribution of TH1-, TH2-, TH17- and regulatory T cell (Tregs subsets was determined by multicolor flow cytometry. We found that CLBP patients exhibit an increased number of anti-inflammatory Tregs, while pro-inflammatory TH17 cells are decreased, resulting in an altered TH17/Treg ratio. Accordingly, FoxP3 and TGF-β-mRNA expression was elevated, while expression of IL-23 was reduced. Serum cytokine analyses proved to be unsuitable to monitor the adaptive immune response in CLBP patients. We further show that even after successful therapy with lasting reduction of pain, T cell subset patterns remained altered after a follow-up period of 6 months. These findings suggest an involvement of TH17/Treg cells in the pathogenesis of CLBP and emphasize the importance of these cells in the crosstalk of pain and immune response.German Clinical Trial Register: Registration Trial DRKS00005954.

  19. The IL-17 and Th17 cell immune response in cervical cancer : angels or demons : it depends on the context

    NARCIS (Netherlands)

    Punt, Birgitte Simone

    2015-01-01

    This thesis provides novel insights into the role of IL-17 and Th17 cells in cervical cancer. While IL-17 was shown to be predominantly produced by innate myeloid cells such as neutrophils and correlated with poor survival, Th17 cells were generally a small cell population correlated with improved

  20. Translational mini-review series on Th17 cells: development of mouse and human T helper 17 cells

    NARCIS (Netherlands)

    de Jong, E.; Suddason, T.; Lord, G. M.

    2010-01-01

    There has been a considerable amount of interest in the immunological community about new phenotypic subsets of CD4(+) T cells, particularly cells that produce the cytokine interleukin (IL)-17 [named T helper type 17 (Th17) cells]. While the initial discovery of Th17 cells and the pathways that

  1. Komórki Th17 w patogenezie reumatoidalnego zapalenia stawów

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    Agnieszka Paradowska-Gorycka

    2010-10-01

    Full Text Available Dzikie komórki CD4+, stymulowane przez komórki prezentująceantygen (APCs i szereg cytokin, ulegają aktywacji i różnicowaniudo wielu subpopulacji limfocytów pomocniczych (Th odgrywającychgłówną rolę w modulowaniu odpowiedzi układu immunologicznego.Komórki Th1 i Th2 uczestniczą w regulacji odpowiedzikomórkowej i humoralnej, komórki Th17 zostały zaś zidentyfikowanejako subpopulacja komórek Th regulujących procesy zapalnepoprzez produkcję odrębnych cytokin, takich jak IL-17. Głównącechą tej subpopulacji komórek jest udział w odpowiedzi skierowanejprzeciwko drobnoustrojom oraz w patogenezie choróbautoimmunologicznych i alergicznych. Znaczenie komórek Th17oraz IL-17 w regulacji poszczególnych etapów procesu zapalnegotoczącego się w reumatoidalnym stawie nadal nie jest w pełnipoznane i stanowi ostatnio cel wielu badań. W prezentowanej pracyomówiono najnowsze doniesienia dotyczące fenotypu, różnicowaniaoraz najważniejszych funkcji biologicznych ludzkich komórekTh17, a także przedstawiono ich rolę w patogeneziereumatoidalnego zapalenia stawów.

  2. Mesenchymal Stem Cells from Patients with Rheumatoid Arthritis Display Impaired Function in Inhibiting Th17 Cells

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    Yue Sun

    2015-01-01

    Full Text Available Mesenchymal stem cells (MSCs possess multipotent and immunomodulatory properties and are suggested to be involved in the pathogenesis of immune-related diseases. This study explored the function of bone marrow MSCs from rheumatoid arthritis (RA patients, focusing on immunomodulatory effects. RA MSCs showed decreased proliferative activity and aberrant migration capacity. No significant differences were observed in cytokine profiles between RA and control MSCs. The effects of RA MSCs on proliferation of peripheral blood mononuclear cells (PBMCs and distribution of specific CD4+ T cell subtypes (Th17, Treg, and Tfh cells were investigated. RA MSCs appeared to be indistinguishable from controls in suppressing PBMC proliferation, decreasing the proportion of Tfh cells, and inducing the polarization of Treg cells. However, the capacity to inhibit Th17 cell polarization was impaired in RA MSCs, which was related to the low expression of CCL2 in RA MSCs after coculture with CD4+ T cells. These findings indicated that RA MSCs display defects in several important biological activities, especially the capacity to inhibit Th17 cell polarization. These functionally impaired MSCs may contribute to the development of RA disease.

  3. Assessment of Th17/Treg cells and Th cytokines in an improved immune thrombocytopenia mouse model.

    Science.gov (United States)

    Zhang, Guoyang; Zhang, Ping; Liu, Hongyun; Liu, Xiaoyan; Xie, Shuangfeng; Wang, Xiuju; Wu, Yudan; Chang, Jianxing; Ma, Liping

    2017-09-01

    The improved passive immune thrombocytopenia (ITP) mouse model has been extensively utilized for the study of ITP. However, how closely this model matches the human inflammation state and immune background is unclear. Our study aimed to explore the profile of Th cytokines and Th17/Treg cells in the model. We induced the ITP mouse model by dose-escalation injection of MWReg30. The serum levels of cytokines (IFN-γ, IL-2, IL-4, IL-10, IL-17A, and TGF-β1) were measured by enzyme-linked immunosorbent assay and the frequency of Th17 and Treg cells was measured by flow cytometry. The mRNA expression of Foxp3 and RORrt was measured by real-time PCR. The serum levels of cytokines IFN-γ, TGF-β1, IL-4, and IL-10 were significantly lower in ITP mice. The secretion of serum proinflammatory cytokines IL-2 and IL-17A and the percentage of Th17 cells showed no statistically significant increase. In ITP mice the frequency of Treg cells and mRNA expression of Foxp3 was significantly lower in splenocytes. Our data suggest that the improved passive ITP mouse model does not mimic the autoimmune inflammatory process of human ITP. Compared with human ITP, this model has a similar change in frequency of Treg cells, which may directly or indirectly result from antibody-mediated platelet destruction due to attenuated release of TGF-β.

  4. Th1 and Th17 Cells in Tuberculosis: Protection, Pathology, and Biomarkers

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    I. V. Lyadova

    2015-01-01

    Full Text Available The outcome of Mycobacterium tuberculosis (Mtb infection ranges from a complete pathogen clearance through asymptomatic latent infection (LTBI to active tuberculosis (TB disease. It is now understood that LTBI and active TB represent a continuous spectrum of states with different degrees of pathogen “activity,” host pathology, and immune reactivity. Therefore, it is important to differentiate LTBI and active TB and identify active TB stages. CD4+ T cells play critical role during Mtb infection by mediating protection, contributing to inflammation, and regulating immune response. Th1 and Th17 cells are the main effector CD4+ T cells during TB. Th1 cells have been shown to contribute to TB protection by secreting IFN-γ and activating antimycobacterial action in macrophages. Th17 induce neutrophilic inflammation, mediate tissue damage, and thus have been implicated in TB pathology. In recent years new findings have accumulated that alter our view on the role of Th1 and Th17 cells during Mtb infection. This review discusses these new results and how they can be implemented for TB diagnosis and monitoring.

  5. Treg/Th17 balance in stable CAD patients with different stages of coronary atherosclerosis.

    Science.gov (United States)

    Potekhina, Alexandra V; Pylaeva, Ekaterina; Provatorov, Sergey; Ruleva, Natalya; Masenko, Valery; Noeva, Elena; Krasnikova, Tatiana; Arefieva, Tatiana

    2015-01-01

    Objective. Immune processes play a significant role in atherosclerosis plaque progression. Regulatory T cells and T helpers 17 were shown to possess anti- and pro-atherogenic activity, respectively. We aimed to investigate the balance of circulating Treg and Th17 in stable angina patients with different stages of coronary atherosclerosis. Methods. Treg, Th17 and Th1 cell frequencies were studied in 117 patients via direct immunofluorescence staining and flow cytometry. Group 1 had intact coronary arteries. Group 2 and Group 3 had undergone previous coronary stenting; in Group 2 no coronary atherosclerosis progression was found, in Group 3 patients had disease progression in non-invaded coronary arteries. Group 4 had severe coronary atherosclerosis. Results. The frequencies of CD4+CD25highCD127low, CD4+foxp3+, and CD4+IL10 + T cells were decreased, and CD4+IL17 + T cells frequencies were increased in group 4 vs. 1. Treg/Th17 ratios were declined in groups 3 and 4 vs. groups 1 and 2. IL-10 level was lower while hsCRP and sCD25 levels were higher in group 4 vs. 1. Conclusion. We assume that the imbalance in pro- and anti-inflammatory/atherogenic lymphocyte subpopulations is associated with atherosclerosis progression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation.

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    Alexandra Schuetz

    2014-12-01

    Full Text Available Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, microbial translocation and subsequent immune-activation, which remain elevated despite antiretroviral therapy (ART correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown. We analyzed mucosal Th17 cells in 42 acute HIV infection (AHI subjects (Fiebig (F stage I-V with a median duration of infection of 16 days and the short-term impact of early initiation of ART. Th17 cells were defined as IL-17+ CD4+ T cells and their function was assessed by the co-expression of IL-22, IL-2 and IFNγ. While intact during FI/II, depletion of mucosal Th17 cell numbers and function was observed during FIII correlating with local and systemic markers of immune-activation. ART initiated at FI/II prevented loss of Th17 cell numbers and function, while initiation at FIII restored Th17 cell numbers but not their polyfunctionality. Furthermore, early initiation of ART in FI/II fully reversed the initially observed mucosal and systemic immune-activation. In contrast, patients treated later during AHI maintained elevated mucosal and systemic CD8+ T-cell activation post initiation of ART. These data support a loss of Th17 cells at early stages of acute HIV infection, and highlight that studies of ART initiation during early AHI should be further explored to assess the underlying mechanism of mucosal Th17 function preservation.

  7. Human Th17 Cells Lack HIV-Inhibitory RNases and Are Highly Permissive to Productive HIV Infection.

    Science.gov (United States)

    Christensen-Quick, Aaron; Lafferty, Mark; Sun, Lingling; Marchionni, Luigi; DeVico, Anthony; Garzino-Demo, Alfredo

    2016-09-01

    Human immunodeficiency virus (HIV) infects and depletes CD4(+) T cells, but subsets of CD4(+) T cells vary in their susceptibility and permissiveness to infection. For example, HIV preferentially depletes interleukin-17 (IL-17)-producing T helper 17 (Th17) cells and T follicular helper (Tfh) cells. The preferential loss of Th17 cells during the acute phase of infection impairs the integrity of the gut mucosal barrier, which drives chronic immune activation-a key determinant of disease progression. The preferential loss of Th17 cells has been attributed to high CD4, CCR5, and CXCR4 expression. Here, we show that Th17 cells also exhibit heightened permissiveness to productive HIV infection. Primary human CD4(+) T cells were sorted, activated under Th17- or Th0-polarizing conditions and infected, and then analyzed by flow cytometry. Th17-polarizing cytokines increased HIV infection, and HIV infection was disproportionately higher among Th17 cells than among IL-17(-) or gamma interferon-positive (IFN-γ(+)) cells, even upon infection with a replication-defective HIV vector with a pseudotype envelope. Further, Th17-polarized cells produced more viral capsid protein. Our data also reveal that Th17-polarized cells have diminished expression of RNase A superfamily proteins, and we report for the first time that RNase 6 inhibits HIV. Thus, our findings link Th17 polarization to increased HIV replication. Our study compares the intracellular replicative capacities of several different HIV isolates among different T cell subsets, providing a link between the differentiation of Th17 cells and HIV replication. Th17 cells are of key importance in mucosal integrity and in the immune response to certain pathogens. Based on our findings and the work of others, we propose a model in which HIV replication is favored by the intracellular environment of two CD4(+) T cell subsets that share several requirements for their differentiation: Th17 and Tfh cells. Characterizing cells that

  8. Optimal clearance of Sporothrix schenckii requires an intact Th17 response in a mouse model of systemic infection.

    Science.gov (United States)

    Ferreira, Lucas Souza; Gonçalves, Amanda Costa; Portuondo, Deivys Leandro; Maia, Danielle Cardoso Geraldo; Placeres, Marisa Campos Polesi; Batista-Duharte, Alexander; Carlos, Iracilda Zeppone

    2015-08-01

    The discovery of Th17 cells, along with many other Th cell subsets in the recent years, has expanded the Th1/Th2 paradigm that had persisted since its proposition by Mosmann in 1986. Defined by the characteristic expression of the transcription factor retinoic-related orphan receptor γt (RORγt) and production of IL-17A (IL-17), Th17 cells are powerful inducers of tissue inflammation with a recognized role against extracellular bacteria and fungi. Despite this, the interest in their study came from the pivotal role they play in the development and maintenance of major chronic inflammatory conditions such as multiple sclerosis, rheumatoid arthritis and Crohn's disease, hence they have been the target of promising new anti-Th17 therapies. Accordingly, the identification of opportunistic pathogens whose clearance relies on the Th17 response is of huge prophylactic importance. As shown here for the first time, this applies to Sporothrix schenckii, a thermo-dimorphic fungus and the causative agent of sporotrichosis. Our results show that both Th17 and Th1/Th17 mixed cells are developed during the S. schenckii systemic mice infection, which also leads to augmented production of IL-17 and IL-22. Also, by using an antibody-mediated IL-23 depletion model, we further demonstrate that optimal fungal clearance, but not survival, depends on an intact Th17 response. Copyright © 2015 Elsevier GmbH. All rights reserved.

  9. Response Gene to Complement-32 Promotes the Imbalance of Treg/Th17 in Patients with Dilated Cardiomyopathy.

    Science.gov (United States)

    Li, Bailing; Zhou, Wei; Tang, Xiaojun; Wang, Wei; Pan, Jiajun; Tan, Mengwei

    2017-10-16

    The imbalance of Treg/Th17 cells plays important role in the pathogenesis of dilated cardiomyopathy (DCM). Response gene to complement (RGC)-32 is a cell cycle regulator that plays an important role in cell proliferation. We evaluated whether the upregulation of RGC-32 was implicated in the homeostasis of Treg/Th17 cells in DCM. The levels of plasma RGC-32, IL-17 and TGF-β1, and the frequencies of circulating CD4+ RGC-32+ T cells, Th17 and Treg cells in patients with DCM were determined by Cytokine-specific sandwich ELISA and the flow cytometer (FCM), respectively. A significant elevation of plasma RGC-32 in patients with DCM compared with healthy control (HC) subjects was observed. This upregulation was associated with an increase in frequency of Th17 and a decrease in frequency of Treg cells. To further assessed the role of RGC-32, we investigated the effects of RGC-32 up- or down-regulation on frequencies of Th17 and Treg cells in peripheral blood mononuclear cells (PBMCs) from subjects. Importantly, overexpression of RGC-32 was accompanied by an augmentation of Th17 and a reduction of Treg expression. In summary, our study demonstrated the up-regulation of RGC-32 contributed to the imbalance of Treg/Th17 cells in patients with DCM. © 2017 The Author(s). Published by S. Karger AG, Basel.

  10. Inhibition of Th1 and Th17 Cells by Medicinal Plants and Their Derivatives: A Systematic Review.

    Science.gov (United States)

    Asadi-Samani, Majid; Bagheri, Nader; Rafieian-Kopaei, Mahmoud; Shirzad, Hedayatollah

    2017-08-01

    Searching for new natural drugs that are capable of targeting Th1 and Th17 may lead to development of more effective treatments for inflammatory and autoimmune diseases. Most of the natural drugs can be derived from plants that are used in traditional medicine and folk medicine. The aim of this systematic review is to identify and introduce plants or plant derivatives that are effective on inflammatory diseases by inhibiting Th1 and Th17 responses. To achieve this purpose, the search terms herb, herbal medicine, herbal drug, medicinal plant, phytochemical, traditional Chinese medicine, Ayurvedic medicine, natural compound, inflammation, inflammatory diseases, Th1, Th17, T helper 1 or T helper 17 were used separately in Title/Keywords/Abstract in Web of Science and PubMed databases. In articles investigating the effect of the medicinal plants and their derivatives in inhibiting Th1 and Th17 cells, the effects of eight extracts of the medicinal plants, 21 plant-based compounds and some of their derivatives, and eight drugs derived from the medicinal plants' compounds in inhibiting Th1 and Th17 cells were reviewed. The results showed that medicinal plants and their derivates are able to suppress Th17 and Th1 T cell functions as well as cytokine secretion and differentiation. The results can be used to produce herbal drugs that suppress Th, especially Th17, responses. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  11. Th1, Th2, and Th17 Cytokine Involvement in Thyroid Associated Ophthalmopathy

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    Jie Shen

    2015-01-01

    Full Text Available To determine serum cytokine profiles in Graves’ disease (GD patients with or without active and inactive thyroid associated ophthalmopathy (TAO, we recruited 65 subjects: 10 GD only (without TAO, 25 GD + active TAO, 20 GD + TAO, and 10 healthy controls. Liquid chip assay was used to measure serum Th1/Th2/Th17 cytokines including IFN-γ (interferon-gamma, TNF-α (tumor necrosis factor-alpha, IL-1α (interleukin-1 alpha, IL-1Ra (IL-1 receptor antagonist, IL-2, IL-4, IL-6, and IL-17 and two chemokines: RANTES (regulated upon activation, normal T cell expressed and secreted and IP-10 (IFN-γ-induced protein 10. Serum levels of TSH (thyroid stimulating hormone receptor autoantibodies (TRAb were measured using an enzyme linked immunosorbent assay. Compared with healthy controls, TAO patients showed significantly elevated serum levels of IFN-γ, TNF-α, IL-1α, IL-4, IL-6, IL-17, and IP-10. Comparing active and inactive TAO, serum Th1 cytokines IFN-γ and TNF-α were elevated in active TAO, while serum Th2 cytokine IL-4 was elevated in inactive TAO. Serum Th17 cytokine IL-17 was elevated in GD but reduced in both active and inactive TAO. A positive correlation was found between TRAb and IFN-γ, TNF-α, IL-1α, IL-2, IL-4, and IL-6. Taken together, serum Th1/Th2/Th17 cytokines and chemokines reflect TAO disease activity and may be implicated in TAO pathogenesis.

  12. Antioxidant and immunomodulatory effects of olive leaf extract on serum level of Th17 related cytokines

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    2015-12-01

    Full Text Available Background: Olive has a protective effect against chronic inflammatory conditions. However, it is not clear weather this effect is due to its immunomodulatory or antioxidant property. The aim of this study was to investigate the effect of olive leaf extract on serum levels of Th-17 related cytokines and its antioxidant properties. Materials and Methods: 40 male rats divided into 5 groups, and were treated by placebo (Control group, vitamin C (as a known and potent antioxidant and different doses of olive leaf extract. Four test groups, received vitamin C 10 mg/kg and olive leaf extract which contained 5, 10 and 15 mg/kg Oleuropein. All treatments were applied for 10 consecutive days orally via gavage. After this period, cardiac puncture was performed to retrieve blood from animals in order to determine interleukin 17, 23 and TGFβ levels in their serum by ELISA method. Glutathione peroxidase (GPx, Superoxide dismutase (SOD, Catalase (CAT activities and thiobarbituric acid reactive substances (TBARS, as a lipid peroxidation marker were assayed in right brain hemisphere of treated animals. Results: TBARS increased significantly in control group when compared to the other groups (p0.05, TGFβ concentration was significantly lower in animals which treated by 5 and 15 mg/kg of Oleuropein. Conclusion: Olive leaf extract, which contains Oleuropein, had a significant antioxidant effect on the brain of studied animals, while it was not able to change the Th-17 cell-related cytokines (Except TGFβ significantly. Therefore, it could conclude that the protective role of olive against chronic degenerative diseases is related to its antioxidant properties rather than its effects on pathogenic cytokine profile of Th17 cells.

  13. IL-17A and Th17 Cells in Lung Inflammation: An Update on the Role of Th17 Cell Differentiation and IL-17R Signaling in Host Defense against Infection

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    Hsing-Chuan Tsai

    2013-01-01

    Full Text Available The significance of Th17 cells and interleukin- (IL-17A signaling in host defense and disease development has been demonstrated in various infection and autoimmune models. Numerous studies have indicated that Th17 cells and its signature cytokine IL-17A are critical to the airway’s immune response against various bacteria and fungal infection. Cytokines such as IL-23, which are involved in Th17 differentiation, play a critical role in controlling Klebsiella pneumonia (K. pneumonia infection. IL-17A acts on nonimmune cells in infected tissues to strengthen innate immunity by inducing the expression of antimicrobial proteins, cytokines, and chemokines. Mice deficient in IL-17 receptor (IL-17R expression are susceptible to infection by various pathogens. In this review, we summarize the recent advances in unraveling the mechanism behind Th17 cell differentiation, IL-17A/IL-17R signaling, and also the importance of IL-17A in pulmonary infection.

  14. Relative Contribution of Th1 and Th17 Cells in Adaptive Immunity to Bordetella pertussis: Towards the Rational Design of an Improved Acellular Pertussis Vaccine

    Science.gov (United States)

    Ross, Pádraig J.; Allen, Aideen C.; Walsh, Kevin; Misiak, Alicja; Lavelle, Ed C.; McLoughlin, Rachel M.; Mills, Kingston H. G.

    2013-01-01

    Whooping cough caused by Bordetella pertussis is a re-emerging infectious disease despite the introduction of safer acellular pertussis vaccines (Pa). One explanation for this is that Pa are less protective than the more reactogenic whole cell pertussis vaccines (Pw) that they replaced. Although Pa induce potent antibody responses, and protection has been found to be associated with high concentrations of circulating IgG against vaccine antigens, it has not been firmly established that host protection induced with this vaccine is mediated solely by humoral immunity. The aim of this study was to examine the relative contribution of Th1 and Th17 cells in host immunity to infection with B. pertussis and in immunity induced by immunization with Pw and Pa and to use this information to help rationally design a more effective Pa. Our findings demonstrate that Th1 and Th17 both function in protective immunity induced by infection with B. pertussis or immunization with Pw. In contrast, a current licensed Pa, administered with alum as the adjuvant, induced Th2 and Th17 cells, but weak Th1 responses. We found that IL-1 signalling played a central role in protective immunity induced with alum-adsorbed Pa and this was associated with the induction of Th17 cells. Pa generated strong antibody and Th2 responses, but was fully protective in IL-4-defective mice, suggesting that Th2 cells were dispensable. In contrast, Pa failed to confer protective immunity in IL-17A-defective mice. Bacterial clearance mediated by Pa-induced Th17 cells was associated with cell recruitment to the lungs after challenge. Finally, protective immunity induced by an experimental Pa could be enhanced by substituting alum with a TLR agonist that induces Th1 cells. Our findings demonstrate that alum promotes protective immunity through IL-1β-induced IL-17A production, but also reveal that optimum protection against B. pertussis requires induction of Th1, but not Th2 cells. PMID:23592988

  15. Interleukin-21 receptor deficiency increases the initial toll-like receptor 2 response but protects against joint pathology by reducing Th1 and Th17 cells during streptococcal cell wall arthritis

    NARCIS (Netherlands)

    Marijnissen, Renoud J.; Roeleveld, Debbie M.; Young, Deborah; Nickerson-Nutter, Cheryl; Abdollahi-Roodsaz, Shahla; de Aquino, Sabrina Garcia; van de Loo, Fons A. J.; van Spriel, Annemiek B.; Boots, Annemieke M. H.; van den Berg, Wim B.; Koenders, Marije I.

    OBJECTIVE: The cytokine interleukin-21 (IL-21) can have both proinflammatory and immunosuppressive effects. The purpose of this study was to investigate the potential dual role of IL-21 in experimental arthritis in relation to Th17 cells. METHODS: Antigen-induced arthritis (AIA) and chronic

  16. Intestinal Microbiota Promotes Psoriasis-Like Skin Inflammation by Enhancing Th17 Response.

    Directory of Open Access Journals (Sweden)

    Zuzana Zákostelská

    Full Text Available Psoriasis is a chronic inflammatory skin disease in which Th17 cells play a crucial role. Since indigenous gut microbiota influences the development and reactivity of immune cells, we analyzed the link among microbiota, T cells and the formation of psoriatic lesions in the imiquimod-induced murine model of psoriasis. To explore the role of microbiota, we induced skin inflammation in germ-free (GF, broad-spectrum antibiotic (ATB-treated or conventional (CV BALB/c and C57BL/6 mice. We found that both mice reared in GF conditions for several generations and CV mice treated with ATB were more resistant to imiquimod-induced skin inflammation than CV mice. The ATB treatment dramatically changed the diversity of gut bacteria, which remained stable after subsequent imiquimod application; ATB treatment resulted in a substantial increase in the order Lactobacillales and a significant decrease in Coriobacteriales and Clostridiales. Moreover, as compared to CV mice, imiquimod induced a lower degree of local and systemic Th17 activation in both GF and ATB-treated mice. These findings suggest that gut microbiota control imiquimod-induced skin inflammation by altering the T cell response.

  17. Differential expression of CD300a/c on human TH1 and TH17 cells

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    Borrego Francisco

    2011-11-01

    Full Text Available Abstract Background Human memory CD4+ T cells can be either CD300a/c+ or CD300a/c- and subsequent analyses showed that CD4+ effector memory T (TEM cells are mostly CD300a/c+, whereas CD4+ central memory T (TCM cells have similar frequencies of CD300a/c+ and CD300a/c- cells. Results Extensive phenotypical and functional characterization showed that in both TCM and TEM cells, the CD300a/c+ subset contained a higher number of TH1 (IFN-γ producing cells. Alternatively, TH17 (IL-17a producing cells tend to be CD300a/c-, especially in the TEM subset. Further characterization of the IL-17a+ cells showed that cells that produce only this cytokine are mostly CD300a/c-, while cells that produce IL-17a in combination with other cytokines, especially IFN-γ, are mostly CD300a/c+, indicating that the expression of this receptor is associated with cells that produce IFN-γ. Co-ligation of the TCR and CD300a/c in CD4+ T cells inhibited Ca2+ mobilization evoked by TCR ligation alone and modulated IFN-γ production on TH1 polarized cells. Conclusion We conclude that the CD300a/c receptors are differentially expressed on human TH1 and TH17 cells and that their ligation is capable of modulating TCR mediated signals.

  18. Enhanced Th17 phenotype in uninfected neonates born from viremic HIV-1-infected pregnant women.

    Science.gov (United States)

    Hygino, Joana; Vieira, Morgana M; Guillermo, Landi V; Silva-Filho, Renato G; Saramago, Carmen; Lima-Silva, Agostinho A; Andrade, Regis M; Andrade, Arnaldao F B; Brindeiro, Rodrigo M; Tanuri, Amilcar; Guimarães, Vander; de Melo Bento, Cleonice Alves

    2011-04-01

    Our objective was to evaluate the in vitro functional profile of T cells from uninfected neonates born from HIV-1-infected pregnant women who controlled (G1) or not (G2) the virus replication. We demonstrated that the lymphoproliferation of T cell to polyclonal activators was higher in the G2 as compared with G1. Nevertheless, no detectable proliferative response was observed in response to HIV-1 antigens in both neonate groups. Cytokine dosage in the supernatants of these polyclonally activated T cell cultures demonstrated that, while IL-10 was the dominant cytokine produced in G1, Th17-related cytokines were significantly higher in G2 neonates. The higher Th17 phenotype tendency in G2 was related to high production of IL-23 by lipopolysaccharide-activated monocyte-derived dendritic cells from these neonates. Our results demonstrated immunological disorders in uninfected neonates born from viremic HIV-1-infected mothers that can help to explain why some of these children have elevated risk of clinical morbidity and mortality due to pathological hypersensitivity.

  19. Th17 Cells and Activated Dendritic Cells Are Increased in Vitiligo Lesions

    Science.gov (United States)

    Fuentes-Duculan, Judilyn; Moussai, Dariush; Gulati, Nicholas; Sullivan-Whalen, Mary; Gilleaudeau, Patricia; Cohen, Jules A.; Krueger, James G.

    2011-01-01

    Background Vitiligo is a common skin disorder, characterized by progressive skin de-pigmentation due to the loss of cutaneous melanocytes. The exact cause of melanocyte loss remains unclear, but a large number of observations have pointed to the important role of cellular immunity in vitiligo pathogenesis. Methodology/Principal Findings In this study, we characterized T cell and inflammation-related dermal dendritic cell (DC) subsets in pigmented non-lesional, leading edge and depigmented lesional vitiligo skin. By immunohistochemistry staining, we observed enhanced populations of CD11c+ myeloid dermal DCs and CD207+ Langerhans cells in leading edge vitiligo biopsies. DC-LAMP+ and CD1c+ sub-populations of dermal DCs expanded significantly in leading edge and lesional vitiligo skin. We also detected elevated tissue mRNA levels of IL-17A in leading edge skin biopsies of vitiligo patients, as well as IL-17A positive T cells by immunohistochemistry and immunofluorescence. Langerhans cells with activated inflammasomes were also noted in lesional vitiligo skin, along with increased IL-1ß mRNA, which suggest the potential of Langerhans cells to drive Th17 activation in vitiligo. Conclusions/Significance These studies provided direct tissue evidence that implicates active Th17 cells in vitiligo skin lesions. We characterized new cellular immune elements, in the active margins of vitiligo lesions (e.g. populations of epidermal and dermal dendritic cells subsets), which could potentially drive the inflammatory responses. PMID:21541348

  20. Endurance exercise diverts the balance between Th17 cells and regulatory T cells.

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    Chava Perry

    Full Text Available Endurance, marathon-type exertion is known to induce adverse changes in the immune system. Increased airway hyper-responsiveness and airway inflammation are well documented in endurance athletes and endurance exercise is considered a major risk factor for asthma in elite athletes. Yet, the mechanisms underlying this phenomenon are still to be deduced. We studied the effect of strenuous endurance exercise (marathon and half-ironman triathlon on CD4+ lymphocyte sub-populations and on the balance between effector and regulatory CD4+ lymphocytes in the peripheral blood of trained athletes, Endurance exercise induced a significant increase in Th17 cells and a sustained decrease in peripheral blood regulatory T cells (Tregs. While interleukin (IL-2 levels remained undetectable, post-race serum IL-6 and transforming growth factor (TGF β levels were significantly elevated. Treg levels in sedentary controls' decreased in vitro after incubation with athletes' post-exercise serum, an effect that was attenuated by supplements of IL-2 or anti IL-6 neutralizing antibodies. Our data suggest that exercise-induced changes in serum cytokine levels promote alterations in Tregs and Th17 cell populations, which may divert the subtle balance in the immune system towards inflammation. This may explain allergic and autoimmune phenomena previously reported in endurance athletes and contribute to our understanding of exercise-related asthma.

  1. ST2 Requires Th2-, but Not Th17-, Type Airway Inflammation in Epicutaneously Antigen-Sensitized Mice

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    Hideaki Morita

    2012-01-01

    Conclusions: The IL-33/ST2 pathway is crucial for Th2-cytokine-mediated eosinophilic, rather than Th17-cytokine-mediated neutrophilic, airway inflammation in mice that had been epicutaneously sensitized with antigens and then challenged with antigen.

  2. Th17 responses and natural IgM antibodies are related to gut microbiota composition in systemic lupus erythematosus patients

    National Research Council Canada - National Science Library

    López, Patricia; de Paz, Banesa; Rodríguez-Carrio, Javier; Hevia, Arancha; Sánchez, Borja; Margolles, Abelardo; Suárez, Ana

    2016-01-01

    .... Enrichment of SLE-M with Treg-inducing bacteria showed that a mixture of two Clostridia strains significantly reduced the Th17/Th1 balance, whereas Bifidobacterium bifidum supplementation prevented CD4...

  3. Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection.

    Directory of Open Access Journals (Sweden)

    David Favre

    2009-02-01

    Full Text Available Chronic immune activation and progression to AIDS are observed after SIV infection in macaques but not in natural host primate species. To better understand this dichotomy, we compared acute pathogenic SIV infection in pigtailed macaques (PTs to non-pathogenic infection in African green monkeys (AGMs. SIVagm-infected PTs, but not SIVagm-infected AGMs, rapidly developed systemic immune activation, marked and selective depletion of IL-17-secreting (Th17 cells, and loss of the balance between Th17 and T regulatory (Treg cells in blood, lymphoid organs, and mucosal tissue. The loss of Th17 cells was found to be predictive of systemic and sustained T cell activation. Collectively, these data indicate that loss of the Th17 to Treg balance is related to SIV disease progression.

  4. Co-incubation with IL-18 potentiates antigen-specific IFN-γ response in a whole-blood stimulation assay for measurement of cell-mediated immune responses in pigs experimentally infected with Lawsonia intracellularis

    DEFF Research Database (Denmark)

    Riber, Ulla; Boesen, Henriette Toft; Jakobsen, Jeanne Toft

    2011-01-01

    The whole-blood interferon-gamma (IFN-γ) assay is a quantitative in-vitro assay for a direct read out of Ag-specific cell-mediated immune (CMI) responses to infectious diseases. The IFN-γ assay is robust in severe intracellular infections like Brucella or mycobacteria, but more difficult to evalu......The whole-blood interferon-gamma (IFN-γ) assay is a quantitative in-vitro assay for a direct read out of Ag-specific cell-mediated immune (CMI) responses to infectious diseases. The IFN-γ assay is robust in severe intracellular infections like Brucella or mycobacteria, but more difficult...

  5. [Alteration of Th17 cells, immunoglobins and complements levels in peripheral blood of patients with refractory recurrent aphthous ulcer].

    Science.gov (United States)

    Yang, Li-Lin; Wang, Wen-Mei; Liu, Ya-Jing; Jiang, Ting-Wang; Wang, Bei-Li

    2017-10-01

    To observe the levels of Th17 cells, immunoglobins and complements in peripheral blood of patients with refractory recurrent aphthous ulcer (refractory RAU) patients. Totally, 30 patients with refractory RAU and 21 healthy controls were enrolled into this study. Flow cytometry was performed to determine the frequency of Th17 cells in the peripheral blood. Immune scatter turbidimetry was adopted to measure the levels of IgA, IgG, IgM, IgE, C3 and C4 in the peripheral blood. Meanwhile, the correlations between the frequency of Th17 cells and the levels of immunoglobins or complements were analyzed. SPSS17.0 software package was used to analyze the date. Compared with the control group, the percentage of Th17 cells (CD3 + CD8 - IL17 + ) in all CD4 + T cells was significantly increased in the refractory RAU group (Prefractory RAU group were significantly higher than those in the control group (Prefractory RAU group and control group. There was negative correlation between the frequency of Th17 cells and the level of IgA (r=-0.477, Prefractory RAU patients are significantly different from healthy human, which may play an important role in the pathogenesis of refractory RAU. There may be some relationship between Th17 cells and the change of humoral immunity in refractory RAU.

  6. Changes and clinical significances of Th17 cells in the peripheral blood of patients with acute cerebral hemorrhage

    Directory of Open Access Journals (Sweden)

    ZHANG Li-tang

    2013-07-01

    Full Text Available This study aims to explore the changes and clinical significances of T helper 17 (Th17 cells in the peripheral blood of patients with acute cerebral hemorrhage. The percentage of Th17 cells were assessed by flow cytometry. The mRNA levels of retinoid-related orphan receptor γt (RORγt were detected by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR. The serum levels of interleukin-17 (IL-17 were measured by enzyme-linked immunosorbent assay (ELISA. According to the examination results, the percentage of Th17 cells, the mRNA expression of RORγt and the serum levels of IL-17 at 24 h, 3 d and 7 d increased significantly in patients with acute cerebral hemorrhage than in normal controls (P = 0.000, for all. Although the patients with acute cerebral hemorrhage had no significant differences in the percentage of Th17 cells, the mRNA expression of ROR γ t comparable with normal controls (P = 0.058, 0.239, the serum levels of IL-17 in patients were statistically higher than those in normal controls at 14 d (P = 0.000. The percentage of Th17 cells and the serum levels of IL-17 increase in the peripheral blood of patients with acute cerebral hemorrhage, suggesting Th17 cells may participate in the occurrence and development of cerebral hemorrhage.

  7. Reciprocity between Regulatory T Cells and Th17 Cells: Relevance to Polarized Immunity in Leprosy

    Science.gov (United States)

    Sadhu, Soumi; Khaitan, Binod Kumar; Joshi, Beenu; Sengupta, Utpal; Nautiyal, Arvind Kumar; Mitra, Dipendra Kumar

    2016-01-01

    T cell defect is a common feature in lepromatous or borderline lepromatous leprosy (LL/BL) patients in contrast to tuberculoid or borderline tuberculoid type (TT/BT) patients. Tuberculoid leprosy is characterized by strong Th1-type cell response with localized lesions whereas lepromatous leprosy is hallmarked by its selective Mycobacterium leprae specific T cell anergy leading to disseminated and progressive disease. FoxP3+ Regulatory T cells (Treg) which are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases also dampen proinflammatory T cells that include T helper 17 (Th17) cells. This study is aimed at evaluating the role of Treg cells in influencing other effector T cells and its relationship with the cytokine polarized state in leprosy patients. Peripheral blood mononuclear cells from of BT/TT (n = 15) and BL/LL (n = 15) patients were stimulated with M. leprae antigen (WCL) in presence of golgi transport inhibitor monensin for FACS based intracellular cytokine estimation. The frequency of Treg cells showed >5-fold increase in BL/LL in comparison to BT/TT and healthy contacts. These cells produced suppressive cytokine, IL-10 in BL/LL as opposed to BT/TT (p = 0.0200) indicating their suppressive function. The frequency of Th17 cells (CD4, CD45RO, IL-17) was, however, higher in BT/TT. Significant negative correlation (r = -0.68, P = 0.03) was also found between IL-10 of Treg cells and IL-17+ T cells in BL/LL. Blocking IL-10/TGF-β restored the IL-17+ T cells in BL/LL patients. Simultaneously, presence of Th17 related cytokines (TGF-β, IL-6, IL-17 and IL-23) decreased the number of FoxP3+ Treg cells concomitantly increasing IL-17 producing CD4+ cells in lepromatous leprosy. Higher frequency of Programmed Death-1/PD-1+ Treg cells and its ligand, PDL-1 in antigen presenting cells (APCs) was found in BL/LL patients. Inhibition of this pathway led to rescue of IFN-γ and IL-17 producing T cells

  8. Multiple Exposures to Ascaris suum Induce Tissue Injury and Mixed Th2/Th17 Immune Response in Mice.

    Science.gov (United States)

    Nogueira, Denise Silva; Gazzinelli-Guimarães, Pedro Henrique; Barbosa, Fernando Sérgio; Resende, Nathália Maria; Silva, Caroline Cavalcanti; de Oliveira, Luciana Maria; Amorim, Chiara Cássia Oliveira; Oliveira, Fabrício Marcus Silva; Mattos, Matheus Silvério; Kraemer, Lucas Rocha; Caliari, Marcelo Vidigal; Gaze, Soraya; Bueno, Lilian Lacerda; Russo, Remo Castro; Fujiwara, Ricardo Toshio

    2016-01-01

    Ascaris spp. infection affects 800 million people worldwide, and half of the world population is currently at risk of infection. Recurrent reinfection in humans is mostly due to the simplicity of the parasite life cycle, but the impact of multiple exposures to the biology of the infection and the consequences to the host's homeostasis are poorly understood. In this context, single and multiple exposures in mice were performed in order to characterize the parasitological, histopathological, tissue functional and immunological aspects of experimental larval ascariasis. The most important findings revealed that reinfected mice presented a significant reduction of parasite burden in the lung and an increase in the cellularity in the bronchoalveolar lavage (BAL) associated with a robust granulocytic pulmonary inflammation, leading to a severe impairment of respiratory function. Moreover, the multiple exposures to Ascaris elicited an increased number of circulating inflammatory cells as well as production of higher levels of systemic cytokines, mainly IL-4, IL-5, IL-6, IL-10, IL-17A and TNF-α when compared to single-infected animals. Taken together, our results suggest the intense pulmonary inflammation associated with a polarized systemic Th2/Th17 immune response are crucial to control larval migration after multiple exposures to Ascaris.

  9. Multiple Exposures to Ascaris suum Induce Tissue Injury and Mixed Th2/Th17 Immune Response in Mice.

    Directory of Open Access Journals (Sweden)

    Denise Silva Nogueira

    2016-01-01

    Full Text Available Ascaris spp. infection affects 800 million people worldwide, and half of the world population is currently at risk of infection. Recurrent reinfection in humans is mostly due to the simplicity of the parasite life cycle, but the impact of multiple exposures to the biology of the infection and the consequences to the host's homeostasis are poorly understood. In this context, single and multiple exposures in mice were performed in order to characterize the parasitological, histopathological, tissue functional and immunological aspects of experimental larval ascariasis. The most important findings revealed that reinfected mice presented a significant reduction of parasite burden in the lung and an increase in the cellularity in the bronchoalveolar lavage (BAL associated with a robust granulocytic pulmonary inflammation, leading to a severe impairment of respiratory function. Moreover, the multiple exposures to Ascaris elicited an increased number of circulating inflammatory cells as well as production of higher levels of systemic cytokines, mainly IL-4, IL-5, IL-6, IL-10, IL-17A and TNF-α when compared to single-infected animals. Taken together, our results suggest the intense pulmonary inflammation associated with a polarized systemic Th2/Th17 immune response are crucial to control larval migration after multiple exposures to Ascaris.

  10. Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development.

    Directory of Open Access Journals (Sweden)

    Seung-Joo Lee

    2012-01-01

    Full Text Available Pathogens can substantially alter gene expression within an infected host depending on metabolic or virulence requirements in different tissues, however, the effect of these alterations on host immunity are unclear. Here we visualized multiple CD4 T cell responses to temporally expressed proteins in Salmonella-infected mice. Flagellin-specific CD4 T cells expanded and contracted early, differentiated into Th1 and Th17 lineages, and were enriched in mucosal tissues after oral infection. In contrast, CD4 T cells responding to Salmonella Type-III Secretion System (TTSS effectors steadily accumulated until bacterial clearance was achieved, primarily differentiated into Th1 cells, and were predominantly detected in systemic tissues. Thus, pathogen regulation of antigen expression plays a major role in orchestrating the expansion, differentiation, and location of antigen-specific CD4 T cells in vivo.

  11. Ustekinumab in Psoriasis Immunopathology with Emphasis on the Th17-IL23 Axis: A Primer

    Directory of Open Access Journals (Sweden)

    Pascale Quatresooz

    2012-01-01

    Full Text Available Psoriasis is a chronic relapsing immunoinflammatory dermatosis that is commonly associated with systemic comorbidities. The pathogenic importance of interleukin (IL-12 and IL-23 is beyond doubt, as well as the involvement of T helper cells (Th1 and Th17 cells. There is upregulation of the p40 subunit shared by IL-12 and IL-23 and of the IL-23 p19 subunit, but not an increased expression of the IL-12 p35 subunit. This indicates that IL-23 appears more involved than IL-12 in the pathogenesis of psoriatic plaques. Ustekinumab is a fully human monoclonal antibody of the immunoglobulin (Ig G1 class targeting the p40 subunit common to both IL-12 and IL-23, thus inhibiting both IL-12 and IL-23 receptor-mediated signalling. Ustekinumab is part of the recent biologic therapies active in psoriasis, autoimmune arthritides, and inflammatory bowel diseases.

  12. Reconstitution of Th17, Tc17 and Treg cells after paediatric haematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Kielsen, Katrine; Ryder, Lars P; Lennox-Hvenekilde, David

    2018-01-01

    Successful reconstitution of T lymphocytes after allogeneic haematopoietic stem cell transplantation (HSCT) is needed to establish the graft-versus-leukaemia effect and an effective anti-microbial defense, but the ratio between functionally different T-cell subsets needs to be balanced to avoid...... behind these associations have not been investigated previously. We hypothesized that increased levels of IL-7 post-transplant alters the balance between immune-regulatory T cell subsets during the post-transplant lymphocyte recovery towards a more pro-inflammatory profile. We quantified Th17 cells, Tc17...... graft-versus-host disease (GVHD). IL-7 is essential for T-cell generation in the thymus and peripheral T-cell homeostasis. High IL-7 levels have been associated with impaired T-cell reconstitution, increased risk of acute GVHD and treatment-related mortality, but the underlying cellular mechanisms...

  13. Omeprazole-induced acute interstitial nephritis: a possible Th1-Th17-mediated injury?

    Science.gov (United States)

    Berney-Meyer, Linda; Hung, Noelyn; Slatter, Tania; Schollum, John Bw; Kitching, A Richard; Walker, Robert J

    2014-06-01

    Omeprazole is an important cause of drug-induced acute interstitial nephritis (AIN). How omeprazole induces injury is unknown. Detailed clinical assessment of 25 biopsy-proven cases of omeprazole-induced AIN showed that all patients presented with impaired renal function, sterile pyuria with varying amounts of proteinuria but no eosinophiluria and no systemic symptoms to suggest a vasculitis. Histological analyses were characteristic of an acute tubulitis with an inflammatory cellular infiltrate. Using modified Banff scheme criteria, mild tubulitis (t1) was present in 56% of cases, a moderate tubulitis (t2) in 24% of cases, and a severe tubulitis in 20% of cases. Most (78%) of cases had mononuclear cell infiltrates, no significant eosinophilic infiltrates were found, and glomeruli were not involved. Immunostaining for CD4, CD8, IL-17A, IL-17F, Foxp3 and T-bet (T cell subsets), CD20 and CD163 defined the cellular infiltrates. The predominant inflammatory cells were CD4+ lymphocytic aggregates (77% of cases), combined with co-staining of CD4 IL and 17A/F in 44-48% of all cases, suggesting a Th17-mediated inflammatory process. T-bet+ cell infiltrates were present to a lesser degree, suggesting additional Th1 involvement. How omeprazole induces this inflammatory response is unclear, but may include direct effects by IL-17 expressing CD4+ cells on renal tubular cells. This large biopsy series of omeprazole-induced AIN demonstrates the features of acute tubulitis, with significant interstitial infiltrates consistent with immunopathological Th17 and Th1 processes. © 2014 Asian Pacific Society of Nephrology.

  14. Intranasal vaccination promotes detrimental Th17-mediated immunity against influenza infection.

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    Asher Maroof

    2014-01-01

    Full Text Available Influenza disease is a global health issue that causes significant morbidity and mortality through seasonal epidemics. Currently, inactivated influenza virus vaccines given intramuscularly or live attenuated influenza virus vaccines administered intranasally are the only approved options for vaccination against influenza virus in humans. We evaluated the efficacy of a synthetic toll-like receptor 4 agonist CRX-601 as an adjuvant for enhancing vaccine-induced protection against influenza infection. Intranasal administration of CRX-601 adjuvant combined with detergent split-influenza antigen (A/Uruguay/716/2007 (H3N2 generated strong local and systemic immunity against co-administered influenza antigens while exhibiting high efficacy against two heterotypic influenza challenges. Intranasal vaccination with CRX-601 adjuvanted vaccines promoted antigen-specific IgG and IgA antibody responses and the generation of polyfunctional antigen-specific Th17 cells (CD4(+IL-17A(+TNFα(+. Following challenge with influenza virus, vaccinated mice transiently exhibited increased weight loss and morbidity during early stages of disease but eventually controlled infection. This disease exacerbation following influenza infection in vaccinated mice was dependent on both the route of vaccination and the addition of the adjuvant. Neutralization of IL-17A confirmed a detrimental role for this cytokine during influenza infection. The expansion of vaccine-primed Th17 cells during influenza infection was also accompanied by an augmented lung neutrophilic response, which was partially responsible for mediating the increased morbidity. This discovery is of significance in the field of vaccinology, as it highlights the importance of both route of vaccination and adjuvant selection in vaccine development.

  15. Dynamics of Th17 cells and their role in Schistosoma japonicum infection in C57BL/6 mice.

    Directory of Open Access Journals (Sweden)

    Xiaoyun Wen

    2011-11-01

    Full Text Available BACKGROUND: The current knowledge of immunological responses to schistosomiasis, a major tropical helminthic disease, is insufficient, and a better understanding of these responses would support vaccine development or therapies to control granuloma-associated immunopathology. CD4(+ T cells play critical roles in both host immune responses against parasitic infection and immunopathology in schistosomiasis. The induction of T helper (Th1, Th2 and T regulatory (Treg cells and their roles in schistosome infections are well-illustrated. However, little in vivo data are available on the dynamics of Th17 cells, another important CD4(+ T cell subset, after Schistosoma japonicum infection or whether these cells and their defining IL-17 cytokine mediate host protective responses early in infection. METHODOLOGY: Levels of Th17 and the other three CD4(+ T cell subpopulations and the cytokines related to induction or repression of Th17 cell generation in different stages of S. japonicum infection were observed. Contrary to reported in vitro studies, our results showed that the Th17 cells were induced along with the Th1, Th2, Treg cells and the IFN-γ and IL-4 cytokines in S. japonicum infected mice. The results also suggested that S. japonicum egg antigens but not adult worm antigens preferentially induced Th17 cell generation. Furthermore, decreasing IL-17 with a neutralizing anti-IL-17 monoclonal antibody (mAb increased schistosome-specific antibody levels and partial protection against S. japonicum infection in mice. CONCLUSIONS: Our study is the first to report the dynamics of Th17 cells during S. japonicum infection and indicate that Th17 cell differentiation results from the integrated impact of inducing and suppressive factors promoted by the parasite. Importantly, our findings suggest that lower IL-17 levels may result in favorable host protective responses. This study significantly contributes to the understanding of immunity to schistosomiasis and

  16. Dynamics of Th17 cells and their role in Schistosoma japonicum infection in C57BL/6 mice.

    Science.gov (United States)

    Wen, Xiaoyun; He, Lei; Chi, Ying; Zhou, Sha; Hoellwarth, Jason; Zhang, Cui; Zhu, Jifeng; Wu, Calvin; Dhesi, Shawn; Wang, Xuefeng; Liu, Feng; Su, Chuan

    2011-11-01

    The current knowledge of immunological responses to schistosomiasis, a major tropical helminthic disease, is insufficient, and a better understanding of these responses would support vaccine development or therapies to control granuloma-associated immunopathology. CD4(+) T cells play critical roles in both host immune responses against parasitic infection and immunopathology in schistosomiasis. The induction of T helper (Th)1, Th2 and T regulatory (Treg) cells and their roles in schistosome infections are well-illustrated. However, little in vivo data are available on the dynamics of Th17 cells, another important CD4(+) T cell subset, after Schistosoma japonicum infection or whether these cells and their defining IL-17 cytokine mediate host protective responses early in infection. Levels of Th17 and the other three CD4(+) T cell subpopulations and the cytokines related to induction or repression of Th17 cell generation in different stages of S. japonicum infection were observed. Contrary to reported in vitro studies, our results showed that the Th17 cells were induced along with the Th1, Th2, Treg cells and the IFN-γ and IL-4 cytokines in S. japonicum infected mice. The results also suggested that S. japonicum egg antigens but not adult worm antigens preferentially induced Th17 cell generation. Furthermore, decreasing IL-17 with a neutralizing anti-IL-17 monoclonal antibody (mAb) increased schistosome-specific antibody levels and partial protection against S. japonicum infection in mice. Our study is the first to report the dynamics of Th17 cells during S. japonicum infection and indicate that Th17 cell differentiation results from the integrated impact of inducing and suppressive factors promoted by the parasite. Importantly, our findings suggest that lower IL-17 levels may result in favorable host protective responses. This study significantly contributes to the understanding of immunity to schistosomiasis and may aid in developing interventions to protect hosts

  17. Intercellular adhesion molecule 1 mediates migration of Th1 and Th17 cells across human retinal vascular endothelium.

    Science.gov (United States)

    Bharadwaj, Arpita S; Schewitz-Bowers, Lauren P; Wei, Lai; Lee, Richard W J; Smith, Justine R

    2013-10-23

    Autoimmune inflammation of the retina causes vision loss in the majority of affected individuals. Th1 or Th17 cells initiate the disease on trafficking from the circulation into the eye across the retinal vascular endothelium. We investigated the ability of human Th1- and Th17-polarized cells to cross a simulated human retinal endothelium, and examined the role of IgG superfamily members in this process. Th1- and Th17-polarized cell populations were generated from human peripheral blood CD4(+) T cells, using two Th1- and Th17-polarizing protocols. Transendothelial migration assays were performed over 18 hours in Boyden chambers, after seeding the transwell membrane with human retinal endothelial cells. In some assays intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), or activated leukocyte cell adhesion molecule (ALCAM) blocking antibody, or isotype- and concentration-matched control antibody, was added to the upper chambers. Th1- and Th17-polarized cells migrated equally efficiently across the human retinal endothelial monolayer. The percentage of IL-17(+) IFN-γ(-) Th17-polarized cells was reduced following migration. Blocking ICAM-1, but not VCAM-1 or ALCAM, significantly reduced migration of Th1- and Th17-polarized cells for a majority of human donors. Taken in the context of other literature on transendothelial migration, our results illustrate the importance of investigating the specific tissue and vascular endothelium when considering helper T cell migration in autoimmune inflammation. Our findings further indicate that while generalizations about involvement of specific adhesion molecules in uveitis and other autoimmune disease may be possible, these may not apply to individual patients universally. The observations are relevant to the use of adhesion blockade for therapeutic purposes.

  18. Persistence of Th17/Tc17 Cell Expression upon Smoking Cessation in Mice with Cigarette Smoke-Induced Emphysema

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    Min-Chao Duan

    2013-01-01

    Full Text Available Th17 and Tc17 cells may be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD, a disease caused predominantly by cigarette smoking. Smoking cessation is the only intervention in the management of COPD. However, even after cessation, the airway inflammation may be present. In the current study, mice were exposed to room air or cigarette smoke for 24 weeks or 24 weeks followed by 12 weeks of cessation. Morphological changes were evaluated by mean linear intercepts (Lm and destructive index (DI. The frequencies of CD8+IL-17+(Tc17 and CD4+IL-17+(Th17 cells, the mRNA levels of ROR gamma and IL-17, and the levels of IL-8, TNF-alpha, and IFN-gamma in lungs or bronchoalveolar lavage fluid of mice were assayed. Here we demonstrated that alveolar enlargement and destruction induced by cigarette smoke exposure were irreversible and that cigarette smokeenhanced these T-cell subsets, and related cytokines were not significantly reduced after smoking cessation. In addition, the frequencies of Th17 and Tc17 cells in lungs of smoke-exposed mice and cessation mice were positively correlated with emphysematous lesions. More important, the frequencies of Tc17 cells were much higher than Th17 cells, and there was a significantly positive correlation between Th17 and Tc17. These results suggested that Th17/Tc17 infiltration in lungs may play a critical role in sustaining lung inflammation in emphysema. Blocking the abnormally increased numbers of Tc17 and Th17 cells may be a reasonable therapeutic strategy for emphysema.

  19. Expansion of IL-6(+) Th17-like cells expressing TLRs correlates with microbial translocation and neurological disabilities in NMOSD patients.

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    Barros, Priscila O; Dias, Aleida S O; Kasahara, Taissa M; Ornelas, Alice M M; Aguiar, Renato S; Leon, Soniza A; Ruiz, Anne; Marignier, Romain; Araújo, Ana Carolina R A; Alvarenga, Regina; Bento, Cleonice A M

    2017-06-15

    Different microbial antigens, by signaling through toll-like receptors (TLR), may contribute to Th17-mediated autoimmune diseases, such as neuromyelitis optica spectrum disorder (NMOSD). The objective of this study was to determine the proportion of different Th17-like cell subsets that express TLR in NMOSD patients. For this study, the frequency of different Th17 cell subsets expressing TLR subsets in healthy individuals (n=20) and NMOSD patients (n=20) was evaluated by cytometry. The peripheral levels of soluble CD14 (sCD14) and cytokines were determined by ELISA. Our results demonstrated that the proportion of peripheral CD4(+) T cells expressing TLR2, 4 and 9 was significantly higher in NMOSD samples than in healthy subjects. In NMOSD, these cells are CD28(+)PD-1(-)CD57(-) and produce elevated levels of IL-17. Among different TLRs(+) Th17-like subsets, the proportion of those that co-express IL-17 and IL-6 was significantly higher in NMOSD patients, which was positively correlated with sCD14 levels and EDSS score. By contrast, the percentage of TLRs(+)Treg17 cells (IL-10(+)IL-17(+)) was negatively related to sCD14 and the severity of NMOSD. In conclusion, the expansion of peripheral IL-6-producing TLR(+) Th17-like cells in NMOSD patients was associated with both bacterial translocation and disease severity. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Increased Th1/Th17 Responses Contribute to Low-Grade Inflammation in Age-Related Macular Degeneration.

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    Chen, Jiajia; Wang, Wenzhan; Li, Qiuming

    2017-01-01

    Age-related macular degeneration (AMD) is the primary cause of senior blindness in developed countries. Mechanisms underlying initiation and development of AMD remained known. We examined the CD4+ T cell compartments and their functions in AMD patients. AMD patients presented significantly higher frequencies of interferon (IFN)-γ-expressing and interleukin (IL)-17-expressing CD4+ T cells than healthy controls. The levels of IFN-γ and IL-17 expression by CD4+ T cells were significantly higher in AMD patients. These IFN-γ-expressing Th1 cells and IL-17-expressing Th17 cells could be selectively enriched by surface CCR3+ and CCR4+CCR6+ expression, respectively. Th1 and Th17 cells from AMD patients promoted the differentiation of monocytes toward M1 macrophages, which were previously associated with retinal damage. Th1 and Th17 cells also increased the level of MHC class I expression in human retinal pigment epithelial (RPE)-1 cells, while Th1 cells increased the frequency of MHC class II-expressing RPE-1 cells. These proinflammatory effects were partly, but not entirely, induced by the secretion of IFN-γ and IL-17. This study demonstrated an enrichment of Th1 cells and Th17 cells in AMD patients. These Th1 and Th17 cells possessed proinflammatory roles in an IFN-γ- and IL-17-dependent fashion, and could potentially serve as therapeutic targets. © 2017 The Author(s). Published by S. Karger AG, Basel.

  1. Increased Th1/Th17 Responses Contribute to Low-Grade Inflammation in Age-Related Macular Degeneration

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    Jiajia Chen

    2017-11-01

    Full Text Available Background/Aims: Age-related macular degeneration (AMD is the primary cause of senior blindness in developed countries. Mechanisms underlying initiation and development of AMD remained known. Methods: We examined the CD4+ T cell compartments and their functions in AMD patients. Results: AMD patients presented significantly higher frequencies of interferon (IFN-γ-expressing and interleukin (IL-17-expressing CD4+ T cells than healthy controls. The levels of IFN-γ and IL-17 expression by CD4+ T cells were significantly higher in AMD patients. These IFN-γ-expressing Th1 cells and IL-17-expressing Th17 cells could be selectively enriched by surface CCR3+ and CCR4+CCR6+ expression, respectively. Th1 and Th17 cells from AMD patients promoted the differentiation of monocytes toward M1 macrophages, which were previously associated with retinal damage. Th1 and Th17 cells also increased the level of MHC class I expression in human retinal pigment epithelial (RPE-1 cells, while Th1 cells increased the frequency of MHC class II-expressing RPE-1 cells. These proinflammatory effects were partly, but not entirely, induced by the secretion of IFN-γ and IL-17. Conclusions: This study demonstrated an enrichment of Th1 cells and Th17 cells in AMD patients. These Th1 and Th17 cells possessed proinflammatory roles in an IFN-γ- and IL-17-dependent fashion, and could potentially serve as therapeutic targets.

  2. Th17 Cells Exhibit Antitumor Effects in MDS Possibly through Augmenting Functions of CD8+ T Cells.

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    Li, Jing; Yue, Lanzhu; Wang, Huaquan; Liu, Chunyan; Liu, Hui; Tao, Jinglian; Qi, Weiwei; Wang, Yihao; Zhang, Wei; Fu, Rong; Shao, Zonghong

    2016-01-01

    Th17 cells are a newly found subset of distinct CD4+ Th effector cells' family and are found to play an important role in cancers. Myelodysplastic syndromes (MDS) are a common malignant hematological disease. Here, we showed that both the percentage and the function of Th17 cells were elevated in low-risk MDS while being decreased in high-risk MDS. Levels of upstream molecules of Th17 cells, IL-6 and IL-23, were higher in low-risk MDS but lower in high-risk MDS patients. The abnormal percentage of Th17 cells was closely related to clinical parameters including karyotype, morphologic blast percentage of bone marrow, peripheral absolute neutrophil count, and hemoglobin concentration. Furthermore, expression rates of perforin and granzyme B in BM CD3+CD8+ cells (cytotoxic T lymphocyte, CTL) positively correlated with levels of IL-17 but negatively correlated with BM blast percentage and could be significantly increased after stimulation with human recombinant IL-17 (rhIL-17). Our results suggested that Th17 cells might play an antitumor effect in the pathogenesis of MDS through IL-17/CTL pathway.

  3. 3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation.

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    Okano, Takaichi; Saegusa, Jun; Nishimura, Keisuke; Takahashi, Soshi; Sendo, Sho; Ueda, Yo; Morinobu, Akio

    2017-02-10

    Recent studies have shown that cellular metabolism plays an important role in regulating immune cell functions. In immune cell differentiation, both interleukin-17-producing T (Th17) cells and dendritic cells (DCs) exhibit increased glycolysis through the upregulation of glycolytic enzymes, such as hexokinase-2 (HK2). Blocking glycolysis with 2-deoxyglucose was recently shown to inhibit Th17 cell differentiation while promoting regulatory T (Treg) cell generation. However, 2-DG inhibits all isoforms of HK. Thus, it is unclear which isoform has a critical role in Th17 cell differentiation and in rheumatoid arthritis (RA) pathogenesis. Here we demonstrated that 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased the arthritis scores and the histological scores in SKG mice, with a significant increase in Treg cells, decrease in Th17 cells, and decrease in activated DCs in the spleen. In vitro, BrPA facilitated the differentiation of Treg cells, suppressed Th17 cells, and inhibited the activation of DCs. These results suggested that BrPA may be a therapeutic target of murine arthritis. Although the role of IL-17 is not clarified in the treatment of RA, targeting cell metabolism to alter the immune cell functions might lead to a new therapeutic strategy for RA.

  4. BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice.

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    Cheung, Kalung; Lu, Geming; Sharma, Rajal; Vincek, Adam; Zhang, Ruihua; Plotnikov, Alexander N; Zhang, Fan; Zhang, Qiang; Ju, Ying; Hu, Yuan; Zhao, Li; Han, Xinye; Meslamani, Jamel; Xu, Feihong; Jaganathan, Anbalagan; Shen, Tong; Zhu, Hongfa; Rusinova, Elena; Zeng, Lei; Zhou, Jiachi; Yang, Jianjun; Peng, Liang; Ohlmeyer, Michael; Walsh, Martin J; Zhang, David Y; Xiong, Huabao; Zhou, Ming-Ming

    2017-03-14

    T-helper 17 (Th17) cells have important functions in adaptor immunity and have also been implicated in inflammatory disorders. The bromodomain and extraterminal domain (BET) family proteins regulate gene transcription during lineage-specific differentiation of naïve CD4(+) T cells to produce mature T-helper cells. Inhibition of acetyl-lysine binding of the BET proteins by pan-BET bromodomain (BrD) inhibitors, such as JQ1, broadly affects differentiation of Th17, Th1, and Th2 cells that have distinct immune functions, thus limiting their therapeutic potential. Whether these BET proteins represent viable new epigenetic drug targets for inflammatory disorders has remained an unanswered question. In this study, we report that selective inhibition of the first bromodomain of BET proteins with our newly designed small molecule MS402 inhibits primarily Th17 cell differentiation with a little or almost no effect on Th1 or Th2 and Treg cells. MS402 preferentially renders Brd4 binding to Th17 signature gene loci over those of housekeeping genes and reduces Brd4 recruitment of p-TEFb to phosphorylate and activate RNA polymerase II for transcription elongation. We further show that MS402 prevents and ameliorates T-cell transfer-induced colitis in mice by blocking Th17 cell overdevelopment. Thus, selective pharmacological modulation of individual bromodomains likely represents a strategy for treatment of inflammatory bowel diseases.

  5. Immune response of Th17-associated cytokines by peripheral blood mononuclear cells from patients with chronic hepatitis C virus infection.

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    Cabral, Milena S; Santos, Taciana P S; Santos, Priscila L; Schinoni, Maria Isabel; Oliveira, Isabela S; Pereira, Ariana B; Atta, Ajax M; Sousa-Atta, Maria Luiza B

    2017-09-29

    Hepatitis C virus (HCV) chronic infection causes severe cellular immune dysfunction. Here, we investigated the production of Th17-associated cytokines by peripheral blood mononuclear cells (PBMCs) of untreated patients with HCV, patients presenting an early virologic response (EVR) after 12weeks of treatment with interferon-α plus ribavirin with or without HCV protease inhibitors, and patients who were nonresponders to HCV therapy. PBMCs were stimulated with HCV core and nonstructural antigens, and the production of Th17-associated cytokines was measured with a Milliplex MAP immunoassay. Core-stimulated PBMCs from both untreated and nonresponder patients produced interleukin (IL)-17A, and vigorous production of IL-17A in response to NS3 antigen was only verified in the untreated group. Nonresponder patients also produced IL-17F after core antigen stimulation. IL-21 production was unaltered in the three groups of patients, whereas IL-17E and IL-22 were not detected. The production of Th17 cytokines by cells from patients showing an EVR was insignificant. IL-17A and IL-17F levels were not correlated with alanine aminotransferase levels or viremia. However, advanced fibrosis was associated with higher IL-17A production in T0 cells stimulated with core antigen. Untreated patients with HCV and patients who were nonresponders to antiviral treatment differed in their PBMC immune responses of Th17-associated cytokines. The early virological response to antiviral treatment dramatically decreased Th17 immune responses to HCV antigens. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Induced Treg Cells Augment the Th17-Mediated Intestinal Inflammatory Response in a CTLA4-Dependent Manner.

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    Nobumasa Watanabe

    Full Text Available Th17 cells and Foxp3+ regulatory T cells (Tregs are thought to promote and suppress inflammatory responses, respectively. However, whether they counteract each other or synergize in regulating immune reactions remains controversial. To determine their interactions, we describe the results of experiments employing mouse models of intestinal inflammation by transferring antigen-specific Th cells (Th1, Th2, and Th17 differentiated in vitro followed by the administration of the cognate antigen via enema. We show that cotransfer of induced Tregs (iTregs suppressed Th1- and Th2-mediated colon inflammation. In contrast, colon inflammation induced by transfer of Th17 cells, was augmented by the cotransfer of iTregs. Furthermore, oral delivery of antigen potentiated Th17-mediated colon inflammation. Administration of a blocking antibody against cytotoxic T lymphocyte-associated antigen 4 (CTLA4 abrogated the effects of cotransfer of iTregs, while the injection of a soluble recombinant immunoglobulin (Ig fusion protein, CTLA4-Ig substituted for the cotransfer of iTregs. These results suggest that antigen-specific activation of iTregs in a local environment stimulates the Th17-mediated inflammatory response in a CTLA4-dependent manner.

  7. IL-27 controls the development of inducible regulatory T cells and Th17 cells via differential effects on STAT1.

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    Neufert, Clemens; Becker, Christoph; Wirtz, Stefan; Fantini, Massimo C; Weigmann, Benno; Galle, Peter R; Neurath, Markus F

    2007-07-01

    IL-27 is an IL-12-related cytokine frequently present at sites of inflammation that can promote both anti- and pro-inflammatory immune responses. Here, we have analyzed the mechanisms how IL-27 may drive such divergent immune responses. While IL-27 suppressed the development of proinflammatory Th17 cells, a novel role for this cytokine in inhibiting the development of anti-inflammatory, inducible regulatory T cells (iTreg) was identified. In fact, IL-27 suppressed the development of adaptive, TGF-beta-induced Forkhead box transcription factor p3-positive (Foxp3(+)) Treg. Whereas the blockade of Th17 development was dependent on the transcription factor STAT1, the suppression of iTreg development was STAT1 independent, suggesting that IL-27 utilizes different signaling pathways to shape T cell-driven immune responses. Our data thus demonstrate that IL-27 controls the development of Th17 and iTreg cells via differential effects on STAT1.

  8. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis.

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    Abdul M Tyagi

    Full Text Available Th17 cells produce IL-17, and the latter promotes bone loss in collagen-induced arthritis in mice. Blocking IL-17 action in mouse model of rheumatoid arthritis reduces disease symptoms. These observations suggest that Th17 cells may be involved in the pathogenesis of bone loss. However, the role of Th17 cell in estrogen (E2 deficiency-induced bone loss is still not very clear. We investigated the effect of E2 on Th17 differentiation in vivo and IL-17 mediated regulation of osteoclast and osteoblast differentiation. Additionally, effect of IL-17 functional block under E2 deficiency-induced bone loss was studied. In murine bone marrow cells, E2 suppressed IL-17 mediated osteoclast differentiation. IL-17 inhibited formation of mineralized nodules in osteoblasts and this effect was suppressed by E2. E2 treatment to mouse calvarial osteoblasts inhibited the IL-17-induced production of osteoclastogenic cytokines and NF-kB translocation. In ovariectomized mice, there was increase in the number of Th17 cells, transcription factors promoting Th17 cell differentiation and circulating IL-17 levels. These effects were reversed by E2 supplementation. Treatment of neutralizing IL-17 monoclonal antibody to Ovx mice mitigated the E2 deficiency-induced trabecular bone loss and reversed the decreased osteoprotegerin-to-receptor activator of nuclear factor kappa B ligand (RANKL transcript levels in long bones, increased osteoclast differentiation from the bone marrow precursor cells and decreased osteoblast differentiation from the bone marrow stromal cells. Our findings indicate that E2 deficiency leads to increased differentiation of Th17 cells with attendant up regulation of STAT3, ROR-γt and ROR-α and downregulation of Foxp3 which antagonizes Th17 cell differentiation. Increased IL-17 production in turn induces bone loss by increasing pro-osteoclastogenic cytokines including TNF-α, IL-6 and RANKL from osteoblasts and functional block of IL-17 prevents bone

  9. Tangeretin has anti-asthmatic effects via regulating PI3K and Notch signaling and modulating Th1/Th2/Th17 cytokine balance in neonatal asthmatic mice

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    L.-L. Liu

    Full Text Available Asthma is a chronic allergic disease characterized by airway inflammation, airway hyper-responsiveness (AHR, and mucus hypersecretion. T-lymphocytes are involved in the pathogenesis of asthma, mediating airway inflammatory reactions by secreting cytokines. The phosphoinositide 3-kinase (PI3K and Notch signaling pathways are associated with T cell signaling, proliferation, and differentiation, and are important in the progression of asthma. Thus, compounds that can modulate T cell proliferation and function may be of clinical value. Here, we assessed the effects of tangeretin, a plant-derived flavonoid, in experimental asthma. BALB/c mice at postnatal day (P 12 were challenged with ovalbumin (OVA. Separate groups of mice (n=18/group were administered tangeretin at 25 or 50 mg/kg body weight by oral gavage. Dexamethasone was used as a positive control. Tangeretin treatment reduced inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF and also restored the normal histology of lung tissues. OVA-specific IgE levels in serum and BALF were reduced. AHR, as determined by airway resistance and lung compliance, was normalized. Flow cytometry analyses revealed a reduced Th17 cell population. Tangeretin reduced the levels of Th2 and Th17 cytokines and raised IFN-γ levels. PI3K signaling was inhibited. The expressions of the Notch 1 receptor and its ligands Jagged 1 and 2 were downregulated by tangeretin. Our findings support the possible use of tangeretin for treating allergic asthma.

  10. ZSTK474, a novel PI3K inhibitor, modulates human CD14+ monocyte-derived dendritic cell functions and suppresses experimental autoimmune encephalomyelitis.

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    Xue, Zhenyi; Li, Wen; Wang, Huafeng; Huang, Biao; Ge, Zhenzhen; Gu, Chao; Liu, Ying; Zhang, Kai; Yang, Juhong; Han, Rong; Peng, Meiyu; Li, Yan; Zhang, Da; Da, Yurong; Yao, Zhi; Zhang, Rongxin

    2014-10-01

    ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine] is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor that exhibits potent antitumor effects. Recent studies have shown that ZSTK474 is also with anti-inflammatory properties in collagen-induced arthritis. However, the effects of ZSTK474 on dendritic cells and inflammatory Th17 cell-mediated autoimmune central nervous system inflammation are not understood. In this study, we demonstrated that ZSTK474 suppressed human CD14(+) monocyte-derived dendritic cell differentiation, maturation, and endocytosis, and further inhibited the stimulatory function of mature dendritic cell on allogeneic T cell proliferation. In addition, ZSTK474 inhibited the expression of dendritic cell-derived Th1 and Th17 cells polarizing cytokines interferon-γ/interleukin (IL)-12 and IL-6/IL-23. Furthermore, our results indicated that the in vivo administration of ZSTK474, which targets the dendritic cell and inflammatory Th1 and Th17 cell, led to a reduction of clinical score, central nervous system inflammation, and demyelination of mouse experimental autoimmune encephalomyelitis. Therefore, ZSTK474 significantly suppressed the human CD14(+) monocyte-derived dendritic cell functions and ameliorated mouse experimental autoimmune encephalomyelitis. We further found that ZSTK474 inhibited the phosphorylation of PI3K downstream signaling Akt and glycogen synthase kinase 3 beta in the dendritic cell. These data suggested that ZSTK474 exerted potent anti-inflammatory and immunosuppressive properties via PI3K signaling and may serve as a potential therapeutic drug for multiple sclerosis and other autoimmune inflammatory diseases. Key messages: STK474 inhibits dendritic cell (DC) differentiation and maturation. ZSTK474 inhibits DC-derived Th1 and Th17-polarizing cytokines. ZSTK474 ameliorates EAE and suppresses DCs, Th1, and Th17 cells in EAE. ZSTK474 reduces CNS inflammation and demyelination of EAE mice. ZSTK474

  11. Local Th17/IgA immunity correlate with protection against intranasal infection with Streptococcus pyogenes.

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    Rasmus Mortensen

    Full Text Available Streptococcus pyogenes (group A streptococcus, GAS is responsible for a wide array of infections. Respiratory transmission via droplets is the most common mode of transmission but it may also infect the host via other routes such as lesions in the skin. To advance the development of a future vaccine against GAS, it is therefore important to investigate how protective immunity is related to the route of vaccine administration. To explore this, we examined whether a parenterally administered anti-GAS vaccine could protect against an intranasal GAS infection or if this would require locally primed immunity. We foundd that a parenteral CAF01 adjuvanted GAS vaccine offered no protection against intranasal infection despite inducing strong systemic Th1/Th17/IgG immunity that efficiently protected against an intraperitoneal GAS infection. However, the same vaccine administered via the intranasal route was able to induce protection against repeated intranasal GAS infections in a murine challenge model. The lack of intranasal protection induced by the parenteral vaccine correlated with a reduced mucosal recall response at the site of infection. Taken together, our results demonstrate that locally primed immunity is important for the defense against intranasal infection with Streptococcus pyogenes.

  12. LATIN AS A LANGUAGE OF INTERNATIONAL COMMUNICATIVE STATUS: MEDICINE OF THE 16TH-17TH CENTURIES.

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    Bieliaieva, O; Lysanets, Yu; Melaschenko, M

    2017-01-01

    The research paper is of interdisciplinary nature, written at the crossroads of the history of medicine, functional stylistics and terminology science. The choice of the 16th century as a starting point of the study is due to the fact that quality changes in book and manuscript writing that took place during this period led to unprecedented development and dissemination of scientific knowledge, including biomedical. The 16th century embraces the life and work of such prominent figures in the history of medicine, as Andreas Vesalius, Gabriele Fallopian, Bartolomeo Eustachi, and Girolamo Fracastoro. The 17th century, which is called the century of "scientific revolution", left not less honourable names in the history of medicine - William Harvey, Marcello Malpighi, Thomas Willis, Jean Pecquet, Francis Glisson, Thomas Sydenham. In the context of this study, these prominent figures are interesting due to the fact that their works were written in Latin and constitute the prototypes of modern scientific style, in particular of such genres as thesis, monograph, scientific article, scientific report, polemic presentation, textbook. On the basis of extensive factual material, it has been demonstrated that during 16th-17th centuries, Latin acted as a fully developed language with a clearly oriented international status. As one of basic tools in scientific knowledge, Latin not only performed the epistemological function which was the priority for the development of medicine, but also served as a means of accumulation, reception, transmission and popularization of achievements in various areas of medical science.

  13. Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis

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    Carvalho, Agostinho; Giovannini, Gloria; De Luca, Antonella; D'Angelo, Carmen; Casagrande, Andrea; Iannitti, Rossana G; Ricci, Giovanni; Cunha, Cristina; Romani, Luigina

    2012-01-01

    The recognition of β-glucans by dectin-1 has been shown to mediate cell activation, cytokine production and a variety of antifungal responses. Here, we report that the functional activity of dectin-1 in mucosal immunity to Candida albicans is influenced by the genetic background of the host. Dectin-1 was required for the proper control of gastrointestinal and vaginal candidiasis in C57BL/6, but not BALB/c mice; in fact, the latter showed increased resistance in the absence of dectin-1. The susceptibility of dectin-1-deficient C57BL/6 mice to infection was associated with defects in IL-17A and aryl hydrocarbon receptor-dependent IL-22 production and in adaptive Th1 responses. In contrast, the resistance of dectin-1-deficient BALB/c mice was associated with increased IL-17A and IL-22 production and the skewing towards Th1/Treg immune responses that provide immunological memory. Disparate canonical/noncanonical NF-κB signaling pathways downstream of dectin-1 were activated in the two different mouse strains. Thus, the net activity of dectin-1 in antifungal mucosal immunity is dependent on the host's genetic background, which affects both the innate cytokine production and the adaptive Th1/Th17 cell activation upon dectin-1 signaling. PMID:22543832

  14. Identification of novel HIV-1 dependency factors in primary CCR4(+)CCR6(+)Th17 cells via a genome-wide transcriptional approach.

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    Cleret-Buhot, Aurélie; Zhang, Yuwei; Planas, Delphine; Goulet, Jean-Philippe; Monteiro, Patricia; Gosselin, Annie; Wacleche, Vanessa Sue; Tremblay, Cécile L; Jenabian, Mohammad-Ali; Routy, Jean-Pierre; El-Far, Mohamed; Chomont, Nicolas; Haddad, Elias K; Sekaly, Rafick-Pierre; Ancuta, Petronela

    2015-12-10

    The HIV-1 infection is characterized by profound CD4(+) T cell destruction and a marked Th17 dysfunction at the mucosal level. Viral suppressive antiretroviral therapy restores Th1 but not Th17 cells. Although several key HIV dependency factors (HDF) were identified in the past years via genome-wide siRNA screens in cell lines, molecular determinants of HIV permissiveness in primary Th17 cells remain to be elucidated. In an effort to orient Th17-targeted reconstitution strategies, we investigated molecular mechanisms of HIV permissiveness in Th17 cells. Genome-wide transcriptional profiling in memory CD4(+) T-cell subsets enriched in cells exhibiting Th17 (CCR4(+)CCR6(+)), Th1 (CXCR3(+)CCR6(-)), Th2 (CCR4(+)CCR6(-)), and Th1Th17 (CXCR3(+)CCR6(+)) features revealed remarkable transcriptional differences between Th17 and Th1 subsets. The HIV-DNA integration was superior in Th17 versus Th1 upon exposure to both wild-type and VSV-G-pseudotyped HIV; this indicates that post-entry mechanisms contribute to viral replication in Th17. Transcripts significantly enriched in Th17 versus Th1 were previously associated with the regulation of TCR signaling (ZAP-70, Lck, and CD96) and Th17 polarization (RORγt, ARNTL, PTPN13, and RUNX1). A meta-analysis using the NCBI HIV Interaction Database revealed a set of Th17-specific HIV dependency factors (HDFs): PARG, PAK2, KLF2, ITGB7, PTEN, ATG16L1, Alix/AIP1/PDCD6IP, LGALS3, JAK1, TRIM8, MALT1, FOXO3, ARNTL/BMAL1, ABCB1/MDR1, TNFSF13B/BAFF, and CDKN1B. Functional studies demonstrated an increased ability of Th17 versus Th1 cells to respond to TCR triggering in terms of NF-κB nuclear translocation/DNA-binding activity and proliferation. Finally, RNA interference studies identified MAP3K4 and PTPN13 as two novel Th17-specific HDFs. The transcriptional program of Th17 cells includes molecules regulating HIV replication at multiple post-entry steps that may represent potential targets for novel therapies aimed at protecting Th17 cells

  15. Preferential induction of Th17 cells in vitro and in vivo by Fucogalactan from Ganoderma lucidum (Reishi).

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    Yoshida, Hideyuki; Suzuki, Mayu; Sakaguchi, Ryota; Tani, Ito; Kotani, Hitoshi; Shudo, Norimasa; Yoshimura, Akihiko

    2012-05-25

    The mushroom known as Reishi (Ganoderma lucidum) has been used as an herbal medicine for tumor treatment and immune system activation. Because its effects on the differentiation of effector T helper cells have not yet been fully understood, we investigated the effects of Reishi and those of its principal ingredient, β-glucan, on the activation of dendritic cells and the differentiation of Th17 cells. Reishi extracts as well as purified β-glucan (Curdran) activated DCs and caused them to produce large amounts of IL-23. β-glucan also enhanced and sustained the transcription of IL-23p19. The MEK-ERK signaling pathway positively regulates IL-23p19 transcription in β-glucan-stimulated DCs. In a mixed leukocyte reaction, Reishi-stimulated DCs preferentially induced Th17 cells. Furthermore, orally-administrated Reishi increased the percentages of Th17 cells and the transcription levels of antimicrobial peptides. Our results show that Reishi and β-glucan activate DCs to produce large amounts of IL-23, which induces Th17 differentiation both in vitro and in vivo. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Hyperreactive Onchocerciasis is Characterized by a Combination of Th17-Th2 Immune Responses and Reduced Regulatory T Cells

    Science.gov (United States)

    Katawa, Gnatoulma; Layland, Laura E.; Debrah, Alex Y.; von Horn, Charlotte; Batsa, Linda; Kwarteng, Alexander; Arriens, Sandra; W. Taylor, David; Specht, Sabine; Hoerauf, Achim; Adjobimey, Tomabu

    2015-01-01

    Clinical manifestations in onchocerciasis range from generalized onchocerciasis (GEO) to the rare but severe hyperreactive (HO)/sowda form. Since disease pathogenesis is associated with host inflammatory reactions, we investigated whether Th17 responses could be related to aggravated pathology in HO. Using flow cytometry, filarial-specific cytokine responses and PCR arrays, we compared the immune cell profiles, including Th subsets, in individuals presenting the two polar forms of infection and endemic normals (EN). In addition to elevated frequencies of memory CD4+ T cells, individuals with HO showed accentuated Th17 and Th2 profiles but decreased CD4+CD25hiFoxp3+ regulatory T cells. These profiles included increased IL-17A+, IL-4+, RORC2+ and GATA3+CD4+ T cell populations. Flow cytometry data was further confirmed using a PCR array since Th17-related genes (IL-17 family members, IL-6, IL-1β and IL-22) and Th2-related (IL-4, IL-13, STAT6) genes were all significantly up-regulated in HO individuals. In addition, stronger Onchocerca volvulus-specific Th2 responses, especially IL-13, were observed in vitro in hyperreactive individuals when compared to GEO or EN groups. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network instigating the development of severe onchocerciasis. PMID:25569210

  17. Cyclosporine A Drives a Th17‐ and Th2‐Mediated Posttransplant Obliterative Airway Disease

    National Research Council Canada - National Science Library

    Lemaître, P. H; Vokaer, B; Charbonnier, L.‐M; Iwakura, Y; Field, K. A; Estenne, M; Goldman, M; Leo, O; Remmelink, M; Moine, A. Le

    2013-01-01

    ...) occurring in cyclosporine A (CsA)‐treated recipients. We found that CsA prevented CD8 + T cell infiltration into the graft and downregulated the Th1 response but affected neither Th2 nor Th17 responses in vivo...

  18. Elevated IL-17 produced by Th17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma

    Science.gov (United States)

    Pelluru, Dheeraj; Fulciniti, Mariateresa; Prabhala, Harsha K.; Nanjappa, Puru; Song, Weihua; Pai, Christine; Amin, Samir; Tai, Yu-Tzu; Richardson, Paul G.; Ghobrial, Irene M.; Treon, Steven P.; Daley, John F.; Anderson, Kenneth C.; Kutok, Jeffery L.

    2010-01-01

    Elevated cytokines in bone marrow (BM) micro-environment (interleukin-6 [IL-6], transforming growth factor-beta [TGF-β], and IL-1β) may play an important role in observed immune dysfunction in multiple myeloma (MM). As IL-6 and TGF-β are important for the generation of T-helper 17 (TH17) cells, we evaluated and observed a significantly elevated baseline and induced frequency of Th17 cells in peripheral blood mononuclear cells (PBMCs) and BM mononuclear cells (BMMCs) from MM patients compared with healthy donors. We observed significant increase in levels of serum IL-17, IL-21, IL-22, and IL-23 in blood and BM in MM compared with healthy donors. We also observed that myeloma PBMCs after TH17 polarization significantly induced IL-1α, IL-13, IL-17, and IL-23 production compared with healthy donor PBMCs. We next observed that IL-17 promotes myeloma cell growth and colony formation via IL-17 receptor, adhesion to bone marrow stromal cells (BMSCs) as well as increased growth in vivo in murine xenograft model of human MM. Additionally, we have observed that combination of IL-17 and IL-22 significantly inhibited the production of TH1-mediated cytokines, including interferon-γ (IFN-γ), by healthy donor PBMCs. In conclusion, IL-17–producing Th17 cells play an important role in MM pathobiology and may be an important therapeutic target for anti-MM activity and to improve immune function. PMID:20395418

  19. C5a regulates IL-12+ DC migration to induce pathogenic Th1 and Th17 cells in sepsis.

    Directory of Open Access Journals (Sweden)

    Ning Ma

    Full Text Available OBJECTIVE: It is well known that complement system C5a is excessively activated during the onset of sepsis. However, it is unclear whether C5a can regulate dentritic cells (DCs to stimulate adaptive immune cells such as Th1 and Th17 in sepsis. METHODS: Sepsis was induced by cecal ligation and puncture (CLP. CLP-induced sepsis was treated with anti-C5a or IL-12. IL-12(+DC, IFNγ(+Th1, and IL-17(+Th17 cells were analyzed by flow cytometry. IL-12 was measured by ELISA. RESULTS: Our studies here showed that C5a induced IL-12(+DC cell migration from the peritoneal cavity to peripheral blood and lymph nodes. Furthermore, IL-12(+DC cells induced the expansion of pathogenic IFNγ(+Th1 and IL-17(+Th17 cells in peripheral blood and lymph nodes. Moreover, IL-12, secreted by DC cells in the peritoneal cavity, is an important factor that prevents the development of sepsis. CONCLUSION: Our data suggests that C5a regulates IL-12(+DC cell migration to induce pathogenic Th1 and Th17 cells in sepsis.

  20. IL-34 Upregulated Th17 Production through Increased IL-6 Expression by Rheumatoid Fibroblast-Like Synoviocytes

    Directory of Open Access Journals (Sweden)

    Bing Wang

    2017-01-01

    Full Text Available Rheumatoid arthritis (RA is a chronic autoimmune disease which is characterized by synovial inflammation and cartilage damage for which causes articular dysfunction. Activation of fibroblast-like synoviocytes (FLS is a critical step that promotes disease progression. In this study, we aimed to explore the effect of interleukin-34 (IL-34 on RA FLS as a proinflammatory factor and IL-34-stimulated FLS on the production of Th17. We found that serum IL-34 levels were increased compared to those of the healthy controls and had positive correlations with C-reactive protein (CRP, erythrocyte sedimentation rate (ESR, rheumatoid factor (RF, and anticyclic citrullinated peptide (CCP antibody accordingly. CSF-1R was also highly expressed on RA FLS. The interaction of IL-34 and CSF-1R promoted a dramatic production of IL-6 by FLS through JNK/P38/NF-κB signaling pathway. Further, the IL-34-stimulated IL-6 secretion by RA FLS was found to upregulate the number of Th17. The treatment of IL-6R antagonist could attenuate the production of Th17 mediated by IL-34-stimulated RA FLS. Our results suggest that the increased IL-34 levels were closely related to the disease activity of RA. Additionally, the overexpression of IL-6 in the IL-34-stimulated FLS promoted the generation of Th17. Therefore, IL-34 was supposed to be involved in the pathogenesis of RA. The inhibition of IL-34 might provide a novel target for therapies of RA.

  1. Th17 Polarization under Hypoxia Results in Increased IL-10 Production in a Pathogen-Independent Manner

    Directory of Open Access Journals (Sweden)

    Roman Volchenkov

    2017-06-01

    Full Text Available The IL-17-producing CD4+ T helper cell (Th17 differentiation is affected by stimulation of the aryl hydrocarbon receptor (AhR pathway and by hypoxia-inducible factor 1 alpha (HIF-1α. In some cases, Th17 become non-pathogenic and produce IL-10. However, the initiating events triggering this phenotype are yet to be fully understood. Here, we show that such cells may be differentiated at low oxygen and regardless of AhR ligand treatment such as cigarette smoke extract. Hypoxia led to marked alterations of the transcriptome of IL-10-producing Th17 cells affecting genes involved in metabolic, anti-apoptotic, cell cycle, and T cell functional pathways. Moreover, we show that oxygen regulates the expression of CD52, which is a cell surface protein that has been shown to suppress the activation of other T cells upon release. Taken together, these findings suggest a novel ability for Th17 cells to regulate immune responses in vivo in an oxygen-dependent fashion.

  2. Chinese Medicine Bu Xu Hua Yu Recipe for the Regulation of Treg/Th17 Ratio Imbalance in Autoimmune Hepatitis

    Directory of Open Access Journals (Sweden)

    Lei Wang

    2015-01-01

    Full Text Available Objectives. The aim of this study is researching the role of the Regulatory T cell (Treg/T helper cell-17 (Th17 cell ratio imbalance in the pathogenesis of autoimmune hepatitis (AIH and the use of the “Bu Xu Hua Yu” recipe in the treatment of AIH. Materials and Methods. Sixty adult male C57/BL6 mice were divided into six different groups. α-Galcer was injected abdominally for production of the animal models. Liver function tests, histological examinations, liver tissue Regulatory T cell, and T helper cell-17 levels tests were carried out. TGF-β1, IL-10, IL-17, and expression of mRNA and protein levels of Foxp3 and ROR-γt were also assessed. Results. Bu Xu Hua Yu method increased the levels of Regulatory T cell, IL-10, and the expression of Foxp3 (P<0.05 in mice liver tissues. Furthermore, there were decreases in the levels of T helper cell-17, IL-17, and expression of RORγt mRNA and protein (P<0.05. The ratio of Treg/Th17 was increased (P<0.05. Conclusion. Mice with AIH have a Treg/Th17 ratio imbalance. Bu Xu Hua Yu method was able to restore the cellular balance of Treg/Th17 through the regulation of the expression of RORγt and Foxp3 and can play an important role in the treatment of AIH.

  3. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving ILC3

    Science.gov (United States)

    Withers, David R.; Hepworth, Matthew R.; Wang, Xinxin; Mackley, Emma C.; Halford, Emily E.; Dutton, Emma E.; Marriott, Clare L.; Brucklacher-Waldert, Verena; Veldhoen, Marc; Kelsen, Judith; Baldassano, Robert N.; Sonnenberg, Gregory F.

    2016-01-01

    RAR-related orphan receptor γt (ROR-γt) directs differentiation of pro-inflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases1–3. However, ROR-γt-dependent group 3 innate lymphoid cells (ILC3s) provide essential immunity and tissue protection in the intestine4–11, suggesting that targeting ROR-γt could also result in impaired host defense to infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 cells but not ILC3s in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Transient genetic deletion of ROR-γt in mature ILC3s also did not impair cytokine responses in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation, and reduced the frequencies of TH17 cells but not ILC3s isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell versus ILC3 responses, and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation. PMID:26878233

  4. Neutrophil mobilization by surface-glycan altered Th17-skewing bacteria mitigates periodontal pathogen persistence and associated alveolar bone loss.

    Directory of Open Access Journals (Sweden)

    Rajendra P Settem

    Full Text Available Alveolar bone (tooth-supporting bone erosion is a hallmark of periodontitis, an inflammatory disease that often leads to tooth loss. Periodontitis is caused by a select group of pathogens that form biofilms in subgingival crevices between the gums and teeth. It is well-recognized that the periodontal pathogen Porphyromonas gingivalis in these biofilms is responsible for modeling a microbial dysbiotic state, which then initiates an inflammatory response destructive to the periodontal tissues and bone. Eradication of this pathogen is thus critical for the treatment of periodontitis. Previous studies have shown that oral inoculation in mice with an attenuated strain of the periodontal pathogen Tannerella forsythia altered in O-glycan surface composition induces a Th17-linked mobilization of neutrophils to the gingival tissues. In this study, we sought to determine if immune priming with such a Th17-biasing strain would elicit a productive neutrophil response against P. gingivalis. Our data show that inoculation with a Th17-biasing T. forsythia strain is effective in blocking P. gingivalis-persistence and associated alveolar bone loss in mice. This work demonstrates the potential of O-glycan modified Tannerella strains or their O-glycan components for harnessing Th17-mediated immunity against periodontal and other mucosal pathogens.

  5. [Erythromycin inhibits elastin peptides-induced differentiation of CD4⁺T cells into Th17 cells].

    Science.gov (United States)

    Liu, Jifeng; Zhong, Xiaoning; He, Zhiyi; Qin, Xianglin; Ya, Leilei; Zhang, Jianquan

    2015-03-01

    To investigate the effect of erythromycin on differentiation into T helper 17 (Th17) cells from CD4⁺T cells exposed to elastin peptides. The CD4⁺T cells from spleen of male BALB/c mice by magnetic bead sorting were randomly divided into the control group (group A), the elastin peptides group (group B) and erythromycin group(group C). The cells in group B and C were cultured in serum-free medium supplemented with 30 μg/mL elastin peptides. The cells in group C were additionally administrated with erythromycin at a dose of 100 μg/mL. All of the CD4⁺T cells were cultured in serum-free culture solution for 24 hours. The number of the Th17 cells was detected by flow cytometry and the expression of retinoic acid related orphan nuclear receptor γt (RORγt) mRNA was measured by fluorescence quantitative PCR in each group. The expressions of NF-κB(p65) and signal transducer and activator of transcription 3 (STAT3) were analyzed by Western blotting. The Th17 cells in group B [(11.32 ± 2.34)%] increased as compared with that in group A [(5.21 ± 1.36)%], and the expression of RORγt mRNA in group B was higher than that in group A. Furthermore, the expressions of NF-κB(p65) and STAT3 proteins in group B increased significantly as compared with those in group A. However, compared with group B, group C presented with the significantly decreased expressions of Th17 cells, RORγt mRNA, NF-κB(p65) and STAT3 proteins. Erythromycin can suppress the differentiation into Th17 cells from CD4⁺T cells exposed to elastin peptides.

  6. Targeting Th17-IL-17 Pathway in Prevention of Micro-Invasive Prostate Cancer in a Mouse Model.

    Science.gov (United States)

    Zhang, Qiuyang; Liu, Sen; Ge, Dongxia; Cunningham, David M; Huang, Feng; Ma, Lin; Burris, Thomas P; You, Zongbing

    2017-06-01

    Chronic inflammation has been associated with the development and progression of human cancers including prostate cancer. The exact role of the inflammatory Th17-IL-17 pathway in prostate cancer remains unknown. In this study, we aimed to determine the importance of Th17 cells and IL-17 in a Pten-null prostate cancer mouse model. The Pten-null mice were treated by Th17 inhibitor SR1001 or anti-mouse IL-17 monoclonal antibody from 6 weeks of age up to 12 weeks of age. For SR1001 treatment, the mice were injected intraperitoneally (i.p.) twice a day with vehicle or SR1001, which was dissolved in a dimethylsulfoxide (DMSO) solution. All mice were euthanized for necropsy at 12 weeks of age. For IL-17 antibody treatment, the mice were injected intravenously (i.v.) once every two weeks with control IgG or rat anti-mouse IL-17 monoclonal antibody, which was dissolved in PBS. The injection time points were at 6, 8, and 10 weeks old. All mice were analyzed for the prostate phenotypes at 12 weeks of age. We found that either SR1001 or anti-IL-17 antibody treatment decreased the formation of micro-invasive prostate cancer in Pten-null mice. The SR1001 or anti-IL-17 antibody treated mouse prostates had reduced proliferation, increased apoptosis, and reduced angiogenesis, as well as reduced inflammatory cell infiltration. By assessing the epithelial-to-mesenchymal transition (EMT) markers, we found that SR1001 or anti-IL-17 antibody treated prostate tissues had weaker EMT phenotype compared to the control treated prostates. These results demonstrated that Th17-IL-17 pathway plays a key role in prostate cancer progression in Pten-null mice. Targeting Th17-IL-17 pathway could prevent micro-invasive prostate cancer formation in mice. Prostate 77:888-899, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  7. Th-17 related regulatory network in the pathogenesis of Arab patients with systemic lupus erythematosus and lupus nephritis.

    Science.gov (United States)

    AlFadhli, Suad; AlFailakawi, Asma'a; Ghanem, Aqeel A M

    2016-05-01

    The present study aimed to identify the genes involved in the pathogenesis of systemic lupus erythematosus (SLE) in Arabs by investigating a panel of 84 genes related to the t helper (Th)17-related regulatory network and to further explore the expression levels of serum interleukin (IL)-17A and IL-17F in a studied cohort. A comparative analysis of gene expression profile in SLE and lupus nephritis (LN) patients against that of healthy controls (HC) was performed. A quantitative real-time polymerase chain reaction (PCR) (Th17 autoimmunity and inflammation) array analysis was performed in peripheral white blood cells of 66 SLE patients under specific medical treatment and 30 age/gender/ethnically matched healthy controls. Statistical analysis was carried out using the RT(2) Profiler TM PCR Data Analysis tool. The analysis of Th17 pathway revealed 14 genes (IL-17A, IL-17C, IL-17D, IL-17F, IL-18, IL-12RB2, IL-23R, CCL2, CCL20, CXCL5, MMP3, RORC, STAT4 and TRAF6) that are differentially expressed in SLE and HC (fold change [FC] < 2, P < 0.0006). No significant difference in expression profiles was observed between SLE and LN. A significant difference in serum concentration of IL-17A (P = 0.002) and IL-17F (P = 0.002) was observed between SLE (13.91 ± 4.25) and LN (18.26 ± 4.24). Our study is the first to investigate a panel of 84 genes related to Th17 regulatory pathway in Arab SLE subjects and the first to explore the effect of current immunosuppression regimens on Th17 regulatory pathway. It paves the way for understanding the etiology of SLE and autoimmune diseases in general. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  8. Th17 Inhibitors in Active Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.

    Science.gov (United States)

    Naik, Girish S; Ming, Wai K; Magodoro, Itai M; Akinwunmi, Babatunde; Dar, Sara; Poulsen, Henrik E; Kristensen, Lars E; Ellervik, Christina

    2017-12-20

    Several biologics targeting the Th17 pathway have been developed for the treatment of psoriatic arthritis (PsA), a disabling disease with moderate response and an increased incidence of serious infections to first-line biologics (TNF-α antagonists). Th17 inhibitors could replace TNF-α antagonists as first-line biologic agents. We determined the overall treatment effect of Th17 pathway inhibitors compared to placebo or active control on American College of Rheumatology (ACR) 20 response at week 12 (primary objective), risk of infections, discontinuation of treatment due to adverse events, and serious adverse events during the placebo-controlled period (12-24 weeks) in adults with active PsA in published randomized controlled trials. The SCOPUS database was searched. The Cochrane risk of bias tool was used for assessing quality. The pooled relative risk (RR) was derived from random effects models. Seven randomized controlled trials were included which randomized 1,718 patients to Th17 inhibitors and 840 to placebo. Patients treated with Th17 inhibitors had an RR of 2.04 (95% CI: 1.79-2.33; p < 0.001) for achieving an ACR20 response at week 12 (I2 = 0%; p = 0.89) compared to placebo-treated patients. There was no evidence of publication bias. The result was consistent for study phase and outcome (ACR50/70), mechanism of action and TNF-α naivety. RR of infections was 1.06 (0.91-1.23), that of candida infections was 3.35 (0.75-14.95), that of serious adverse events was 0.82 (0.42-1.59) and that of discontinuation of treatment was 0.54 (0.31-0.93) among treated versus placebo subjects. No incident cases of tuberculosis were reported. In patients with active PsA, biologics targeting the Th17 axis produce a clinically significant improvement in joint disease activity with acceptable safety and tolerability for short-term treatment compared to placebo. © 2017 S. Karger AG, Basel.

  9. Th-17, monokines, collagen type V, and primary graft dysfunction in lung transplantation.

    Science.gov (United States)

    Bobadilla, Joseph L; Love, Robert B; Jankowska-Gan, Ewa; Xu, Qingyong; Haynes, Lynn D; Braun, Ruedi K; Hayney, Mary S; Munoz del Rio, Alejandro; Meyer, Keith; Greenspan, Daniel S; Torrealba, Jose; Heidler, Kathleen M; Cummings, Oscar W; Iwata, Takekazu; Brand, David; Presson, Robert; Burlingham, William J; Wilkes, David S

    2008-03-15

    The pathogenesis of primary graft dysfunction (PGD), a serious complication of lung transplantation, is poorly understood. Human studies and rodent models have shown that collagen type V (col[V]), stimulates IL-17-dependent cellular immunity after lung transplantation. To determine whether patients with end-stage lung disease develop pretransplant col(V)-specific cellular immunity, and if so, the impact of this response on PGD. Trans-vivo delayed-type hypersensitivity (TV-DTH) assays were used to evaluate memory T-cell responses to col(V) in 55 patients awaiting lung transplantation. Pa(O(2))/Fi(O(2)) index data were used to assess PGD. Univariate risk factor analysis was performed to identify variables associated with PGD. Rats immunized with col(V) or irrelevant antigen underwent lung isografting to determine if prior anti-col(V) immunity triggers PGD in the absence of alloreactivity. We found that 58.8% (10/17) of patients with idiopathic pulmonary fibrosis, and 15.8% (6/38) of patients without idiopathic pulmonary fibrosis tested while on the wait list for a lung transplant were col(V) DTH positive. Col(V) reactivity was CD4(+) T-cell and monocyte mediated, and dependent on IL-17, IL-1beta, and tumor necrosis factor (TNF)-alpha. Pa(O(2))/Fi(O(2)) indices were impaired significantly 6-72 hours after transplantation in col(V)-reactive versus nonreactive patients. Univariate risk factor analysis identified only preoperative TV-DTH to col(V) and ischemic time as predictors of PGD. Finally, in a rat lung isograft model, col(V) sensitization resulted in significantly lower Pa(O(2))/Fi(O(2)), increased local TNF-alpha and IL-1beta production, and a moderate-to-severe bronchiolitis/vasculitis when compared with control isografts. The data suggest that activation of innate immunity by col(V)-specific Th-17 memory cells represents a novel pathway to PGD after lung transplantation.

  10. mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing TH1/TH17/Treg Profile.

    Directory of Open Access Journals (Sweden)

    Shurong Hu

    Full Text Available It has been established that mammalian target of Rapamycin (mTOR inhibitors have anti-inflammatory effects in models of experimental colitis. However, the underlying mechanism is largely unknown. In this research, we investigate the anti-inflammatory effects of AZD8055, a potent mTOR inhibitor, on T cell response in dextran sulfate sodium (DSS-induced colitis in mice, a commonly used animal model of inflammatory bowel diseases (IBD. Severity of colitis is evaluated by changing of body weight, bloody stool, fecal consistency, histology evaluation and cytokine expression. We find that AZD8055 treatment attenuates DSS-induced body weight loss, colon length shortening and pathological damage of the colon. And AZD8055 treatment decreases colonic expression of genes encoding the pro-inflammatory cytokines interferon-γ, interleukin (IL-17A, IL-1β,IL-6 and tumor necrosis factor(TNF-a and increases colonic expression of anti-inflammatory cytokines IL-10. We show that AZD8055 treatment decreases the percentages of CD4+ T cells and CD8+ T cells in spleen, lymph nodes and peripheral blood of mice. We also find that AZD8055 treatment significantly reduces the number of T helper 1(TH1 cells and TH17 cells and increases regulatory T (Treg cells in the lamina propria and mesenteric lymph nodes. Furthermore, we demonstrates that AZD8055 suppresses the proliferation of CD4+ and CD8+ T cells and the differentiation of TH1/TH17 cells and expands Treg cells in vitro. The results suggest that, in experimental colitis, AZD8055 exerts anti-inflammatory effect by regulating T helper cell polarization and proliferation.

  11. Evaluation of cell-mediated immune responses and bacterial clearance in 6-10 months old water buffalo (Bubalus bubalis) experimentally vaccinated with four dosages of commercial Brucella abortus strain RB51 vaccine.

    Science.gov (United States)

    Diptee, M D; Adesiyun, A A; Asgarali, Z; Campbell, M; Fosgate, G T

    2005-07-15

    Thirty water buffalo, obtained from a brucellosis-free farm, were used to evaluate cell-mediated immune responses and bacterial clearance in response to vaccination with Brucella abortus strain RB51 (RB51) in a dose-response study. The animals were randomly divided into five treatment groups. Groups I--V received the recommended dose (RD) of RB51 vaccine once, RD twice 4 weeks apart, double RD once, double RD twice 4 weeks apart and saline once, respectively. Cell-mediated immune response to RB51 was assessed by the histological examination of haematoxylin and eosin (H&E) stained sections of lymph nodes draining the sites of inoculation and by comparison of stimulation indices (SI) derived from gamma interferon (IFN-gamma) assay. A mixture of cytoplasmic proteins from B. melitensis B115 (brucellergene) was used as a specific antigenic stimulus to peripheral blood mononuclear cells (PBMC) and lymph node mononuclear cells (LNMC) up to 22 post-initial-inoculation week (PIW). Supernatants harvested at 18-24h after the in vitro antigenic stimulus were assayed for their IFN-gamma content by using a commercial sandwich enzyme-linked immunosorbent assay (ELISA) kit. Clearance of RB51 was assessed by the sequential immunohistochemical examination of sections of draining lymph nodes post-inoculation. There was no observable expansion of the deep cortex of lymph nodes on H&E sections indicating poor T-cell stimulation. All group V (control) water buffalo PBMC ELISA values were negative (SIRB51 occurred between 4 and 6 PIW in treatment groups I and III and between 6 and 12 PIW in groups II and IV. RB51 was not detected in any of the control animals at sampling intervals post-inoculation.

  12. Long-Lasting Effects of BCG Vaccination on Both Heterologous Th1/Th17 Responses and Innate Trained Immunity

    DEFF Research Database (Denmark)

    Kleinnijenhuis, Johanneke; Quintin, Jessica; Preijers, Frank

    2013-01-01

    We have recently shown that BCG (Bacillus Calmette-Guérin) vaccination in healthy volunteers induces epigenetic reprogramming of monocytes, leading to increased cytokine production in response to nonrelated pathogens for up to 3 months after vaccination. This phenomenon was named 'trained immunity......'. In the present study we assessed whether BCG was able to induce long-lasting effects on both trained immunity and heterologous T helper 1 (Th1) and Th17 immune responses 1 year after vaccination. The production of TNFα and IL-1β to mycobacteria or unrelated pathogens was higher after 2 weeks and 3 months...... in proinflammatory cytokine production after stimulation with the TLR4 ligand lipopolysaccharide. The heterologous production of Th1 (IFN-γ) and Th17 (IL-17 and IL-22) immune responses to nonmycobacterial stimulation remained strongly elevated even 1 year after BCG vaccination. In conclusion, BCG induces sustained...

  13. Human mucosal leishmaniasis: neutrophils infiltrate areas of tissue damage that express high levels of Th17-related cytokines.

    Science.gov (United States)

    Boaventura, Viviane S; Santos, Claire S; Cardoso, Cristina R; de Andrade, José; Dos Santos, Washington L C; Clarêncio, Jorge; Silva, João S; Borges, Valeria M; Barral-Netto, Manoel; Brodskyn, Claudia I; Barral, Aldina

    2010-10-01

    Mucosal leishmaniasis (ML) is characterised by severe tissue destruction. Herein, we evaluated the involvement of the IL-17-type response in the inflammatory infiltrate of biopsy specimens from 17 ML patients. IL-17 and IL-17-inducing cytokines (IL-1β, IL-23, IL-6 and TGF-β) were detected by immunohistochemistry in ML patients. IL-17(+) cells exhibited CD4(+), CD8(+) or CD14(+) phenotypes, and numerous IL-17(+) cells co-expressed the CC chemokine receptor 6 (CCR6). Neutrophils, a hallmark of Th17-mediated inflammation, were regularly detected in necrotic and perinecrotic areas and stained positive for neutrophil elastase, myeloperoxidase and MMP-9. Taken together, these observations demonstrate the existence of Th17 cells in ML lesions associated with neutrophils in areas of tissue injury and suggest that IL-17 is involved in ML pathogenesis.

  14. Synthesis of Th17 cytokines in the culture of peripheral blood mononuclear cells stimulated with Borrelia burgdorferi sensu lato

    Directory of Open Access Journals (Sweden)

    Sambor Grygorczuk

    2016-06-01

    Full Text Available [b]Introduction and objective. [/b]Th17 lymphocytes and their cytokines, interleukin 17A (IL-17A, IL-17F and IL-22, participate in the response to extracellular bacteria and in the autoimmunity and may be engaged in the pathogenesis of Lyme borreliosis. Concentrations were measured of IL-17A, IL-17F and IL-22 in the supernatant of the peripheral blood mononuclear cells (PBMC culture stimulated with [i]Borrelia burgdorferi sensu lato[/i] ([i]B. burgdorferi[/i]. [b]Materials and method.[/b] The study group consisted of 13 patients with early disseminated and late Lyme borreliosis and a control group of 7 healthy persons. PBMC cultures were stimulated for 48 hours with [i]B. burgdorferi [/i]spirochetes of three pathogenic species: [i]B. burgdorferi[/i] sensu stricto, B. afzelii or B. garinii, in the multiplicity of infection 10:1. Concentrations of Th17 cytokines IL-17A, IL-17F and IL-22, as well as Th2/immunoregulatory cytokine IL-10 were measured with ELISA assays. [b]Results. [/b]Expression of IL-17A, IL-17F and IL-22 increased under stimulation, simultaneously with the increased IL-10 expression. Concentration of IL-17F tended to be lower in early neuroborreliosis than in late Lyme borreliosis and than in controls. [i]B. afzelii[/i] elicited higher expression of IL-17A than the other two species. [b]Conclusions.[/b] IL-17A, IL-17F and IL-22 are synthesized simultaneously by PBMC stimulated with [i]B. burgdorferi[/i]. There is no antagonism between Th17 response and IL-10 expression. The role of Th17 cytokines seems to differ depending on the clinical stage of Lyme borreliosis and on the [i]B. burgdorferi[/i] species.

  15. Th-17 regulatory cytokines IL-21, IL-23, and IL-6 enhance neutrophil production of IL-17 cytokines during asthma.

    Science.gov (United States)

    Halwani, Rabih; Sultana, Asma; Vazquez-Tello, Alejandro; Jamhawi, Amer; Al-Masri, Abeer A; Al-Muhsen, Saleh

    2017-11-01

    In a subset of severe asthma patients, chronic airway inflammation is associated with infiltration of neutrophils, Th-17 cells and elevated expression of Th-17-derived cytokines (e.g., interleukin [IL]-17, IL-21, IL-22). Peripheral neutrophils from allergic asthmatics are known to express higher IL-17 cytokine levels than those from healthy subjects, but the regulatory mechanisms involved are not well understood. We hypothesize that Th-17 regulatory cytokines could modulate IL-17 expression in neutrophils. Peripheral blood neutrophils isolated from asthmatics were stimulated with IL-21, IL-23, and IL-6 cytokines and their ability to produce IL-17A and IL-17F was determined relative to healthy controls. Signal transducer and activator of transcription 3 (STAT3) phosphorylation levels were measured in stimulated neutrophil using flow cytometry. The requirement for STAT3 phosphorylation was determined by blocking its activation using a specific chemical inhibitor. Stimulating asthmatic neutrophils with IL-21, 23, and 6 enhanced the production of IL-17A and IL-17F at significantly higher levels comparatively to healthy controls. Stimulating neutrophils with IL-21, IL-23, and IL-6 cytokines enhanced STAT3 phosphorylation, in all cases. Interestingly, inhibiting STAT3 phosphorylation using a specific chemical inhibitor dramatically blocked the ability of neutrophils to produce IL-17, demonstrating that STAT3 activation is the major factor mediating IL-17 gene expression. These findings suggest that neutrophil infiltration in lungs of severe asthmatics may represent an important source of pro-inflammatory IL-17A and -F cytokines, a production enhanced by Th-17 regulatory cytokines, and thus providing a feedback mechanism that sustains inflammation. Our results suggest that STAT3 pathway could be a potential target for regulating neutrophilic inflammation during severe asthma.

  16. Ancestry Estimation Based on Morphoscopic Traits in a Sample of African Slaves from Lagos, Portugal (15th-17th Centuries)

    OpenAIRE

    Coelho, C.; Navega, D.; Cunha, E.; Ferreira, M. T.; Wasterlain, S. N.

    2017-01-01

    In 2009, a skeletal collection of 158 individuals was excavated in Valle da Gafaria, Lagos, Portugal. These individuals were buried in an unusual way, having been discarded in an urban dump located outside the medieval city walls, dated from the 15th-17th centuries. Lagos was, at the time, an important slave trade harbour, and during the excavation, the morphological appearance of the skulls and the presence of intentionally modified teeth in some individuals raised suspicion that they were A...

  17. Potential pathogenetic role of Th17, Th0, and Th2 cells in erosive and reticular oral lichen planus.

    Science.gov (United States)

    Piccinni, M-P; Lombardelli, L; Logiodice, F; Tesi, D; Kullolli, O; Biagiotti, R; Giudizi, Mg; Romagnani, S; Maggi, E; Ficarra, G

    2014-03-01

    The role of Th17 cells and associated cytokines was investigated in oral lichen planus. 14 consecutive patients with oral lichen planus were investigated. For biological studies, tissues were taken from reticular or erosive lesions and from normal oral mucosa (controls) of the same patient. mRNA expression for IL-17F, IL-17A, MCP-1, IL-13, IL-2, IL-10, IL-1β, RANTES, IL-4, IL-12B, IL-8, IFN-γ, TNF-α, IL-1α, IL-18, TGF-β1, IL-23R, IL-7, IL-15, IL-6, MIG, IP-10, LTB, VEGF, IL-5, IL-27, IL-23A, GAPDH, PPIB, Foxp3, GATA3, and RORC was measured using the QuantiGene 2.0. Results showed that Th17-type and Th0-type molecules' mRNAs, when compared with results obtained from tissue controls, were increased in biopsies of erosive lesions, whereas Th2-type molecules' mRNAs were increased in reticular lesions. When the CD4+ T-cell clones, derived from oral lichen planus tissues and tissue controls, were analyzed, a higher prevalence of Th17 (confirmed by an increased CD161 expression) and Th0 CD4+ T clones was found in erosive lesions, whereas a prevalence of Th2 clones was observed in reticular lesions. Our data suggest that Th17, Th0, and Th2 cells, respectively, may have a role in the pathogenesis of erosive and reticular oral lichen planus. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Assessment of a One-Step Intracellular Staining in Th1, Th2 and Th17 Cells of Clinical Samples.

    Science.gov (United States)

    Lin, Xianghua; Luo, Xiaohong; Wang, Ying; Wu, Qiuju; Xiao, Wangxian; Lin, Dijing; Duan, Chaohui

    2015-01-01

    Flow cytometry is a potent tool to dissect the phenotypes and functions of cell subsets by measuring multiple parameters on a single-cell basis. However, intracellular staining may be time consuming and more steps, particularly in cytokines, could be problematic for its use in daily routine or in large cohort testing. Lately, a novel reagent has been developed to perform intracellular staining in one step. The objective of our study was thus to assess this new method in comparison with the reference technique by focusing on CD4+ T-cell subsets such as Th1, Th2, and Th17 cells in clinical samples. Peripheral blood was collected from 10 children with aplastic anemia and 10 healthy volunteers and stained using the reference and one-step methods. Different subsets of CD4+ T-cells, which are defined as Th1, Th2 and Th17 cells, were investigated by flow cytometry. The repetitive experiment was designed to study intraassay precision. Correlations were studied using Pearson's correlation coefficient test. When comparing results obtained with the two techniques, no statistical differences between the percentages of Th1, Th2, and Th17 cells were observed. Besides, a nice correlation between percentages of Th1 cells obtained with the two different methods was identified in the global population (r: 0.777, p cells (r: 0.875, p cells (r: 0.886, p step procedures. Importantly, flow cytometry staining obtained with the one-step method was very robust with a nice intra-assay precision and a better discriminative power and repeatability. With better staining quality and a shorter realization time, one-step intracellular staining may provide an efficient way for daily routine testing of Th1, Th2 and Th17 cells, as well as for further research.

  19. Autoimmune Renal Disease Is Exacerbated by S1P-Receptor-1-Dependent Intestinal Th17 Cell Migration to the Kidney.

    Science.gov (United States)

    Krebs, Christian F; Paust, Hans-Joachim; Krohn, Sonja; Koyro, Tobias; Brix, Silke R; Riedel, Jan-Hendrik; Bartsch, Patricia; Wiech, Thorsten; Meyer-Schwesinger, Catherine; Huang, Jiabin; Fischer, Nicole; Busch, Philipp; Mittrücker, Hans-Willi; Steinhoff, Ulrich; Stockinger, Brigitta; Perez, Laura Garcia; Wenzel, Ulrich O; Janneck, Matthias; Steinmetz, Oliver M; Gagliani, Nicola; Stahl, Rolf A K; Huber, Samuel; Turner, Jan-Eric; Panzer, Ulf

    2016-11-15

    Th17 cells are most abundant in the gut, where their presence depends on the intestinal microbiota. Here, we examined whether intestinal Th17 cells contribute to extra-intestinal Th17 responses in autoimmune kidney disease. We found high frequencies of Th17 cells in the kidneys of patients with antineutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis. We utilized photoconversion of intestinal cells in Kaede mice to track intestinal T cell mobilization upon glomerulonephritis induction, and we found that Th17 cells egress from the gut in a S1P-receptor-1-dependent fashion and subsequently migrate to the kidney via the CCL20/CCR6 axis. Depletion of intestinal Th17 cells in germ-free and antibiotic-treated mice ameliorated renal disease, whereas expansion of these cells upon Citrobacter rodentium infection exacerbated pathology. Thus, in some autoimmune settings, intestinal Th17 cells migrate into target organs, where they contribute to pathology. Targeting the intestinal Th17 cell "reservoir" may present a therapeutic strategy for these autoimmune disorders. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  20. A study of the changes of Th17 cells and IL-23 in patients with Guillain-Barré syndrome

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    Gai-ping HE

    2014-06-01

    Full Text Available Guillain-Barré syndrome (GBS is an acute autoimmune-mediated inflammatory neuropathy. In this paper, the percentage of Th17 in peripheral blood lymphocyte and the level of IL-23 in serum and cerebrospinal fluid (CSF of patients with GBS were detected. Twenty-five patients with GBS and 20 controls were analyzed. The percentage of Th17 cells in patients with GBS was (4.86 ± 0.60%, which was higher than that in controls [(2.71 ± 0.54%; t = 2.616, P = 0.012]. Serum IL-23 increased in patients with GBS [(111.80 ± 13.84 pg/ml vs (72.55 ± 8.19 pg/ml; t = 2.300, P = 0.026]. The level of IL-23 in serum and CSF from patients with GBS before therapy [(110.50 ± 15.66 and (102.30 ± 7.52 pg/ml] declined to normal after therapy [(74.13 ± 6.18 and (72.92 ± 12.09 pg/ml], and the difference was statistically significant (t = 2.557, P = 0.022; t = 1.422, P = 0.046. Th17 cells and IL-23 increased in patients with GBS, indicating that they may involve in the pathogenesis of GBS. doi: 10.3969/j.issn.1672-6731.2014.06.012

  1. An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses

    Science.gov (United States)

    Sano, Teruyuki; Huang, Wendy; Hall, Jason A.; Yang, Yi; Chen, Alessandra; Gavzy, Samuel J.; Lee, June-Yong; Ziel, Joshua; Miraldi, Emily R.; Bonneau, Richard; Littman, Dan R.

    2015-01-01

    SUMMARY RORγt+ Th17 cells are important for mucosal defenses, but also contribute to autoimmune disease. They accumulate in the intestine in response to microbiota and produce IL-17 cytokines. Segmented filamentous bacteria (SFB) are Th17-inducing commensals that potentiate autoimmunity in mice. RORγt+ T cells were induced in mesenteric lymph nodes early after SFB colonization and distributed across different segments of the gastrointestinal tract. However, robust IL-17A production was restricted to the ileum, where SFB makes direct contact with the epithelium and induces serum amyloid A proteins 1 and 2 (SAA1/2), which promote local IL-17A expression in RORγt+ T cells. We identified an SFB-dependent role of type 3 innate lymphoid cells (ILC3), which secreted IL-22 that induced epithelial SAA production in a Stat3-dependent manner. This highlights the critical role of tissue microenvironment in activating effector functions of committed Th17 cells, which may have important implications for how these cells contribute to inflammatory disease. PMID:26411290

  2. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity.

    Science.gov (United States)

    Kleinnijenhuis, Johanneke; Quintin, Jessica; Preijers, Frank; Benn, Christine Stabell; Joosten, Leo A B; Jacobs, Cor; van Loenhout, Joke; Xavier, Ramnik J; Aaby, Peter; van der Meer, Jos W M; van Crevel, Reinout; Netea, Mihai G

    2014-01-01

    We have recently shown that BCG (Bacillus Calmette-Guérin) vaccination in healthy volunteers induces epigenetic reprogramming of monocytes, leading to increased cytokine production in response to nonrelated pathogens for up to 3 months after vaccination. This phenomenon was named 'trained immunity'. In the present study we assessed whether BCG was able to induce long-lasting effects on both trained immunity and heterologous T helper 1 (Th1) and Th17 immune responses 1 year after vaccination. The production of TNFα and IL-1β to mycobacteria or unrelated pathogens was higher after 2 weeks and 3 months postvaccination, but these effects were less pronounced 1 year after vaccination. However, monocytes recovered 1 year after vaccination had an increased expression of pattern recognition receptors such as CD14, Toll-like receptor 4 (TLR4) and mannose receptor, and this correlated with an increase in proinflammatory cytokine production after stimulation with the TLR4 ligand lipopolysaccharide. The heterologous production of Th1 (IFN-γ) and Th17 (IL-17 and IL-22) immune responses to nonmycobacterial stimulation remained strongly elevated even 1 year after BCG vaccination. In conclusion, BCG induces sustained changes in the immune system associated with a nonspecific response to infections both at the level of innate trained immunity and at the level of heterologous Th1/Th17 responses. Copyright © 2013 S. Karger AG, Basel

  3. Evaluation of Th1 and Th17 cells cytokines in cell culture stimulated in women with recurrent spontaneous abortion

    Directory of Open Access Journals (Sweden)

    Y Varghaiyan

    2013-10-01

    Full Text Available Introduction: Various immunological abnormalities have been reported in women with RSA of unknown aetiologies including autoimmune abnormalities and increased cellular immunity such as elevated natural killer (NK , Th1 and Th17 cell levels. Th17 and Th1 cells play a central role during inflammation. Th1 cells product cytokines IFN-γ, IL-2 and Th17 cells mainly cytokines IL-17A, F, IL-22. The aim of this study is evaluation of Th1 and Th17 activity in women with recurrent spontaneous abortion. Methods: In this case-control study, 30 women with history of two or more abortion who at least 3 months past after last abortion considered as case group and 30 normal fertile healthy women with at least one delivery as control group. We determined the levels of IL-17A, F and IFN-γ in cell culture supernatant of peripheral blood mononuclear cells (PBMC stimulated with the mitogen phytohemagglutinin (PHA by enzyme-linked immunosorbent assay (ELISA method and compared in the two groups. The results obtained using the one-sample kolmogorov-smirnov Test, Kruskal-wallis Test and Spearman were analyzed using SPSS 16 software. Results: The level of IFN- γ in case group was significantly higher than control group (186/53±30/41 versus 88/06±21/44 pg/ml, P < 0.005. Also the level of IL-17 A, F in case group was significantly higher than control group (84/74±21/26 versus 28/41±8 pg/ml, P < 0.01. IFN-γ concentration showed positive correlation with IL-17 A, F in case group (P=0.015, r= 0.455. Conclusion: In this study the increased levels of cytokines IFN- γ and IL-17 A, F in women with recurrent spontaneous abortion shows a propensity of pro inflammation via Th17 and Th1 immunity and may be these cells play a pivotal role in rejecting fetus antigens.

  4. Regulatory effect of transcription factors RORγt on the Th17/Treg balances in pregnant asthma mice

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    Jia-jia MA

    2012-06-01

    Full Text Available Objective  To observe the expression changes in Th17-related cytokines and retinoid acid receptor-related orphan receptor gamma t (RORγt in mouse model of asthma during pregnancy, and to explore the effects of dexamethasone (DXM on Th17 cell secretory function and airway inflammation in mice. Methods  Thirty female BALB/c mice were divided into three groups at random (n=10 per group: healthy pregnancy (HP group, asthma in pregnancy (AP group and dexamethasone (DXM treated group (DXM group. The mice were treated as follows: those in AP and DXM groups were sensitized with an intraperitoneal injection of chicken ovalbumin-aluminum hydroxide [OVA/A1(OH3] suspension on days 0, 7 and 14. The HP mice were sensitized with normal saline (NS following the same protocol. All the mice were then bred with male BALB/c male mice. Pregnant mice in AP and DXM groups were exposed to 40-minute of 50g/L OVA aerosol for seven consecutive days starting from day 21. Dexamethasone in a dose of 1mg/kg was injected intraperitoneally in DXM mice 30 minutes before inhaling 50g/L OVA aerosol, while the HP group received NS only. The airway responsiveness to corresponding concentrations of inhaled acetylcholine was recorded 24h after the final OVA challenge. The index of airflow obstruction was expressed as enhanced pause (Penh and its mean value after each nebulization. The airway tone is further expressed as the Penh(% after being normalized by the baseline value. Total and differential cell counts in bronchoalveolar lavage fluid (BALF were carried out in each sample. The histological changes in the lungs were assessed using light microscopy. The propotions of Th17 and Treg cell in mice peripheral blood cells were calculated and the Th17/Treg ratio was determined by flow cytometry. IL-17, IL-23, IFN-γand RORγt levels in the serum of mice were quantified by using ELISA technique. RT-PCR and Western blotting were performed to determine the levels of IL-17, RORγt, IL

  5. Disparate Effects of Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis and Cuprizone-Induced Demyelination.

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    Justin D Glenn

    Full Text Available Mesenchymal stem cells (MSCs are pleiotropic cells with potential therapeutic benefits for a wide range of diseases. Because of their immunomodulatory properties they have been utilized to treat autoimmune diseases such as multiple sclerosis (MS, which is characterized by demyelination. The microenvironment surrounding MSCs is thought to affect their differentiation and phenotype, which could in turn affect the efficacy. We thus sought to dissect the potential for differential impact of MSCs on central nervous system (CNS disease in T cell mediated and non-T cell mediated settings using the MOG35-55 experimental autoimmune encephalomyelitis (EAE and cuprizone-mediated demyelination models, respectively. As the pathogeneses of MS and EAE are thought to be mediated by IFNγ-producing (TH1 and IL-17A-producing (TH17 effector CD4+ T cells, we investigated the effect of MSCs on the development of these two key pathogenic cell groups. Although MSCs suppressed the activation and effector function of TH17 cells, they did not affect TH1 activation, but enhanced TH1 effector function and ultimately produced no effect on EAE. In the non- T cell mediated cuprizone model of demyelination, MSC administration had a positive effect, with an overall increase in myelin abundance in the brain of MSC-treated mice compared to controls. These results highlight the potential variability of MSCs as a biologic therapeutic tool in the treatment of autoimmune disease and the need for further investigation into the multifaceted functions of MSCs in diverse microenvironments and the mechanisms behind the diversity.

  6. Levels of hepatic Th17 cells and regulatory T cells upregulated by hepatic stellate cells in advanced HBV-related liver fibrosis.

    Science.gov (United States)

    Li, Xiaoyan; Su, Yujie; Hua, Xuefeng; Xie, Chan; Liu, Jing; Huang, Yuehua; Zhou, Liang; Zhang, Min; Li, Xu; Gao, Zhiliang

    2017-04-11

    Liver fibrosis which mainly occurs upon chronic hepatitis virus infection potentially leads to portal hypertension, hepatic failure and hepatocellular carcinoma. However, the immune status of Th17 and Treg cells in liver fibrosis is controversial and the exact mechanisms remain largely elusive. Liver tissues and peripheral blood were obtained simultaneously from 32 hepatitis B virus infected patients undergoing surgery for hepatocellular carcinoma at the medical center of Sun Yat-sen University. Liver tissues at least 3 cm away from the tumor site were used for the analyses. Levels of Th17 cells and regulatory T cells were detected by flow cytometry analysis and immunohistochemistry. In vitro experiment, we adopted magnetic cell sorting to investigate how hepatic stellate cells regulate the levels of Th17 cells and regulatory T cells. We found that hepatic Th17 cells and regulatory T cells were increased in patients with advanced stage HBV-related liver fibrosis. Hepatic stellate cells upregulated the levels of Th17 cells and regulatory T cells via PGE2/EP2 and EP4 pathway. We found that the increased levels of Th17 cells and regulatory T cells were upregulated by hepatic stellate cells. These results may provide insight into the role of hepatic stellate cells and Th17 cells and regulatory T cells in the persistence of fibrosis and into the occurrence of hepatocellular carcinoma following cirrhosis.

  7. IL-23 signaling in Th17 cells is inhibited by HIV infection and is not restored by HAART: Implications for persistent immune activation.

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    Jason R Fernandes

    Full Text Available HIV infection causes a profound depletion of gut derived Th17 cells, contributing to loss of mucosal barrier function and an increase in microbial translocation, thus driving systemic immune activation. Despite normalization of circulating CD4+ T cell counts with highly active antiretroviral therapy (HAART, Th17 frequency and function often remain impaired. Given the importance of interleukin (IL-23 in the generation and stabilization of Th17 cells we hypothesized that impaired IL-23 signaling causes persistent Th17 dysfunction in HIV infection.The effects of in vitro HIV infection on responses to IL-23 in Th17 cells were examined. These included the production of IL-17, phosphorylated STAT3 (pSTAT3 and the transcription of retinoic acid orphan receptor C (RORC gene. Blood derived Th17 cells from untreated and HAART-treated HIV-infected individuals were also examined for the IL-23 induced production of phosphorylated STAT3 (pSTAT3 and the expression of the IL-23 receptors.In vitro HIV infection significantly inhibited IL-17 production and IL-23 induced pSTAT3 while expression of RORC RNA was unaffected. Th17 cells isolated from untreated and HAART-treated HIV-infected individuals showed complete loss of IL-23 induced pSTAT3 without a decrease in the expression of the IL-23 receptors.This study is the first to demonstrate an effect of HIV on the IL-23 signaling pathway in Th17 cells. We show that in vitro and in vivo HIV infection results in impaired IL-23 signaling which is not reversed by HAART nor is it a result of reduced receptor expression, suggesting that HIV interferes with IL-23-activated signaling pathways. These findings may explain the inability of HAART to restore Th17 frequency and function and the resulting persistent chronic immune activation observed in HIV infected individuals.

  8. An increased expression profile of Th9/IL-9 correlated with Th17/IL-17 in patients with immune thrombocytopenia.

    Science.gov (United States)

    Qiao, Jianlin; Li, Xiaoqian; Wu, Yulu; Wu, Xiaoqing; Zhu, Feng; Liu, Na; Qi, Kunming; Cheng, Hai; Li, Depeng; Sun, Haiying; Zeng, Lingyu; Xu, Kailin

    2017-05-01

    Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disease, characterized by dysregulation of cellular immunity. Th9 cells were recently identified as a new subtype of Th cells, characterized by preferential production of IL-9. Given the pleiotropic function of IL-9, Th9 cells are demonstrated to be involved in various autoimmune diseases. However, whether Th9 cells are involved in the pathogenesis of ITP remains unclear. In this study, 49 active ITP patients, 39 ITP with remission and 20 healthy controls were included. Peripheral blood mononuclear cells (PBMCs) were isolated from ITP and controls for measuring Th9 and Th17 cells by flow cytometry. Meanwhile, RNA was isolated from PBMCs for the measurement of the mRNA level of PU.1, IRF4, BATF, and RORγt by quantitative real-time PCR. Plasma levels of IL-9 and IL-17 were detected by ELISA. Our results showed that higher expressions of Th9, IL-9, and associated transcription factors (PU.1, IRF4, and BATF) were found in active ITP patients and restored to the normal level (except IL-9) in patients in remission. Meanwhile, Th9 cells and the IL-9 plasma level were positively correlated with Th17 cells and the IL-17 level in ITP patients, respectively. Moreover, a positive correlation of IRF4 or BATF with RORγt was found. In conclusion, an aberrant expression profile of Th9/IL-9 was associated with pathogenesis of ITP possibly through cooperatively working with Th17/IL-17 and therapeutically targeting Th9/IL-9 might be a novel approach in the treatment of ITP.

  9. Ulmus davidiana var. japonica Nakai upregulates eosinophils and suppresses Th1 and Th17 cells in the small intestine.

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    Han-Sung Lee

    Full Text Available The bark of Ulmus davidiana var. japonica Nakai (Ulmaceae has been used in traditional Korean medicine for chronic inflammation in the gastrointestinal tract. Here we investigated the frequency and cytokine profile of the major immune cells in the small intestinal lamina propria (SI LP, spleen, and mesenteric lymph nodes (MLNs of mice treated orally with Ulmus davidiana var. japonica Nakai bark water extract (UDE to address the immunomodulatory role of this herb in intestinal homeostasis. B6 mice were given 5g/kg UDE once daily for 14 days. They were then sacrificed, and cells were isolated from the spleen, MLNs, and SI LP. The proportion of B versus T lymphocytes, CD4(+ versus CD8(+ T lymphocytes, Th1 and Th17 cells, and Foxp3(+ regulatory T cells in the spleen, MLNs, and SI LP were analyzed. The frequency of antigen-presenting cells (APCs, including dendritic cells, macrophages, and eosinophils in the SI LP and the expression of costimulatory molecules on APCs were also evaluated. The numbers and frequencies of Th1 and Th17 cells in the SI LP were significantly reduced in the UDE-treated mice compared with PBS controls. In addition, the proportion of IL-4-producing eosinophils in the SI LP was significantly elevated in the UDE-treated mice compared with controls. Taken together, these data indicate that UDE up-regulates the number and frequency of SI LP eosinophils, which can down-regulate the Th1 and Th17 responses via IL-4 secretion and contribute to intestinal homeostasis.

  10. Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective study

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    Malmvall Bo-Eric

    2011-04-01

    Full Text Available Abstract Background Previous studies indicate that successful resolution of Lyme neuroborreliosis (NB is associated with a strong T helper (Th 1-type cytokine response in the cerebrospinal fluid (CSF followed by a down-regulating Th2 response, whereas the role of the recently discovered Th17 cytokine response is unknown. Methods To investigate the relative contribution of different Th associated cytokine/chemokine responses, we used a multiple bead array to measure the levels of CXCL10 (Th1 marker, CCL22 (Th2 marker, IL-17 (Th17 marker and CXCL8 (general inflammation marker, in serum and in CSF from untreated patients with confirmed NB (n = 133, and non-NB patients (n = 96, and related the findings to clinical data. Samples from patients with possible early NB (n = 15 and possible late NB (n = 19 were also analysed, as well as samples from an additional control group with orthopaedic patients (n = 17, where CSF was obtained at spinal anaesthesia. Results The most prominent differences across groups were found in the CSF. IL-17 was elevated in CSF in 49% of the patients with confirmed NB, but was not detectable in the other groups. Patients with confirmed NB and possible early NB had significantly higher CSF levels of CXCL10, CCL22 and CXCL8 compared to both the non-NB group and the control group (p Borrelia-antibodies. Conclusion Our results support the notion that early NB is dominated by a Th1-type response, eventually accompanied by a Th2 response. Interestingly, IL-17 was increased exclusively in CSF from patients with confirmed NB, suggesting a hitherto unknown role for Th17 in NB. However, for conclusive evidence, future prospective studies are needed.

  11. Impact of dietary gluten on regulatory T cells and Th17 cells in BALB/c mice.

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    Julie Christine Antvorskov

    Full Text Available Dietary gluten influences the development of type 1 diabetes (T1D and a gluten-free (GF diet has a protective effect on the development of T1D. Gluten may influence T1D due to its direct effect on intestinal immunity; however, these mechanisms have not been adequately studied. We studied the effect of a GF diet compared to a gluten-containing standard (STD diet on selected T cell subsets, associated with regulatory functions as well as proinflammatory Th17 cells, in BALB/c mice. Furthermore, we assessed diet-induced changes in the expression of various T cell markers, and determined if changes were confined to intestinal or non-intestinal lymphoid compartments. The gluten-containing STD diet led to a significantly decreased proportion of γδ T cells in all lymphoid compartments studied, although an increase was detected in some γδ T cell subsets (CD8(+, CD103(+. Further, it decreased the proportion of CD4(+CD62L(+ T cells in Peyer's patches. Interestingly, no diet-induced changes were found among CD4(+Foxp3(+ T cells or CD3(+CD49b(+cells (NKT cells and CD3(-CD49b(+ (NK cells. Mice fed the STD diet showed increased proportions of CD4(+CD45RB(high+ and CD103(+ T cells and a lower proportion of CD4(+CD45RB(low+ T cells in both mucosal and non-mucosal compartments. The Th17 cell population, associated with the development of autoimmunity, was substantially increased in pancreatic lymph nodes of mice fed the STD diet. Collectively, our data indicate that dietary gluten influences multiple regulatory T cell subsets as well as Th17 cells in mucosal lymphoid tissue while fewer differences were observed in non-mucosal lymphoid compartments.

  12. Clinical Significance of IL-23 Regulating IL-17A and/or IL-17F Positive Th17 Cells in Chronic Periodontitis

    OpenAIRE

    Zhenhua Luo; Hui Wang; Yunlong Wu; Zheng Sun; Yafei Wu

    2014-01-01

    Objective. To investigate the expression level and clinical significance of (IL-17A+ and/or IL-17F+) Th17 cells under IL-23 regulation in patients of chronic periodontitis (CP) and healthy controls (HC). Materials and Methods. The whole peripheral blood samples were collected from 30 CP patients and 25 healthy controls. Flow cytometry was used to test the (IL-17A+ and/or IL-17F+) Th17 expression level. Recombinant human IL-23 (rhIL-23) was used to detect Th17 differentiation and expansion. Co...

  13. Endogenous glucocorticoid increases the basal level of Treg-Th17 balance under early phase of stress

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    WANG Hai-yan

    2012-12-01

    Full Text Available 【Abstract】 Objective: To explore the changes of Treg-Th17 balance influenced by corticosterone, major ef-fect hormone of hypothalamic-pituitary-adrenal (HPA axis under running stress. Methods: A total of 25 corticotropin-releasing hor-mone (CRH wildtype (CRH+/+ and knockout (CRH-/- mice were adopt and divided into 4 groups as follows: CRH+/+ ctrl, CRH+/+ stress, CRH-/- ctrl and CRH-/- stress. All mice in stress groups were under 2 h running. After 1 h, blood plasma in all groups was collected and the ex-pression of corticosterone and IL-17A was detected by ELISA. Meanwhile, unicell suspensions of peripheral lymph node and spleen in each group were prepared too and stained by PE-CD4 and FITC-CD25, then the changes of Treg (CD4+CD25+ in different groups were checked by flow cytometry; all data were statistically analyzed by the software of WinMDI 2.9, SPSS 11.5, Origin 7.5 and Matlab 2-D and 3-D plot function. Results: The levels of corticosterone were signifi-cantly higher in stress groups than that in correspond-ing control groups (P<0.05, especially in CRH+/+ stress group (P<0.01. However, the changes of Tregs were not obvious between stress groups and control groups with respective genotypes (P<0.05. Compared with that in CRH+/+ control group, the ratio of Treg and the expres-sion of IL-17A in CRH-/- stress group were significantly higher than those in control group (P<0.05. Combined with the expression levels of corticosterone, Treg and Th17, our study suggests that endogenous glucocorti-coid with basal level may cause the changes in Treg-Th17 balance. Moreover, as the corticosterone level increases, the expression of Treg and Th17 appears to manifest antagonistic fluctuant status with a rising ten-dency in general. Conclusion: Endogenous glucocorticoid under early stage of stress may increase the function of T lymphocyte immunity to some extent. Key words: Stress disorders, post-traumatic; Glucocorticoids; Corticotropin-releasing hormone

  14. The role of stromal mast cells in the modification of CD4 CD25 Foxp3 regulatory T cells, Th17 lymphocytes and cytotoxic lymphocytes Tc1 in the development and progression of tumor

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    Katarzyna Starska

    2010-08-01

    Full Text Available Despite the lack of direct evidence that immune surveillance cells protect against tumor development, indirect clinical observations and experimental studies indicate activity in the immune response against cancer cells of various origin. Little is known about the effects of the stromal tumor mast cell (MC in the activity of immune cells, i.e. CD4[sup] [/sup]CD25[sup] [/sup]Foxp3[sup] [/sup] regulatory T cells, Th17 lymphocytes, cytotoxic lymphocytes Tc1 and their mutual modulatory function and regulation of the antitumor immune response. Factors synthesized by stromal tumor mast cells including histamine, COX-2, CXCL8 (IL-8, VEGF, IL-6, TNF, iNOS, MMP-8, and MMP-9 may, on the one hand, directly affect the activity of T lymphocyte subpopulations, i.e. iTreg, Tc1, and Th17, and thus regulate immunological processes occurring in the vicinity of the tumor. On the other hand, through effects on angiogenesis, apoptosis, the cell cycle, secretion of cytokines and the expression of adhesion molecules, they may indirectly determine the progression of the neoplasm. Understanding the regulatory mechanisms occurring in the system: tumor stroma mast cell → immune cells infiltrating the tumor (iTreg, Tc1, Th17 lymphocytes → expression of factors involved in angiogenesis, apoptosis, the cell cycle, and secretion of cytokines and adhesion molecules creates the future possibility of influencing the activation and regulation of selected proneoplastic and antineoplastic factors appearing in the neoplasm environment. Research on these mechanisms may be the beginning of a new approach to the fight against cancer growth and provide an opportunity to introduce new methods of treatment. The aim of this study was to present the current knowledge on the role of stromal tumor CD117[sup] [/sup] mast cells and factors secreted by these cells in the activation of T lymphocyte subpopulations, i.e. CD4[sup] [/sup]CD25[sup] [/sup]Foxp3[sup] [/sup]regulatory T cells, Th17

  15. Periodontal pathogens directly promote autoimmune experimental arthritis by inducing a TLR2- and IL-1-driven Th17 response

    NARCIS (Netherlands)

    Aquino, S.G. de; Abdollahi-Roodsaz, S.; Koenders, M.I.; Loo, F.A.J. van de; Pruijn, G.; Marijnissen, R.J.; Walgreen, B.; Helsen, M.M.A.; Bersselaar, L.A.M. van den; Molon, R.S. de; Avila Campos, M.J.; Cunha, F.Q.; Cirelli, J.A.; Berg, W.B. van den

    2014-01-01

    Increasing epidemiologic evidence supports a link between periodontitis and rheumatoid arthritis. The actual involvement of periodontitis in the pathogenesis of rheumatoid arthritis and the underlying mechanisms remain, however, poorly understood. We investigated the influence of concomitant

  16. IL-1R and MyD88 signalling in CD4+ T cells promote Th17 immunity and atherosclerosis.

    Science.gov (United States)

    Engelbertsen, Daniel; Rattik, Sara; Wigren, Maria; Vallejo, Jenifer; Marinkovic, Goran; Schiopu, Alexandru; Björkbacka, Harry; Nilsson, Jan; Bengtsson, Eva

    2018-01-01

    The role of CD4+ T cells in atherosclerosis has been shown to be dependent on cytokine cues that regulate lineage commitment into mature T helper sub-sets. In this study, we tested the roles of IL-1R1 and MyD88 signalling in CD4+ T cells in atherosclerosis. We transferred apoe-/-myd88+/+ or apoe-/-myd88-/- CD4+ T cells to T- and B-cell-deficient rag1-/-apoe-/- mice fed high fat diet. Mice given apoe-/-myd88-/- CD4+ T cells exhibited reduced atherosclerosis compared with mice given apoe-/-myd88+/+ CD4+ T cells. CD4+ T cells from apoe-/-myd88-/- produced less IL-17 but similar levels of IFN-γ. Treatment of human CD4+ T cells with a MyD88 inhibitor inhibited IL-17 secretion in vitro. Transfer of il1r1-/- CD4+ T cells recapitulated the phenotype seen by transfer of myd88-/- CD4+ T cells with reduced lesion development and a reduction in Th17 and IL-17 production compared with wild type CD4+ T cell recipients. Relative collagen content of lesions was reduced in mice receiving il1r1-/- CD4+ T cells. We demonstrate that both IL1R and MyD88 signalling in CD4+ T cells promote Th17 immunity, plaque growth and may regulate plaque collagen levels.

  17. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell–dependent inflammation

    Science.gov (United States)

    Wang, Jian; Li, Fengqi; Wei, Haiming; Lian, Zhe-Xiong; Sun, Rui

    2014-01-01

    Influenza in humans is often accompanied by gastroenteritis-like symptoms such as diarrhea, but the underlying mechanism is not yet understood. We explored the occurrence of gastroenteritis-like symptoms using a mouse model of respiratory influenza infection. We found that respiratory influenza infection caused intestinal injury when lung injury occurred, which was not due to direct intestinal viral infection. Influenza infection altered the intestinal microbiota composition, which was mediated by IFN-γ produced by lung-derived CCR9+CD4+ T cells recruited into the small intestine. Th17 cells markedly increased in the small intestine after PR8 infection, and neutralizing IL-17A reduced intestinal injury. Moreover, antibiotic depletion of intestinal microbiota reduced IL-17A production and attenuated influenza-caused intestinal injury. Further study showed that the alteration of intestinal microbiota significantly stimulated IL-15 production from intestinal epithelial cells, which subsequently promoted Th17 cell polarization in the small intestine in situ. Thus, our findings provide new insights into an undescribed mechanism by which respiratory influenza infection causes intestinal disease. PMID:25366965

  18. Serum Th1, Th2 and Th17 cytokine profiles and alpha-enolase levels in recurrent aphthous stomatitis.

    Science.gov (United States)

    Ozyurt, Kemal; Celik, Ahmet; Sayarlıoglu, Mehmet; Colgecen, Emine; Incı, Rahime; Karakas, Tuba; Kelles, Mehmet; Cetin, Gozde Y

    2014-10-01

    All aspects of aetiopathogenesis of recurrent aphthous stomatitis (RAS) have not been elucidated. RAS and Behçet's disease (BD) have clinical and immunological characteristics in common. Although T17 cytokines and alpha-enolase have been shown to play effective roles in BD and many other autoinflammatory diseases recently, their roles in RAS have not been studied extensively. In the present study, we investigated levels of several Th1, Th2 and Th17 pathways related cytokines and alpha-enolase to elucidate pathogenesis of RAS and to obtain data about possible treatment alternatives for the condition. Serum interleukin-1, interleukin-13, interleukin-17, interleukin-18, interferon gamma and alpha-enolase levels in 24 patients with RAS, 30 patients with BD and 20 healthy controls were measured. Serum interleukin-1, interleukin-13, interleukin-17, interleukin-18, interferon gamma and alpha-enolase levels were higher in patients with RAS and patients with BD than in healthy controls (P < 0.005). Like Th1 and Th2 cells, Th17 cells were found to be effective in pathogenesis of RAS. In addition, alpha-enolase, the levels of which were high, may play an important role in etio-pathogenesis of RAS. Further studies to be designed in the light of these findings are required to shed light on pathogenesis and treatment of the condition. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation.

    Science.gov (United States)

    Wang, Jian; Li, Fengqi; Wei, Haiming; Lian, Zhe-Xiong; Sun, Rui; Tian, Zhigang

    2014-11-17

    Influenza in humans is often accompanied by gastroenteritis-like symptoms such as diarrhea, but the underlying mechanism is not yet understood. We explored the occurrence of gastroenteritis-like symptoms using a mouse model of respiratory influenza infection. We found that respiratory influenza infection caused intestinal injury when lung injury occurred, which was not due to direct intestinal viral infection. Influenza infection altered the intestinal microbiota composition, which was mediated by IFN-γ produced by lung-derived CCR9(+)CD4(+) T cells recruited into the small intestine. Th17 cells markedly increased in the small intestine after PR8 infection, and neutralizing IL-17A reduced intestinal injury. Moreover, antibiotic depletion of intestinal microbiota reduced IL-17A production and attenuated influenza-caused intestinal injury. Further study showed that the alteration of intestinal microbiota significantly stimulated IL-15 production from intestinal epithelial cells, which subsequently promoted Th17 cell polarization in the small intestine in situ. Thus, our findings provide new insights into an undescribed mechanism by which respiratory influenza infection causes intestinal disease. © 2014 Wang et al.

  20. Th17-related cytokines in mucositis: is there any difference between peri-implantitis and periodontitis patients?

    Science.gov (United States)

    Teixeira, Mayla Kezy Silva; Lira-Junior, Ronaldo; Telles, Daniel Moraes; Lourenço, Eduardo José Veras; Figueredo, Carlos Marcelo

    2017-07-01

    This study aimed to compare Th17-related cytokines named IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, sCD40L and TNF-α in peri-implant fluid (PIF) from mucositis sites in patients having either peri-implantitis, periodontitis or without interproximal alveolar bone loss. Thirty-three patients diagnosed with peri-implant mucositis were divided into three groups: individuals with peri-implant mucositis but without any signs of interproximal alveolar bone loss (group 1, n = 10), individuals with peri-implantitis (group 2, n = 14) and individuals with periodontitis (group 3, n = 9). Probing depth (PD), clinical attachment level (CAL), visible plaque index and bleeding on probing were measured. PIF was collected from mucositis sites in patients from the three groups and from peri-implantitis (group 2) and periodontitis sites (group 3). Cytokines were measured by a bead-based multiplex assay. Probing depth was significantly lower in group 1 when compared to both groups 2 and 3 (P implantitis sites (P = 0.04). The expression of Th17-related cytokines in PIF from mucositis sites seems to be similar regardless the presence or not of alveolar bone loss around implants or teeth. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. EGCG attenuates autoimmune arthritis by inhibition of STAT3 and HIF-1α with Th17/Treg control.

    Directory of Open Access Journals (Sweden)

    Eun-Ji Yang

    Full Text Available Epigallocatechin-3-gallate (EGCG is a green tea polyphenol exerting potent anti-oxidant and anti-inflammatory effects by inhibiting signaling and gene expression. The objective of the study was to evaluate the effect of EGCG on interleukin (IL-1 receptor antagonist knockout (IL-1RaKO autoimmune arthritis models. IL-1RaKO arthritis models were injected intraperitoneally with EGCG three times per week after the first immunization. EGCG decreased the arthritis index and showed protective effects against joint destruction in the IL-1RaKO arthritis models. The expression of pro-inflammatory cytokines, oxidative stress proteins, and p-STAT3 (Y705 and p-STAT3 (S727, mTOR and HIF-1α were significantly lower in mice treated with EGCG. EGCG reduced osteoclast markers in vivo and in vitro along with anti-osteoclastic activity was observed in EGCG-treated IL-1RaKO mice. The proportion of Foxp3(+ Treg cells increased in the spleens of mice treated with EGCG, whereas the proportion of Th17 cells reduced. In vitro, p-STAT3 (Y705 and p-STAT3 (S727, HIF1α and glycolytic pathway molecules were decreased by EGCG. EGCG suppressed the activation of mTOR and subsequently HIF-1α, which is considered as a metabolic check point of Th17/Treg differentiation supporting the therapeutic potential of EGCG in autoimmune arthritis.

  2. Central role of IL-17/Th17 immune responses and the gut microbiota in the pathogenesis of intestinal fibrosis.

    Science.gov (United States)

    Ray, Shuvra; De Salvo, Carlo; Pizarro, Theresa T

    2014-11-01

    Intestinal fibrosis is a serious, yet common, outcome in patients with inflammatory bowel disease (IBD). Despite advances in developing novel treatment modalities to control chronic gut inflammation characteristic of IBD, no effective antifibrotic therapies exist to date. As such, a deeper understanding of the molecular mechanisms underlying intestinal fibrosis and the availability of relevant animal models are critical to move this area of investigation forward. Emerging concepts in the pathogenesis of intestinal fibrosis include the central role of interleukin (IL)-17 and Th17 immune responses, although their precise contribution to chronic inflammation and IBD remains controversial. Other novel mediators of intestinal fibrosis, such as tumor necrosis factor-like ligand 1A and components of the renin-angiotensin system, support the importance of IL-17. Additionally, recent studies utilizing novel mouse models highlight the significance of the gut microbiota and link components of bacterial sensing, including nucleotide-binding oligomerization domain-containing protein 2, to IL-17/Th17 immune responses in the development of inflammation-associated intestinal fibrosis. Recent progress in identifying key mediators, novel animal models, and important mechanistic pathways in the pathogenesis of intestinal fibrosis holds promise for the development of effective antifibrotics in an area of significant, unmet clinical need.

  3. Interleukin-10 deficiency impairs regulatory T cell-derived neuropilin-1 functions and promotes Th1 and Th17 immunity.

    Science.gov (United States)

    Wang, Shimin; Gao, Xiang; Shen, Guobo; Wang, Wei; Li, Jingyu; Zhao, Jingyi; Wei, Yu-Quan; Edwards, Carl K

    2016-04-14

    Regulatory T cells (Tregs) expand in peripheral lymphoid organs and can produce immunosuppressive cytokines to support tumor growth. IL-10 abrogation efficiently induces Treg formation but dampens tumoral neuropilin-1 (Nrp-1) Treg signaling, which simultaneously augments Th1 and Th17 immunity. These effects are associated with the plasticity and stability of Tregs and effector T cell functions that can limit tumorigenesis. Within the tumor microenvironment, there appears to be a "mutual antagonism" between immunoenhancement and immunosuppression mechanisms, eventually leading to decreased metastasis. In contrast, tumor progression is paralleled by a reduction in Nrp-1-producing Tregs controlled by the IL-10 and TGF-β1 levels. However, Th1, Th17 and Treg immunity is primarily regulated by IL-10 or Nrp-1 and not TGF-β1 except when combined with IL-10. These results emphasize the important implications for the therapeutic use of Tregs. The number of Treg cells must be maintained in a healthy and dynamic homeostatic range to prevent malignant diseases. Moreover, Treg-mediated immunosuppression can be limited by reducing tumor-derived Treg Nrp-1 levels.

  4. Palaeopathological Evidence of Infectious Disease in a Skeletal Population from Late Medieval Riga, Latvia (15Th-17Th Centuries AD

    Directory of Open Access Journals (Sweden)

    Gerhards Guntis

    2017-04-01

    Full Text Available The aim of this study was to evaluate the presence of infectious disease in the Dome Church (Riga Cathedral Cemetery population, dating from the late medieval period (15th-17th centuries AD. A total of 274 individuals were macroscopically observed for evidence of infectious disease, and seven individuals with lesions possibly associated with a bacterial infection affecting the skeleton were selected for further analysis. Pathological changes on the outer table of the skull and in the long bones of legs characteristic of venereal syphilis were observed in four female and one male individual. Likewise, changes possibly related to late congenital syphilis were observed in a 14-15-year-old non-adult individual. All these individuals were buried in a small area adjacent to the northern wall of the Dome Church, which possibly belonged to a hospital or a shelter. The evidence for venereal syphilis from the cemetery complements historical data about the spread of the disease in Riga during the 16th-17th centuries AD. One adult male individual had destructive changes in the lower spine, which could be associated with tuberculosis (TB. So far, this is the first individual with possible TB from the archaeological populations of Riga. This research provides unique evidence about infectious disease in skeletal populations from the late medieval period in Latvia, and the results will be used as the basis for future research in the subject, including extraction of ancient pathogen DNA.

  5. Human periodontal ligament cells facilitate leukocyte recruitment and are influenced in their immunomodulatory function by Th17 cytokine release.

    Science.gov (United States)

    Konermann, A; Beyer, M; Deschner, J; Allam, J P; Novak, N; Winter, J; Jepsen, S; Jäger, A

    2012-01-01

    The objective of this in vitro study was to examine the immunomodulatory impact of human periodontal ligament (PDL) cells on the nature and magnitude of the leukocyte infiltrate in periodontal inflammation, particularly with regard to Th17 cells. PDL cells were challenged with pro-inflammatory cytokines (IL-1ß, IL-17A, and IFN-γ) and analyzed for the expression of cytokines involved in periodontal immunoinflammatory processes (IL-6, MIP-3 alpha, IL-23A, TGFß1, IDO, and CD274). In order to further investigate a direct involvement of PDL cells in leukocyte function, co-culture experiments were conducted. The expression of the immunomodulatory cytokines studied was significantly increased under pro-inflammatory conditions in PDL cells. Although PDL cells did not stimulate leukocyte proliferation or Th17 differentiation, these cells induced the recruitment of leukocytes. The results of our study suggest that PDL cells might be involved in chronic inflammatory mechanisms in periodontal tissues and thus in the transition to an adaptive immune response in periodontitis. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Hypothyroidism in Noninterferon Treated-HCV Infected Individuals Is Associated with Abnormalities in the Regulation of Th17 Cells

    Directory of Open Access Journals (Sweden)

    Luis A. Salazar

    2010-01-01

    Full Text Available HCV-Ag-specific TH17 cells secrete IL17, a cytokine involved in autoimmune diseases and regulated by IL10 and TGF-b. 5–12% of patients with chronic HCV infection have hypothyroidism. We evaluated the role of these cytokines in this patients by determining serum concentration of TsH, T3, free T4, IL2, IL10, IL12, IL17, TGF-b, anti-TG, TPO, CCP, GBM, and cardiolipin antibodies in 87 chronically noninterferon treated HCV-infected patients. 20 patients (group A had elevated TsH values (>5 μUI/ml whereas the remaining 67 (group B had normal values. The percentage of anti-TPO, TG, GBM, and cardiolipin antibodies in group A patients (33%, 41%, 5% and 5%, resp. as well as IL17, IL2 and TGF-b concentrations (25±23 pg/ml, 643±572 pg/ml, and 618±221 pg/ml, resp. were significantly higher than group B. Abnormal Th17 regulation mediated by IL-2 and low TGF-b concentrations is associated with hypothyroidism in chronically-infected HCV patients.

  7. Defining the functional states of Th17 cells [v1; ref status: indexed, http://f1000r.es/51y

    Directory of Open Access Journals (Sweden)

    Youjin Lee

    2015-05-01

    Full Text Available The molecular mechanisms governing T helper (Th cell differentiation and function have revealed a complex network of transcriptional and protein regulators. Cytokines not only initiate the differentiation of CD4 Th cells into subsets but also influence the identity, plasticity and effector function of a T cell. Of the subsets, Th17 cells, named for producing interleukin 17 (IL-17 as their signature cytokine, secrete a cohort of other cytokines, including IL-22, IL-21, IL-10, IL-9, IFNγ, and GM-CSF.  In recent years, Th17 cells have emerged as key players in host defense against both extracellular pathogens and fungal infections, but they have also been implicated as one of the main drivers in the pathogenesis of autoimmunity, likely mediated in part by the cytokines that they produce. Advances in high throughput genomic sequencing have revealed unexpected heterogeneity in Th17 cells and, as a consequence, may have tremendous impact on our understanding of their functional diversity. The assortment in gene expression may also identify different functional states of Th17 cells. This review aims to understand the interplay between the cytokine regulators that drive Th17 cell differentiation and functional states in Th17 cells.

  8. Generation of IL-8 and IL-9 Producing CD4+ T Cells Is Affected by Th17 Polarizing Conditions and AHR Ligands

    Directory of Open Access Journals (Sweden)

    Michaela Gasch

    2014-01-01

    Full Text Available The T helper cell subsets Th1, Th2, Th17, and Treg play an important role in immune cell homeostasis, in host defense, and in immunological disorders. Recently, much attention has been paid to Th17 cells which seem to play an important role in the early phase of the adoptive immune response and autoimmune disease. When generating Th17 cells under in vitro conditions the amount of IL-17A producing cells hardly exceeds 20% while the nature of the remaining T cells is poorly characterized. As engagement of the aryl hydrocarbon receptor (AHR has also been postulated to modulate the differentiation of T helper cells into Th17 cells with regard to the IL-17A expression we ask how far do Th17 polarizing conditions in combination with ligand induced AHR activation have an effect on the production of other T helper cell cytokines. We found that a high proportion of T helper cells cultured under Th17 polarizing conditions are IL-8 and IL-9 single producing cells and that AHR activation results in an upregulation of IL-8 and a downregulation of IL-9 production. Thus, we have identified IL-8 and IL-9 producing T helper cells which are subject to regulation by the engagement of the AHR.

  9. Plasma levels of Th17-related cytokines and complement C3 correlated with aggressive behavior in patients with schizophrenia.

    Science.gov (United States)

    Li, Haozhe; Zhang, Qinting; Li, Ningning; Wang, Fan; Xiang, Hui; Zhang, Zongfeng; Su, Yousong; Huang, Yueqi; Zhang, Shengyu; Zhao, Guoqing; Zhou, Rubai; Mao, Ling; Lin, Zhiguang; Cai, Weixiong; Fang, Yiru; Xie, Bin; Zhao, Min; Hong, Wu

    2016-12-30

    Increasing evidence indicates that immune inflammatory processes, especially autoimmune reaction, should be considered in the pathophysiology of schizophrenia and aggressive behavior. The present study aimed to explore the correlation between immune factors (C3 and Th17-related cytokines) and aggressive behavior in schizophrenia patients. Forty schizophrenia patients and forty age- and gender-matched healthy controls participated in the study. Blood samples were assessed by ELISA upon enrollment. Positive and negative syndrome scale (PANSS) and modified overt aggression scale (MOAS) were used to estimate the severity and aggressive symptoms of schizophrenia patients. Plasma levels of IL-17, IL-23, and TGF-β1 in schizophrenia patients were significantly higher than those in healthy controls [(37.63±17.82) vs. (29.34±10.38)pg/ml, p=0.02; (101.40±135.26) vs. (13.09±5.94) pg/ml, p=0.01; (2864.57±2163.61) vs. (1839.69±1797.73)pg/ml, p=0.04], whereas C3 levels were significantly lower in schizophrenia patients [( 120,479.67± 65,612.50) vs. ( 208,060.21± 217,008.21)ng/ml, p=0.02]. IL-17, IL-23, and TGF-β1 levels were positively related to total scores of MOAS (p=0.02, p=0.02 and p=0.03, respectively) and PANSS (p=0.04, p=0.04 and p=0.02, respectively), whereas C3 levels were negatively related to total PANSS scores (p=0.03). IL-17 and IL-23 levels were positively correlated with PANSS excited component scores (p=0.04 and p=0.01, respectively). Our findings suggested that the Th17-related cytokine levels were positively related to the severity of schizophrenia and aggressive behavior, whereas C3 levels were negatively related to the severity of schizophrenia. This study demonstrated that elevated levels of Th17-related cytokines and decreased levels of C3 could be potential biomarkers for schizophrenia and aggressive behavior. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. The genome of th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment.

    Science.gov (United States)

    Sczesnak, Andrew; Segata, Nicola; Qin, Xiang; Gevers, Dirk; Petrosino, Joseph F; Huttenhower, Curtis; Littman, Dan R; Ivanov, Ivaylo I

    2011-09-15

    Perturbations of the composition of the symbiotic intestinal microbiota can have profound consequences for host metabolism and immunity. In mice, segmented filamentous bacteria (SFB) direct the accumulation of potentially proinflammatory Th17 cells in the intestinal lamina propria. We present the genome sequence of SFB isolated from monocolonized mice, which classifies SFB phylogenetically as a unique member of Clostridiales with a highly reduced genome. Annotation analysis demonstrates that SFB depend on their environment for amino acids and essential nutrients and may utilize host and dietary glycans for carbon, nitrogen, and energy. Comparative analyses reveal that SFB are functionally related to members of the genus Clostridium and several pathogenic or commensal "minimal" genera, including Finegoldia, Mycoplasma, Borrelia, and Phytoplasma. However, SFB are functionally distinct from all 1200 examined genomes, indicating a gene complement representing biology relatively unique to their role as a gut commensal closely tied to host metabolism and immunity. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Local Th17/IgA immunity correlate with protection against intranasal infection with Streptococcus pyogenes

    DEFF Research Database (Denmark)

    Mortensen, Rasmus; Christensen, Dennis; Hansen, Lasse Bøllehuus

    2017-01-01

    the intranasal route was able to induce protection against repeated intranasal GAS infections in a murine challenge model. The lack of intranasal protection induced by the parenteral vaccine correlated with a reduced mucosal recall response at the site of infection. Taken together, our results demonstrate...... vaccine against GAS, it is therefore important to investigate how protective immunity is related to the route of vaccine administration. To explore this, we examined whether a parenterally administered anti-GAS vaccine could protect against an intranasal GAS infection or if this would require locally...... primed immunity. We foundd that a parenteral CAF01 adjuvanted GAS vaccine offered no protection against intranasal infection despite inducing strong systemic Th1/Th17/IgG immunity that efficiently protected against an intraperitoneal GAS infection. However, the same vaccine administered via...

  12. Coenzyme Q10 Inhibits Th17 and STAT3 Signaling Pathways to Ameliorate Colitis in Mice.

    Science.gov (United States)

    Lee, Seon-Yeong; Lee, Seung Hoon; Yang, Eun-Ji; Kim, Jae-Kyung; Kim, Eun-Kyung; Jung, KyungAh; Jung, Hongsoon; Lee, Kyungjin; Lee, Han Hee; Lee, Bo-In; Park, Sung-Hwan; Shin, Dong Yun; Cho, Mi-La

    2017-09-01

    Coenzyme Q10 (CoQ10) is a powerful antioxidant substance synthesized in the body. The current study aimed to determine whether CoQ10 suppresses inflammation and inhibits p-STAT3 expression in an experimental colitis mouse model. The mice were orally fed with CoQ10 once a day for 13 days. Histological analysis of the colons was performed by immunohistochemistry. Expression of IL-17, FOXP3, p53, AMPK, and mTOR and activation of p-STAT3 and p-STAT5 in lymph node and spleen tissues were detected by confocal microscopy of stained tissue sections. The relative mRNA expression was measured with real-time PCR, and protein levels were examined by western blot. CoQ10 reduced the disease activity index score and the colon histological score. It also reduced inflammatory mediators in the colon and increased the colon length. The expression of IL-17 and p-STAT3 was decreased with CoQ10 treatment. In contrast, CoQ10 treatment increased the expression of p-AMPK and FOXP3. Expression of anti-inflammatory cytokines was shown to increase in colitis mice treated with CoQ10. These results suggested that CoQ10 may reduce the severity of colitis and suppress inflammation through the inhibition of p-STAT3 and IL-17. These results support the use of CoQ10 as a potential targeted therapy for the treatment of colitis.

  13. Lactobacillus casei BL23 regulates Treg and Th17 T-cell populations and reduces DMH-associated colorectal cancer.

    Science.gov (United States)

    Lenoir, Marion; Del Carmen, Silvina; Cortes-Perez, Naima G; Lozano-Ojalvo, Daniel; Muñoz-Provencio, Diego; Chain, Florian; Langella, Philippe; de Moreno de LeBlanc, Alejandra; LeBlanc, Jean Guy; Bermúdez-Humarán, Luis G

    2016-09-01

    Chronic intestinal inflammation alters host physiology and could lead to colorectal cancer (CRC). We have previously reported beneficial effects of the probiotic strain of Lactobacillus casei BL23 in different murine models of intestinal inflammation. In addition, there is an emerging interest on the potential beneficial effects of probiotics to treat CRC. We thus explored whether L. casei BL23 displays protective effects on CRC. Mice were subcutaneously injected with 1,2-dimethylhydrazine (DMH) weekly during 10 weeks and orally administered with L. casei BL23 in the drinking water until the 10th week. Multiple plaque lesions in the large intestine were observed macroscopically and counted and intestinal tissues were also histologically analyzed. Finally, T-cell populations and cytokine production were evaluated after co-incubation of L. casei BL23 with spleen cells from non-treated mice to determine the immuno-modulatory effects of this bacterium. Our results show that oral treatment with this probiotic bacterium modulates host immune responses and significantly protect mice against DMH-induced CRC. This protection may be associated with the modulation of regulatory T-cells towards a Th17-biased immune response accompanied by the expression of regulatory cytokines (IL-6, IL-17, IL-10 and TGF-β), as demonstrated in L. casei BL23-treated splenocytes, but also with the colonic expression of IL-22 observed in vivo on L. casei BL23-treated mice; suggesting the induction of a fine-tune Th17-biased response. Altogether our results reveal the high potential of L. casei BL23 to treat CRC and opens new frontiers for the study of immunomodulatory functions of probiotics.

  14. A novel epitope from CD22 regulates Th1 and Th17 cell function in systemic lupus erythematosus.

    Science.gov (United States)

    Yuan, Jing; Yu, Miao; Cao, Ai-Lin; Chen, Xiao; Zhang, Li-Hua; Song, You; Cheng, Xiang; Zhou, Zi-Hua; Wang, Min; Guo, He-Ping; Du, Rong; Liao, Yu-Hua

    2013-01-01

    The published antibodies (Abs) against CD22 on B cells including Epratuzumab could inhibit B cell activation mainly through binding to C2-set Ig domain of CD22, but they are rarely reported to modulate the pathogenic CD4(+) T cell function in systemic lupus erythematosus (SLE). Recently, it was proved that the extracellular amino-terminal V-set Ig domain of CD22 might mediate the interaction of B and T cells, but for now the exact effect of this domain on CD4(+) T cell biology have not been identified. Thus, in this study, we screened out a peptide termed B2285 from this V-set Ig domain, developed the novel specific anti-B2285 Abs in rabbits, and investigated their effects in MRL/lpr mice with spontaneous SLE. The results showed that anti-B2285 Abs could ameliorate the disease severity obviously in spontaneous SLE mice with the decreased differentiations of Th1 and Th17 cells and no changes of Th2 and Treg cells. In co-cultured B cells and CD4(+) T cells, this specific anti-CD22 Abs was observed to inhibit the anti-dsDNA Abs production, CD4(+) T cells proliferation, the protein levels of T-bet and RORγt, and the mRNA levels of TNF-α, IFN-γ, IL-6 and IL-17 in CD4(+) T cells. Moreover, the expression of CD45RO on CD4(+) T cells could be also apparently diminished by this novel Abs. The data suggested that anti-B2285 Abs could slow SLE progression significantly by regulating Th1 and Th17 cells function via B-T cell interaction and the cytokine network regulation. The treatment against V-set Ig domain of CD22 would be a valuable therapeutic method for SLE and other autoimmune diseases.

  15. A novel epitope from CD22 regulates Th1 and Th17 cell function in systemic lupus erythematosus.

    Directory of Open Access Journals (Sweden)

    Jing Yuan

    Full Text Available The published antibodies (Abs against CD22 on B cells including Epratuzumab could inhibit B cell activation mainly through binding to C2-set Ig domain of CD22, but they are rarely reported to modulate the pathogenic CD4(+ T cell function in systemic lupus erythematosus (SLE. Recently, it was proved that the extracellular amino-terminal V-set Ig domain of CD22 might mediate the interaction of B and T cells, but for now the exact effect of this domain on CD4(+ T cell biology have not been identified. Thus, in this study, we screened out a peptide termed B2285 from this V-set Ig domain, developed the novel specific anti-B2285 Abs in rabbits, and investigated their effects in MRL/lpr mice with spontaneous SLE. The results showed that anti-B2285 Abs could ameliorate the disease severity obviously in spontaneous SLE mice with the decreased differentiations of Th1 and Th17 cells and no changes of Th2 and Treg cells. In co-cultured B cells and CD4(+ T cells, this specific anti-CD22 Abs was observed to inhibit the anti-dsDNA Abs production, CD4(+ T cells proliferation, the protein levels of T-bet and RORγt, and the mRNA levels of TNF-α, IFN-γ, IL-6 and IL-17 in CD4(+ T cells. Moreover, the expression of CD45RO on CD4(+ T cells could be also apparently diminished by this novel Abs. The data suggested that anti-B2285 Abs could slow SLE progression significantly by regulating Th1 and Th17 cells function via B-T cell interaction and the cytokine network regulation. The treatment against V-set Ig domain of CD22 would be a valuable therapeutic method for SLE and other autoimmune diseases.

  16. Piper nigrum extract ameliorated allergic inflammation through inhibiting Th2/Th17 responses and mast cells activation.

    Science.gov (United States)

    Bui, Thi Tho; Piao, Chun Hua; Song, Chang Ho; Shin, Hee Soon; Shon, Dong-Hwa; Chai, Ok Hee

    2017-12-01

    Piper nigrum (Piperaceae) is commonly used as a spice and traditional medicine in many countries. P. nigrum has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the effect of P. nigrum on allergic asthma has not been known. This study investigated the effect of P. nigrum ethanol extracts (PNE) on airway inflammation in asthmatic mice model. In the ovalbumin (OVA)-induced allergic asthma model, we analysed the number of inflammatory cells and cytokines production in bronchoalveolar lavage fluid (BALF) and lung tissue; histological structure; as well as the total immunoglobulin (Ig)E, anti-OVA IgE, anti-OVA IgG1 and histamine levels in serum. The oral administration (200 mg/kg) of PNE reduced the accumulation of inflammatory cells (eosinophils, neutrophils in BALF and mast cells in lung tissue); regulated the balance of the cytokines production of Th1, Th2, Th17 and Treg cells, specifically, inhibited the expressions of GATA3, IL-4, IL-6, IL-1β, RORγt, IL-17A, TNF-α and increased the secretions of IL-10, INF-γ in BALF and lung homogenate. Moreover, PNE suppressed the levels of total IgE, anti-OVA IgE, anti-OVA IgG1 and histamine release in serum. The histological analysis showed that the fibrosis and infiltration of inflammatory cells were also ameliorated in PNE treated mice. On the other hand, PNE inhibited the allergic responses via inactivation of rat peritoneal mast cells degranulation. These results suggest that PNE has therapeutic potential for treating allergic asthma through inhibiting Th2/Th17 responses and mast cells activation. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Iguratimod ameliorates inflammatory responses by modulating the Th17/Treg paradigm in dextran sulphate sodium-induced murine colitis.

    Science.gov (United States)

    Jiang, Xue-Pei; Huang, Xie-Lin; Yang, Zao-Peng; Wang, Shun-Cai; Xie, Wei; Miao, Lei; Tang, Li; Huang, Zhi-Ming

    2018-01-01

    Inflammatory bowel disease (IBD) is an autoimmune disease with an abnormal and persistent immune response. Iguratimod, a novel anti-rheumatic drug, exhibits anti-inflammatory effects and regulates immune response. The role of iguratimod in intestinal mucosal inflammation and immunity has not been examined. The aim of this study was to investigate whether iguratimod ameliorates dextran sulphate sodium (DSS)-induced murine colitis and its potential regulatory mechanism. Murine colitis was induced by administering 2.5% DSS for 5days. Some mice were administered iguratimod (5, 30mg/kg) by oral gavage once daily for 7days, beginning on the day 3 after colitis induction. Our study showed that iguratimod alleviates the symptoms of colitis and suppresses intestinal tissue damage, including macroscopic and histopathological manifestations. Moreover, iguratimod reduced interleukin (IL)-6, IL-17, and tumour necrosis factor-α levels, and increased the expression levels of IL-10 and TGF-β. In addition, iguratimod downregulated the proportion of Th17 cells, the level of transcription factor retinoic acid-related orphan receptor γt (RORγt), and the phosphorylation of signal transducer and activator of transcription-3 (STAT3), and upregulated the proportion of Treg cells, the level of transcription factor forkhead box p3 (Foxp3), and the phosphorylation of STAT5 in the colonic tissues. In conclusion, iguratimod plays a protective role in mice with DSS-induced colitis via anti-inflammatory effects and regulation of Th17/Treg cells. Therefore, use of iguratimod may serve as a novel therapeutic strategy for the treatment of IBD. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Staphylococcus aureus-derived extracellular vesicles induce neutrophilic pulmonary inflammation via both Th1 and Th17 cell responses.

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    Kim, M-R; Hong, S-W; Choi, E-B; Lee, W-H; Kim, Y-S; Jeon, S G; Jang, M H; Gho, Y S; Kim, Y-K

    2012-10-01

    Recent evidence indicates that Staphylococcus aureus, one of the most important human pathogens, secretes vesicles into the extracellular milieu. To evaluate whether inhalation of S. aureus-derived extracellular vesicles (EV) is causally related to the pathogenesis of inflammatory pulmonary diseases. Staphylococcus aureus EV were prepared by sequential ultrafiltration and ultracentrifugation. The innate immune response was evaluated in vitro after the application of EV to airway epithelial cells and alveolar macrophages. In vivo innate and adaptive immune responses were evaluated after airway exposure to EV. Adjuvant effects of EV on the development of hypersensitivity to inhaled allergens were also evaluated after airway sensitization with S. aureus EV and ovalbumin (OVA). Staphylococcus aureus and S. aureus EV were detected in house dust. Alveolar macrophages produced both tumor necrosis α (TNF-α) and interleukin 6 (IL-6) after in vitro stimulation with S. aureus EV, whereas airway epithelial cells produced only IL-6. Repeated airway exposure to S. aureus EV induced both Th1 and Th17 cell responses and neutrophilic pulmonary inflammation, mainly via a Toll-like receptor 2 (TLR2)-dependent mechanism. In terms of adjuvant effects, airway sensitization with S. aureus EV and OVA resulted in neutrophilic pulmonary inflammation after OVA challenge alone. This phenotype was partly reversed by the absence of interferon γ (IFN-γ) or IL-17. Staphylococcus aureus EV can induce Th1 and Th17 neutrophilic pulmonary inflammation, mainly in a TLR2-dependent manner. Additionally, S. aureus EV enhance the development of airway hypersensitivity to inhaled allergens. © 2012 John Wiley & Sons A/S.

  19. Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes.

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    Kristi Alnek

    Full Text Available The production of several cytokines could be dysregulated in type 1 diabetes (T1D. In particular, the activation of T helper (Th type 1 (Th1 cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF and interleukin (IL-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α, Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8, but not human leukocyte antigen (HLA genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.

  20. The imbalance between Treg and Th17 cells caused by FTY720 treatment in skin allograft rejection

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    Alessandra Gonçalves Commodaro

    2012-07-01

    Full Text Available OBJECTIVES: FTY720 modulates CD4+T cells by the augmentation of regulatory T cell activity, secretion of suppressive cytokines and suppression of IL-17 secretion by Th17 cells. To further understand the process of graft rejection/acceptance, we evaluated skin allograft survival and associated events after FTY720 treatment. METHODS: F1 mice (C57BL/6xBALB/c and C57BL/6 mice were used as donors for and recipients of skin transplantation, respectively. The recipients were transplanted and either not treated or treated with FTY720 by gavage for 21 days to evaluate the allograft survival. In another set of experiments, the immunological evaluation was performed five days post-transplantation. The spleens, axillary lymph nodes and skin allografts of the recipient mice were harvested for phenotyping (flow cytometry, gene expression (real-time PCR and cytokine (Bio-Plex analysis. RESULTS: The FTY720 treatment significantly increased skin allograft survival, reduced the number of cells in the lymph nodes and decreased the percentage of Tregs at this site in the C57BL/6 recipients. Moreover, the treatment reduced the number of graft-infiltrating cells and the percentage of CD4+ graft-infiltrating cells. The cytokine analysis (splenocytes showed decreased levels of IL-10, IL-6 and IL-17 in the FTY720-treated mice. We also observed a decrease in the IL-10, IL-6 and IL-23 mRNA levels, as well as an increase in the IL-27 mRNA levels, in the splenocytes of the treated group. The FTY720-treated mice exhibited increased mRNA levels of IL-10, IL-27 and IL-23 in the skin graft. CONCLUSIONS: Our results demonstrated prolonged but not indefinite skin allograft survival by FTY720 treatment. This finding indicates that the drug did not prevent the imbalance between Tr1 and Th17 cells in the graft that led to rejection.

  1. Development and function of invariant natural killer T cells producing T(h2- and T(h17-cytokines.

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    Hiroshi Watarai

    2012-02-01

    Full Text Available There is heterogeneity in invariant natural killer T (iNKT cells based on the expression of CD4 and the IL-17 receptor B (IL-17RB, a receptor for IL-25 which is a key factor in T(H2 immunity. However, the development pathway and precise function of these iNKT cell subtypes remain unknown. IL-17RB⁺iNKT cells are present in the thymic CD44⁺/⁻ NK1.1⁻ population and develop normally even in the absence of IL-15, which is required for maturation and homeostasis of IL-17RB⁻iNKT cells producing IFN-γ. These results suggest that iNKT cells contain at least two subtypes, IL-17RB⁺ and IL-17RB⁻ subsets. The IL-17RB⁺iNKT subtypes can be further divided into two subtypes on the basis of CD4 expression both in the thymus and in the periphery. CD4⁺ IL-17RB⁺iNKT cells produce T(H2 (IL-13, T(H9 (IL-9 and IL-10, and T(H17 (IL-17A and IL-22 cytokines in response to IL-25 in an E4BP4-dependent fashion, whereas CD4⁻ IL-17RB⁺iNKT cells are a retinoic acid receptor-related orphan receptor (RORγt⁺ subset producing T(H17 cytokines upon stimulation with IL-23 in an E4BP4-independent fashion. These IL-17RB⁺iNKT cell subtypes are abundantly present in the lung in the steady state and mediate the pathogenesis in virus-induced airway hyperreactivity (AHR. In this study we demonstrated that the IL-17RB⁺iNKT cell subsets develop distinct from classical iNKT cell developmental stages in the thymus and play important roles in the pathogenesis of airway diseases.

  2. Sexual dimorphism in an animal model of Sjögren's syndrome: a potential role for Th17 cells

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    Alexandria Voigt

    2015-11-01

    Full Text Available Sjögren's syndrome is a complex autoimmune disease with an array of diverse immunological, genetic and environmental etiologies, making identification of the precise autoimmune mechanism difficult to define. One of the most distinctive aspects of Sjögren's syndrome is the high sexual dimorphism with women affected 10-20 times more than men. It is nearly impossible to study the sexual dimorphic development of Sjögren's syndrome in human patients; therefore it is pertinent to develop an appropriate animal model which resembles human disease. The data indicated that female C57BL/6.NOD-Aec1Aec2 mice developed an earlier onset of sialadenitis with a higher composition of CD3+ T cells and a 10-fold increase in glandular infiltration of Th17 cells at the onset of clinical disease compared to male mice. Inflammatory Th17 cells of female mice exhibited a stronger proliferation in response to disease-specific antigen than their male counterpart. At the clinical disease stage, altered autoantibody patterns can be detected in females whereas they are seldom observed in male C57BL/6.NOD-Aec1Aec2 mice. Interestingly, male C57BL/6.NOD-Aec1Aec2 mice developed an earlier loss of secretory function, despite the fact that female C57BL/6.NOD-Aec1Aec2 mice exhibited a more rapid secretory loss. This data indicates the strong sexual dimorphism in the SjS-susceptible C57BL/6.NOD-Aec1Aec2 animal model, making it an appropriate animal model to examine human disease.

  3. STAT3 activation in Th17 and Th22 cells controls IL-22-mediated epithelial host defense during infectious colitis.

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    Backert, Ingo; Koralov, Sergei B; Wirtz, Stefan; Kitowski, Vera; Billmeier, Ulrike; Martini, Eva; Hofmann, Katharina; Hildner, Kai; Wittkopf, Nadine; Brecht, Katrin; Waldner, Maximilian; Rajewsky, Klaus; Neurath, Markus F; Becker, Christoph; Neufert, Clemens

    2014-10-01

    The Citrobacter rodentium model mimics the pathogenesis of infectious colitis and requires sequential contributions from different immune cell populations, including innate lymphoid cells (ILCs) and CD4(+) lymphocytes. In this study, we addressed the role of STAT3 activation in CD4(+) cells during host defense in mice against C. rodentium. In mice with defective STAT3 in CD4(+) cells (Stat3(ΔCD4)), the course of infection was unchanged during the innate lymphoid cell-dependent early phase, but significantly altered during the lymphocyte-dependent later phase. Stat3(ΔCD4) mice exhibited intestinal epithelial barrier defects, including downregulation of antimicrobial peptides, increased systemic distribution of bacteria, and prolonged reduction in the overall burden of C. rodentium infection. Immunomonitoring of lamina propria cells revealed loss of virtually all IL-22-producing CD4(+) lymphocytes, suggesting that STAT3 activation was required for IL-22 production not only in Th17 cells, but also in Th22 cells. Notably, the defective host defense against C. rodentium in Stat3(∆CD4) mice could be fully restored by specific overexpression of IL-22 through a minicircle vector-based technology. Moreover, expression of a constitutive active STAT3 in CD4(+) cells shaped strong intestinal epithelial barrier function in vitro and in vivo through IL-22, and it promoted protection from enteropathogenic bacteria. Thus, our work indicates a critical role of STAT3 activation in Th17 and Th22 cells for control of the IL-22-mediated host defense, and strategies expanding STAT3-activated CD4(+) lymphocytes may be considered as future therapeutic options for improving intestinal barrier function in infectious colitis. Copyright © 2014 by The American Association of Immunologists, Inc.

  4. B Cell, Th17, and Neutrophil Related Cerebrospinal Fluid Cytokine/Chemokines Are Elevated in MOG Antibody Associated Demyelination.

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    Kavitha Kothur

    Full Text Available Myelin oligodendrocyte glycoprotein antibody (MOG Ab associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination.To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS and -negative (NEG groups.We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM = 8, transverse myelitis (TM = 2 n = 10] and serum MOG Ab NEG (ADEM = 5, TM = 4, n = 9 demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls.The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19 as well as some of Th17 related cytokines (IL-6 AND G-CSF compared to MOG Ab NEG group (all p<0.01. In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies.Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.

  5. Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation.

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    Marks, E; Naudin, C; Nolan, G; Goggins, B J; Burns, G; Mateer, S W; Latimore, J K; Minahan, K; Plank, M; Foster, P S; Callister, R; Veysey, M; Walker, M M; Talley, N J; Radford-Smith, G; Keely, S

    2017-09-01

    Intestinal inflammatory lesions are inherently hypoxic, due to increased metabolic demands created by cellular infiltration and proliferation, and reduced oxygen supply due to vascular damage. Hypoxia stabilizes the transcription factor hypoxia-inducible factor-1α (HIF) leading to a coordinated induction of endogenously protective pathways. We identified IL12B as a HIF-regulated gene and aimed to define how the HIF-IL-12p40 axis influenced intestinal inflammation. Intestinal lamina propria lymphocytes (LPL) were characterized in wild-type and IL-12p40 -/- murine colitis treated with vehicle or HIF-stabilizing prolyl-hydroxylase inhibitors (PHDi). IL12B promoter analysis was performed to examine hypoxia-responsive elements. Immunoblot analysis of murine and human LPL supernatants was performed to characterize the HIF/IL-12p40 signaling axis. We observed selective induction of IL-12p40 following PHDi-treatment, concurrent with suppression of Th1 and Th17 responses in murine colitis models. In the absence of IL-12p40, PHDi-treatment was ineffective. Analysis of the IL12B promoter identified canonical HIF-binding sites. HIF stabilization in LPLs resulted in production of IL-12p40 homodimer which was protective against colitis. The selective induction of IL-12p40 by HIF-1α leads to a suppression of mucosal Th1 and Th17 responses. This HIF-IL12p40 axis may represent an endogenously protective mechanism to limit the progression of chronic inflammation, shifting from pro-inflammatory IL-12p70 to an antagonistic IL-12p40 homodimer.

  6. Association between Th17-related cytokines and risk of non-small cell lung cancer among patients with or without chronic obstructive pulmonary disease.

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    Liao, Chen; Yu, Zu-Bin; Meng, Gang; Wang, Li; Liu, Qing-Yun; Chen, Liu-Tong; Feng, Shuang-Shuang; Tu, Hong-Bo; Li, Ya-Fei; Bai, Li

    2015-09-01

    CD4 (+) T helper 17 (Th17) cells play critical roles in inflammation and tumor development. The involvement of Th17 cells in chronic obstructive pulmonary disease (COPD)-type inflammation-associated lung cancer has also been confirmed in animal models. However, to the authors' knowledge, it is unknown whether the role of Th17 cells is different in patients with lung cancer complicated with COPD compared with those without COPD. In the current study, the authors attempted to determine the association between the circulating levels of Th17-related cytokines and the clinical characteristics of non-small cell lung cancer (NSCLC) in patients with or without COPD. The authors designed a matched case-control study that included 70 patients with NSCLC with COPD, 148 patients with NSCLC without COPD, and 148 healthy controls. The data regarding the clinicopathological features of these participants were collected. Circulating levels of Th17-related cytokines, including interleukin (IL) 23 (IL-23), IL-17A, IL-17F, IL-22, and tumor necrosis factor-α, were measured. The circulating levels of IL-23, IL-17A, IL-17F, IL-22, and tumor necrosis factor-α were found to be significantly higher in the patients with NSCLC compared with the healthy controls (Pdisease compared with those with stage IIIB to stage IV disease (P<.05). In addition, the 5 Th17-related cytokines demonstrated pairwise correlations, with Spearman rank correlation coefficients of 0.646 to 0.888 (P<.05). The results of the current study indicate a clear association between the Th17-related cytokine profile and the risk of NSCLC complicated by the presence or absence of COPD. © 2015 American Cancer Society.

  7. Human Blood CD1c+ Dendritic Cells Promote Th1 and Th17 Effector Function in Memory CD4+ T Cells

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    Ingrid M. Leal Rojas

    2017-08-01

    Full Text Available Dendritic cells (DC initiate the differentiation of CD4+ helper T cells into effector cells including Th1 and Th17 responses that play an important role in inflammation and autoimmune disease pathogenesis. In mice, Th1 and Th17 responses are regulated by different conventional (c DC subsets, with cDC1 being the main producers of IL-12p70 and inducers of Th1 responses, while cDC2 produce IL-23 to promote Th17 responses. The role that human DC subsets play in memory CD4+ T cell activation is not known. This study investigated production of Th1 promoting cytokine IL-12p70, and Th17 promoting cytokines, IL-1β, IL-6, and IL-23, by human blood monocytes, CD1c+ DC, CD141+ DC, and plasmacytoid DC and examined their ability to induce Th1 and Th17 responses in memory CD4+ T cells. Human CD1c+ DC produced IL-12p70, IL-1β, IL-6, and IL-23 in response to R848 combined with LPS or poly I:C. CD141+ DC were also capable of producing IL-12p70 and IL-23 but were not as proficient as CD1c+ DC. Activated CD1c+ DC were endowed with the capacity to promote both Th1 and Th17 effector function in memory CD4+ T cells, characterized by high production of interferon-γ, IL-17A, IL-17F, IL-21, and IL-22. These findings support a role for CD1c+ DC in autoimmune inflammation where Th1/Th17 responses play an important role in disease pathogenesis.

  8. Maintenance of intestinal Th17 cells and reduced microbial translocation in SIV-infected rhesus macaques treated with interleukin (IL-21.

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    Suresh Pallikkuth

    Full Text Available In pathogenic HIV and SIV infections of humans and rhesus macaques (RMs, preferential depletion of CD4⁺ Th17 cells correlates with mucosal immune dysfunction and disease progression. Interleukin (IL-21 promotes differentiation of Th17 cells, long-term maintenance of functional CD8⁺ T cells, and differentiation of memory B cells and antibody-secreting plasma cells. We hypothesized that administration of IL-21 will improve mucosal function in the context of pathogenic HIV/SIV infections. To test this hypothesis, we infected 12 RMs with SIV(mac239 and at day 14 post-infection treated six of them with rhesus rIL-21-IgFc. IL-21-treatment was safe and did not increase plasma viral load or systemic immune activation. Compared to untreated animals, IL-21-treated RMs showed (i higher expression of perforin and granzyme B in total and SIV-specific CD8⁺ T cells and (ii higher levels of intestinal Th17 cells. Remarkably, increased levels of Th17 cells were associated with reduced levels of intestinal T cell proliferation, microbial translocation and systemic activation/inflammation in the chronic infection. In conclusion, IL-21-treatment in SIV-infected RMs improved mucosal immune function through enhanced preservation of Th17 cells. Further preclinical studies of IL-21 may be warranted to test its potential use during chronic infection in conjunction with antiretroviral therapy.

  9. Arctigenin functions as a selective agonist of estrogen receptor β to restrict mTORC1 activation and consequent Th17 differentiation.

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    Wu, Xin; Tong, Bei; Yang, Yan; Luo, Jinque; Yuan, Xusheng; Wei, Zhifeng; Yue, Mengfan; Xia, Yufeng; Dai, Yue

    2016-12-20

    Arctigenin was previously proven to inhibit Th17 cell differentiation and thereby attenuate colitis in mice by down-regulating the activation of mechanistic target of rapamycin complex 1 (mTORC1). The present study was performed to address its underlying mechanism in view of estrogen receptor (ER). The specific antagonist PHTPP or siRNA of ERβ largely diminished the inhibitory effect of arctigenin on the mTORC1 activation in T cell lines and primary CD4+ T cells under Th17-polarization condition, suggesting that arctigenin functioned in an ERβ-dependent manner. Moreover, arctigenin was recognized to be an agonist of ERβ, which could bind to ERβ with a moderate affinity, promote dissociation of ERβ/HSP90 complex and nuclear translocation and phosphorylation of ERβ, and increase the transcription activity. Following activation of ERβ, arctigenin inhibited the activity of mTORC1 by disruption of ERβ-raptor-mTOR complex assembly. Deficiency of ERβ markedly abolished arctigenin-mediated inhibition of Th17 cell differentiation. In colitis mice, the activation of ERβ, inhibition of mTORC1 activation and Th17 response by arctigenin were abolished by PHTPP treatment. In conclusion, ERβ might be the target protein of arctigenin responsible for inhibition of mTORC1 activation and resultant prevention of Th17 cell differentiation and colitis development.

  10. Cyclic AMP-Responsive Element-Binding Protein (CREB is Critical in Autoimmunity by Promoting Th17 but Inhibiting Treg Cell Differentiation

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    Xiaohu Wang

    2017-11-01

    Full Text Available The molecular mechanisms that govern differential T cell development into pro-inflammatory Th17 vs. regulatory T (Treg cells remain unclear. Here, we show that selective deletion of CREB in T cells or Th17 cells impaired Th17 cell differentiation in vitro and in vivo, and led to resistance to autoimmune diseases. Mechanistically, CREB, activated by CD3-PKC-ϴ signaling, plays a key role in regulating Th17 cell differentiation, at least in part through directly binding to the Il17-Il17f gene locus. Unexpectedly, although dispensable for FOXP3 expression and for the homeostasis and suppressive function of thymus-derived Treg cells, CREB negatively regulates the survival of TGF-β-induced Treg cells, and deletion of CREB resulted in increased FOXP3+ Treg cells in the intestine and protection in a colitis model. Thus, CREB is critical in autoimmune diseases by promoting Th17 cell and inhibiting de novo Treg cell generation.

  11. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the T(H)17 lineage-specific transcription factor RORgamma t.

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    Ayyoub, Maha; Deknuydt, Florence; Raimbaud, Isabelle; Dousset, Christelle; Leveque, Lucie; Bioley, Gilles; Valmori, Danila

    2009-05-26

    Recent studies have suggested a close relationship between CD4(+)FOXP3(+) regulatory T cells (Tregs) and proinflammatory IL-17-producing T helper cells (T(H)17) expressing the lineage-specific transcription factor RORgamma t. We report here the unexpected finding that human memory Tregs secrete IL-17 ex vivo and constitutively express RORgamma t. IL-17-secreting Tregs share some phenotypic and functional features with conventional T(H)17 cells, expressing high levels of CCR4 and CCR6 and low levels of CXCR3. However, unlike conventional T(H)17 cells, they express low levels of CD161 and mostly fail to cosecrete IL-22 and TNF-alpha ex vivo. Ex vivo secretion of IL-17 and constitutive expression of RORgamma t by human memory Tregs suggest that, in addition to their well-known suppressive functions, these cells likely play additional, as yet undescribed, proinflammatory functions.

  12. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the TH17 lineage-specific transcription factor RORγt

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    Ayyoub, Maha; Deknuydt, Florence; Raimbaud, Isabelle; Dousset, Christelle; Leveque, Lucie; Bioley, Gilles; Valmori, Danila

    2009-01-01

    Recent studies have suggested a close relationship between CD4+FOXP3+ regulatory T cells (Tregs) and proinflammatory IL-17-producing T helper cells (TH17) expressing the lineage-specific transcription factor RORγt. We report here the unexpected finding that human memory Tregs secrete IL-17 ex vivo and constitutively express RORγt. IL-17-secreting Tregs share some phenotypic and functional features with conventional TH17 cells, expressing high levels of CCR4 and CCR6 and low levels of CXCR3. However, unlike conventional TH17 cells, they express low levels of CD161 and mostly fail to cosecrete IL-22 and TNF-α ex vivo. Ex vivo secretion of IL-17 and constitutive expression of RORγt by human memory Tregs suggest that, in addition to their well-known suppressive functions, these cells likely play additional, as yet undescribed, proinflammatory functions. PMID:19439651

  13. The 3 major types of innate and adaptive cell-mediated effector immunity.

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    Annunziato, Francesco; Romagnani, Chiara; Romagnani, Sergio

    2015-03-01

    The immune system has tailored its effector functions to optimally respond to distinct species of microbes. Based on emerging knowledge on the different effector T-cell and innate lymphoid cell (ILC) lineages, it is clear that the innate and adaptive immune systems converge into 3 major kinds of cell-mediated effector immunity, which we propose to categorize as type 1, type 2, and type 3. Type 1 immunity consists of T-bet(+) IFN-γ-producing group 1 ILCs (ILC1 and natural killer cells), CD8(+) cytotoxic T cells (TC1), and CD4(+) TH1 cells, which protect against intracellular microbes through activation of mononuclear phagocytes. Type 2 immunity consists of GATA-3(+) ILC2s, TC2 cells, and TH2 cells producing IL-4, IL-5, and IL-13, which induce mast cell, basophil, and eosinophil activation, as well as IgE antibody production, thus protecting against helminthes and venoms. Type 3 immunity is mediated by retinoic acid-related orphan receptor γt(+) ILC3s, TC17 cells, and TH17 cells producing IL-17, IL-22, or both, which activate mononuclear phagocytes but also recruit neutrophils and induce epithelial antimicrobial responses, thus protecting against extracellular bacteria and fungi. On the other hand, type 1 and 3 immunity mediate autoimmune diseases, whereas type 2 responses can cause allergic diseases. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  14. Expression of IL-23/Th17-related cytokines in basal cell carcinoma and in the response to medical treatments.

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    Cristina Pellegrini

    Full Text Available Several immune-related markers have been implicated in basal cell carcinoma (BCC pathogenesis. The BCC inflammatory infiltrate is dominated by Th2 cytokines, suggesting a specific state of immunosuppression. In contrast, regressing BCC are characterized by a Th1 immune response with IFN-γ promoting a tumor suppressive activity. IL-23/Th17-related cytokines, as interleukin (IL-17, IL-23 and IL-22, play a significant role in cutaneous inflammatory diseases, but their involvement in skin carcinogenesis is controversial and is poorly investigated in BCC. In this study we investigated the expression of IFN-γ, IL-17, IL-23 and IL-22 cytokines in BCC at the protein and mRNA level and their modulation during imiquimod (IMQ treatment or photodynamic therapy (PDT. IFN-γ, IL-17, IL-23 and IL-22 levels were evaluated by immunohistochemistry and quantitative Real Time PCR in 41 histopathologically-proven BCCs (28 superficial and 13 nodular from 39 patients. All BCC samples were analyzed at baseline and 19 of 41 also during medical treatment (9 with IMQ 5% cream and 10 with MAL-PDT. Association between cytokines expression and clinico-pathological variables was evaluated. Higher levels of IFN-γ, IL-17, IL-23 and IL-22 were found in BCCs, mainly in the peritumoral infiltrate, compared to normal skin, with the expression being correlated to the severity of the inflammatory infiltrate. IFN-γ production was higher in superficial BCCs compared to nodular BCCs, while IL-17 was increased in nodular BCCs. A significant correlation was found between IFN-γ and IL-17 expression with both cytokines expressed by CD4+ and CD8+ T-cells. An increase of all cytokines occurred during the inflammatory phase induced by IMQ and at the early time point of PDT treatment, with significant evidence for IFN-γ, IL-23, and IL-22. Our results confirm the role of IFN-γ and support the involvement of IL-23/Th17-related cytokines in BCC pathogenesis and in the inflammatory response

  15. Th1, Th2, Th17, and regulatory cytokines in children with different clinical forms of allergy.

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    Stelmaszczyk-Emmel, Anna; Zawadzka-Krajewska, Anna; Kopatys, Agata; Demkow, Urszula

    2013-01-01

    In addition to Th2 cells, other T cell subsets, like Th1, Th17, and regulatory T cells are also involved in the pathogenesis of allergic rhinitis, food allergy, and other allergic diseases. The aim of the study was to evaluate a wide profile of cytokines in the plasma from children with pollen/dust and cow milk allergy with the use of a multiplex Cytometric Bead Array (CBA) test. Twenty children with allergy: 11 with pollen/dust and 9 with cow milk allergy were enrolled into the study. For the analysis of INFγ, IL-2, IL-4, IL-6, IL-10, IL-17A, and TNFα levels, a flow cytometric test was used. TGFβ concentration was measured using an ELISA test. Concentrations of almost all of the detected cytokines in the patient's plasma were below 1 pg/ml, with no significant difference between the groups examined. The level of IL-17A was higher in pollen/dust allergy group (median 12.73 pg/ml; 25th percentile-Q1/75th percentile-Q3; 9.28/15.83) in comparison to cow milk allergy group (median 7.86 pg/ml - Q1/Q3; 7.86/14.37). Children with cow milk allergy had a slightly higher concentration of TGFβ than children with pollen/dust allergy (median 28.7 ng/ml - Q1/Q3; 19.77/33.00 vs. 17.84 ng/ml - Q1/Q3; 11.21/23.75, respectively); the difference did not reach statistical significance. We conclude that plasma concentration of Th1, Th2, and Th17 regulatory cytokines are relatively low in allergic children. The CBA test, which could be useful in pediatric practice as it requires a relatively small plasma sample volume, is not sensitive enough to measure low cytokine levels, since its detection limit and the standard curve are not appropriate for the concentrations of these mediators expected in clinical samples.

  16. Enhanced Th1/Th17 Functions of CD161+ CD8+ T Cells in Mucosal Tissues of Rhesus Macaques.

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    Namita Rout

    Full Text Available Expression of the C-type lectin-like receptor CD161 by human T cells is associated with type-17 responses, which play critical regulatory roles in immunity and inflammation at mucosal sites. However, the functions of CD161-expressing T cells in macaques, the pre-clinical model of several human diseases, remain unknown. This study examined the phenotypic and functional characteristics of CD161+ T cells in peripheral blood, mucosal tissues and lymph nodes of rhesus macaques. Majority of CD161-expressing T cells in peripheral blood and lung/intestinal mucosal tissues of rhesus macaques were found to be CD8+CD4- in phenotype. There was a significant enrichment of CD161+CD8+ T cells in the lungs and colonic mucosa (16.1%±6.6 and 16.8%±5.7 in comparison to peripheral blood (4.2%±1.2 and mesenteric lymph nodes (1.3%±0.8. Regardless of the tissue compartment, CD161+CD8+ T cells mainly comprised of γδ T cells and TCR Vα7.2+ MAIT cells (up to 80%, and displayed Th1 and Th17 cytokine responses to mitogen stimulation. Mucosal CD161+CD8+ T cells were characterized by very high expression of CD69, a recent activation marker that is preferentially expressed on tissue resident cells. Furthermore, lung and colonic mucosal CD161+CD8+ T cells showed enhanced IFN-γ, IL-17, and Perforin production in comparison to those in blood. Thus, macaque CD161+CD8+ T cells represent mucosal tissue-homing innate-like CD8+ T-cell populations with Th1/Th17 type cytokine and cytotoxic effector functions that can potentially enhance the recruitment of adaptive immune cells and control initial pathogen burden/dissemination in tissues. Analysis of their role in early immune responses to mucosal pathogens will be valuable in the design of vaccines and therapeutics.

  17. The IDO–AhR Axis Controls Th17/Treg Immunity in a Pulmonary Model of Fungal Infection

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    Eliseu Frank de Araújo

    2017-07-01

    Full Text Available In infectious diseases, the enzyme indoleamine 2,3 dioxygenase-1 (IDO1 that catalyzes the tryptophan (Trp degradation along the kynurenines (Kyn pathway has two main functions, the control of pathogen growth by reducing available Trp and immune regulation mediated by the Kyn-mediated expansion of regulatory T (Treg cells via aryl hydrocarbon receptor (AhR. In pulmonary paracoccidioidomycosis (PCM caused by the dimorphic fungus Paracoccidioides brasiliensis, IDO1 was shown to control the disease severity of both resistant and susceptible mice to the infection; however, only in resistant mice, IDO1 is induced by TGF-β signaling that confers a stable tolerogenic phenotype to dendritic cells (DCs. In addition, in pulmonary PCM, the tolerogenic function of plasmacytoid dendritic cells was linked to the IDO1 activity. To further evaluate the function of IDO1 in pulmonary PCM, IDO1-deficient (IDO1−/− C57BL/6 mice were intratracheally infected with P. brasiliensis yeasts and the infection analyzed at three postinfection periods regarding several parameters of disease severity and immune response. The fungal loads and tissue pathology of IDO1−/− mice were higher than their wild-type controls resulting in increased mortality rates. The evaluation of innate lymphoid cells showed an upregulated differentiation of the innate lymphoid cell 3 phenotype accompanied by a decreased expansion of ILC1 and NK cells in the lungs of infected IDO1−/− mice. DCs from these mice expressed elevated levels of costimulatory molecules and cytokine IL-6 associated with reduced production of IL-12, TNF-α, IL-1β, TGF-β, and IL-10. This response was concomitant with a marked reduction in AhR production. The absence of IDO1 expression caused an increased influx of activated Th17 cells to the lungs with a simultaneous reduction in Th1 and Treg cells. Accordingly, the suppressive cytokines IL-10, TGF-β, IL-27, and IL-35 appeared in reduced levels in the lungs of

  18. Expression of IL-23/Th17-related cytokines in basal cell carcinoma and in the response to medical treatments.

    Science.gov (United States)

    Pellegrini, Cristina; Orlandi, Augusto; Costanza, Gaetana; Di Stefani, Alessandro; Piccioni, Antonella; Di Cesare, Antonella; Chiricozzi, Andrea; Ferlosio, Amedeo; Peris, Ketty; Fargnoli, Maria Concetta

    2017-01-01

    Several immune-related markers have been implicated in basal cell carcinoma (BCC) pathogenesis. The BCC inflammatory infiltrate is dominated by Th2 cytokines, suggesting a specific state of immunosuppression. In contrast, regressing BCC are characterized by a Th1 immune response with IFN-γ promoting a tumor suppressive activity. IL-23/Th17-related cytokines, as interleukin (IL)-17, IL-23 and IL-22, play a significant role in cutaneous inflammatory diseases, but their involvement in skin carcinogenesis is controversial and is poorly investigated in BCC. In this study we investigated the expression of IFN-γ, IL-17, IL-23 and IL-22 cytokines in BCC at the protein and mRNA level and their modulation during imiquimod (IMQ) treatment or photodynamic therapy (PDT). IFN-γ, IL-17, IL-23 and IL-22 levels were evaluated by immunohistochemistry and quantitative Real Time PCR in 41 histopathologically-proven BCCs (28 superficial and 13 nodular) from 39 patients. All BCC samples were analyzed at baseline and 19 of 41 also during medical treatment (9 with IMQ 5% cream and 10 with MAL-PDT). Association between cytokines expression and clinico-pathological variables was evaluated. Higher levels of IFN-γ, IL-17, IL-23 and IL-22 were found in BCCs, mainly in the peritumoral infiltrate, compared to normal skin, with the expression being correlated to the severity of the inflammatory infiltrate. IFN-γ production was higher in superficial BCCs compared to nodular BCCs, while IL-17 was increased in nodular BCCs. A significant correlation was found between IFN-γ and IL-17 expression with both cytokines expressed by CD4+ and CD8+ T-cells. An increase of all cytokines occurred during the inflammatory phase induced by IMQ and at the early time point of PDT treatment, with significant evidence for IFN-γ, IL-23, and IL-22. Our results confirm the role of IFN-γ and support the involvement of IL-23/Th17-related cytokines in BCC pathogenesis and in the inflammatory response during IMQ and

  19. Leprosy Reactions Show Increased Th17 Cell Activity and Reduced FOXP3+ Tregs with Concomitant Decrease in TGF-β and Increase in IL-6.

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    Saini, Chaman; Siddiqui, Anisuddin; Ramesh, Venkatesh; Nath, Indira

    2016-04-01

    50% of leprosy patients suffer from episodes of Type 1/ reversal reactions (RR) and Type 2/ Erythema Nodosum Leprosum (ENL) reactions which lead to morbidity and nerve damage. CD4+ subsets of Th17 cells and CD25+FOXP3+ regulatory T cells (Tregs) have been shown to play a major role in disease associated immunopathology and in stable leprosy as reported by us and others. The aim of our study was to analyze their role in leprosy reactions. Quantitative reverse transcribed PCR (qPCR), flowcytometry and ELISA were used to respectively investigate gene expression, cell phenotypes and supernatant levels of cytokines in antigen stimulated PBMC cultures in patients with stable disease and those undergoing leprosy reactions. Both types of reactions are associated with significant increase of Th17 cells and associated cytokines IL-17A, IL-17F, IL-21, IL-23 and chemokines CCL20, CCL22 as compared to matching stable forms of leprosy. Concurrently patients in reactions show reduction in FOXP3+ Treg cells as well as reduction in TGF-β and increase in IL-6. Moreover, expression of many T cell markers, cytokines, chemokines and signaling factors were observed to be increased in RR as compared to ENL reaction patients. Patients with leprosy reactions show an imbalance in Th17 and Treg populations. The reduction in Treg suppressor activity is associated withhigherTh17cell activity. The combined effect of reduced TGF-β and enhanced IL-6, IL-21 cytokines influence the balance between Th17 or Treg cells in leprosy reactions as reported in the murine models and autoimmune diseases. The increase in Th17 cell associated cytokines may contribute to lesional inflammation.

  20. Leprosy Reactions Show Increased Th17 Cell Activity and Reduced FOXP3+ Tregs with Concomitant Decrease in TGF-β and Increase in IL-6.

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    Chaman Saini

    2016-04-01

    Full Text Available 50% of leprosy patients suffer from episodes of Type 1/ reversal reactions (RR and Type 2/ Erythema Nodosum Leprosum (ENL reactions which lead to morbidity and nerve damage. CD4+ subsets of Th17 cells and CD25+FOXP3+ regulatory T cells (Tregs have been shown to play a major role in disease associated immunopathology and in stable leprosy as reported by us and others. The aim of our study was to analyze their role in leprosy reactions.Quantitative reverse transcribed PCR (qPCR, flowcytometry and ELISA were used to respectively investigate gene expression, cell phenotypes and supernatant levels of cytokines in antigen stimulated PBMC cultures in patients with stable disease and those undergoing leprosy reactions. Both types of reactions are associated with significant increase of Th17 cells and associated cytokines IL-17A, IL-17F, IL-21, IL-23 and chemokines CCL20, CCL22 as compared to matching stable forms of leprosy. Concurrently patients in reactions show reduction in FOXP3+ Treg cells as well as reduction in TGF-β and increase in IL-6. Moreover, expression of many T cell markers, cytokines, chemokines and signaling factors were observed to be increased in RR as compared to ENL reaction patients.Patients with leprosy reactions show an imbalance in Th17 and Treg populations. The reduction in Treg suppressor activity is associated withhigherTh17cell activity. The combined effect of reduced TGF-β and enhanced IL-6, IL-21 cytokines influence the balance between Th17 or Treg cells in leprosy reactions as reported in the murine models and autoimmune diseases. The increase in Th17 cell associated cytokines may contribute to lesional inflammation.

  1. RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F.

    Science.gov (United States)

    Leppkes, Moritz; Becker, Christoph; Ivanov, Ivaylo I; Hirth, Sebastian; Wirtz, Stefan; Neufert, Clemens; Pouly, Sandrine; Murphy, Andrew J; Valenzuela, David M; Yancopoulos, George D; Becher, Burkhard; Littman, Dan R; Neurath, Markus F

    2009-01-01

    IL-17-producing CD4(+) T-helper cells (Th17) contribute to chronic autoimmune inflammation in the brain, and levels of Th17-derived cytokines increase in patients with colitis, suggesting a role in pathogenesis. We analyzed the roles of Th17 cells and the transcription factor retinoic acid receptor-related organ receptor (ROR)gamma, which regulates Th17 differentiation, in chronic intestinal inflammation. Using an adoptive transfer model of colitis, we compared the colitogenic potential of wild-type, interleukin-17A (IL-17A)-, IL-17F-, IL-22-, and RORgamma-deficient CD4(+)CD25(-) T cells in RAG1-null mice. Adoptive transfer of IL-17A-, IL-17F-, or IL-22-deficient T lymphocytes into RAG1-null mice caused severe colitis that was indistinguishable from that caused by wild-type cells. In contrast, transfer of RORgamma-null T cells failed to increase mucosal IL-17 cytokine levels and did not induce colitis. Treatment with IL-17A was able to restore colitis after transfer of RORgamma-null T cells, indicating a crucial role for Th17 cells in pathogenesis. Treatment of RAG1 mice that received IL-17F-null (but not wild-type) T cells with a neutralizing anti-IL-17A antibody significantly suppressed disease, indicating redundant biological effects of IL-17A and IL-17F. We have identified a crucial role of RORgamma-expressing Th17 cells in chronic intestinal inflammation. RORgamma controls IL-17A and IL-17F production, and these cytokines have a redundant but highly pathogenic role in gut inflammation. Reagents that target RORgamma or a combination of anti-IL-17A and anti-IL-17F might be developed as therapeutics for chronic colitis.

  2. Paradoxical Expansion of Th1 and Th17 Lymphocytes in Rheumatoid Arthritis Following Infliximab Treatment: a Possible Explanation for a Lack of Clinical Response.

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    Talotta, Rossella; Berzi, Angela; Atzeni, Fabiola; Batticciotto, Alberto; Clerici, Mario; Sarzi-Puttini, Piercarlo; Trabattoni, Daria

    2015-08-01

    The immunogenicity of anti-TNF-α drugs may affect their safety and efficacy. Infliximab (IFX), a chimeric monoclonal antibody, induces antibody formation in up to 60% of cases. Some studies have suggested the involvement of a Th1 response to TNFα blockers following immunization, but the triggering of Th17 responses has never been reported. The aim of this study is to investigate whether the immunogenicity of IFX affects the Th1, Th17 and Treg compartments in rheumatoid arthritis (RA) patients failing IFX therapy, and verify whether this may be responsible for treatment failure. The study involved 55 patients with RA (15 treatment-naïve patients; 20 IFX responders; 20 IFX non-responders) and 10 healthy controls. PBMCs were cultured in the presence/absence of IFX, and the variations in the percentage of Th1, Th17 and Treg lymphocytes following IFX treatment were analysed. IFX-specific Th1 and Th17 responses and an increase in IL-21 production were observed in patients failing IFX (p < 0.01, p < 0.05, and p < 0.01 respectively). In contrast, IFX incubation reduced significantly Th1 and Th17 responses and IL-21 production (p < 0.05) in successfully-treated subjects, but did not affect these responses in healthy controls or treatment-naïve patients. RA patients may have impaired peripheral tolerance, which could favour the development of an aberrant immunological response to biological drugs. The loss of therapeutic effectiveness of IFX and the onset of adverse events may be due to a paradoxical activation of Th17 or Th1 lymphocytes following sensitisation, thus worsening the patients' inflammatory status.

  3. Arctigenin functions as a selective agonist of estrogen receptor ? to restrict mTORC1 activation and consequent Th17 differentiation

    OpenAIRE

    Wu, Xin; Tong, Bei; Yang, Yan; Luo, Jinque; Yuan, Xusheng; Wei, Zhifeng; Yue, Mengfan; Xia, Yufeng; Dai, Yue

    2016-01-01

    Arctigenin was previously proven to inhibit Th17 cell differentiation and thereby attenuate colitis in mice by down-regulating the activation of mechanistic target of rapamycin complex 1 (mTORC1). The present study was performed to address its underlying mechanism in view of estrogen receptor (ER). The specific antagonist PHTPP or siRNA of ER? largely diminished the inhibitory effect of arctigenin on the mTORC1 activation in T cell lines and primary CD4+ T cells under Th17-polarization condit...

  4. The Th1/Th2/Th17/Treg paradigm induced by stachydrine hydrochloride reduces uterine bleeding in RU486-induced abortion mice.

    Science.gov (United States)

    Li, Xia; Wang, Bin; Li, Yuzhu; Wang, Li; Zhao, Xiangzhong; Zhou, Xianbin; Guo, Yuqi; Jiang, Guosheng; Yao, Chengfang

    2013-01-09

    The Th1/Th2/Th17/Treg paradigm plays an important role in achieving maternal-fetal immunotolerance and participates in RU486-induced abortion. Excessive uterine bleeding is the most common side effect of RU486-induced abortion; however, its etiopathogenesis has not been fully understood. Therefore, elucidating the correlation between the Th1/Th2/Th17/Treg paradigm and the volume of uterine bleeding may offer novel therapeutic target for reducing uterine bleeding in RU486-induced abortion. Leonurus sibiricus has been used in clinics to reduce postpartum hemorrhage with low toxicity and high efficiency; however, the effective constituents and therapeutic mechanism have not been described. Stachydrine hydrochloride is the main constituent of L. sibiricus, therefore L. sibiricus is regarded as a candidate for reducing uterine bleeding in RU486-induced abortion mice by regulating the Th1/Th2/Th17/Treg paradigm. The purpose of this study was to determine the Th1/Th2/Th17/Treg paradigm in uterine bleeding of RU486-induced abortion mice and to elucidate the immunopharmacologic effects of stachydrine hydrochloride on inducing the Th1/Th2/Th17/Treg paradigm in reducing the uterine bleeding volume in RU486-induced abortion mice. To investigate the Th1/Th2/Th17/Treg paradigm in uterine bleeding during RU486-induced abortion mice, pregnant BALB/c mice were treated with high- and low-dose RU486 (1.5mg/kg and 0.9 mg/kg, respectively), and the serum progesterone (P(4)) protein level, uterine bleeding volume, and proportions of Th1/Th2/Th17/Treg cells in mice at the maternal-fetal interface were detected by ELISA assay, alkaline hematin photometric assay, and flow cytometry, respectively. To determine the regulatory effect of stachydrine hydrochloride on the Th1/Th2/Th17/Treg paradigm in vitro, splenocytes of non-pregnant mice were separated and treated with P(4,) RU486, and/or stachydrine hydrochloride (10(-5)M, 10(-4)M, and 10(-3)M, respectively). The proportions of Th1/Th2/Th17

  5. The Role of T Helper (TH17 Cells as a Double-Edged Sword in the Interplay of Infection and Autoimmunity with a Focus on Xenobiotic-Induced Immunomodulation

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    Nasr Y. A. Hemdan

    2013-01-01

    Full Text Available Extensive research in recent years suggests that exposure to xenobiotic stimuli plays a critical role in autoimmunity induction and severity and that the resulting response would be exacerbated in individuals with an infection-aroused immune system. In this context, heavy metals constitute a prominent category of xenobiotic substances, known to alter divergent immune cell responses in accidentally and occupationally exposed individuals, thereby increasing the susceptibility to autoimmunity and cancer, especially when accompanied by inflammation-triggered persistent sensitization. This perception is learned from experimental models of infection and epidemiologic studies and clearly underscores the interplay of exposure to such immunomodulatory elements with pre- or postexposure infectious events. Further, the TH17 cell subset, known to be associated with a growing list of autoimmune manifestations, may be the “superstar” at the interface of xenobiotic exposure and autoimmunity. In this review, the most recently established links to this nomination are short-listed to create a framework to better understand new insights into TH17’s contributions to autoimmunity.

  6. Complete genome sequences of rat and mouse segmented filamentous bacteria, a potent inducer of th17 cell differentiation.

    Science.gov (United States)

    Prakash, Tulika; Oshima, Kenshiro; Morita, Hidetoshi; Fukuda, Shinji; Imaoka, Akemi; Kumar, Naveen; Sharma, Vineet K; Kim, Seok-Won; Takahashi, Mahoko; Saitou, Naruya; Taylor, Todd D; Ohno, Hiroshi; Umesaki, Yoshinori; Hattori, Masahira

    2011-09-15

    Segmented filamentous bacteria (SFB) are noncultivable commensals inhabiting the gut of various vertebrate species and have been shown to induce Th17 cells in mice. We present the complete genome sequences of both rat and mouse SFB isolated from SFB-monocolonized hosts. The rat and mouse SFB genomes each harbor a single circular chromosome of 1.52 and 1.59 Mb encoding 1346 and 1420 protein-coding genes, respectively. The overall nucleotide identity between the two genomes is 86%, and the substitution rate was estimated to be similar to that of the free-living E. coli. SFB genomes encode typical genes for anaerobic fermentation and spore and flagella formation, but lack most of the amino acid biosynthesis enzymes, reminiscent of pathogenic Clostridia, exhibiting large dependency on the host. However, SFB lack most of the clostridial virulence-related genes. Comparative analysis with clostridial genomes suggested possible mechanisms for host responses and specific adaptations in the intestine. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. Th17- and Treg-related cytokine and mRNA expression are associated with acute and resolving Kawasaki disease.

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    Guo, M M-H; Tseng, W-N; Ko, C-H; Pan, H-M; Hsieh, K-S; Kuo, H-C

    2015-03-01

    Kawasaki disease is a vasculitis most commonly afflicting children Kawasaki disease. Blood samples were obtained from 186 children with Kawasaki disease at 24 h before IVIG therapy, followed by 3 days and 21 days after IVIG therapy. Thirty children with an acute febrile infectious disease and 30 healthy children were obtained as control. Plasma levels of Th17- and Treg-related cytokines including IL-6, IL-17A, IL-10, TGF-β, and mRNA expression levels of RORγt and Foxp3 were tested. Patients with Kawasaki disease had higher levels of plasma IL-17A (25.35 ± 3.21 vs 7.78 ± 1.78 pg/ml, P Kawasaki disease was associated with higher IL-17A and IL-6, a cytokine profile similar to other autoimmune diseases. IVIG therapy resulted in increased expression of Treg-related FoxP3. IVIG resistance was associated with higher levels of IL-10 and IL-17A. Our findings provide further evidence that Kawasaki disease is an autoimmune-like disease. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Increased systemic Th17 cytokines are associated with diastolic dysfunction in children and adolescents with diabetic ketoacidosis.

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    William H Hoffman

    Full Text Available Diastolic dysfunction suggestive of diabetic cardiomyopathy is established in children with T1DM, but its pathogenesis is not well understood. We studied the relationships of systemic inflammatory cytokines/chemokines and cardiac function in 17 children with T1DM during and after correction of diabetic ketoacidosis (DKA. Twenty seven of the 39 measured cytokines/chemokines were elevated at 6-12 hours into treatment of DKA compared to values after DKA resolution. Eight patients displayed at least one parameter of diastolic abnormality (DA during acute DKA. Significant associations were present between nine of the cytokine/chemokine levels and the DA over time. Interestingly, four of these nine interactive cytokines (GM-CSF, G-CSF, IL-12p40, IL-17 are associated with a Th17 mediated cell response. Both the DA and CCL7 and IL-12p40, had independent associations with African American patients. Thus, we report occurrence of a systemic inflammatory response and the presence of cardiac diastolic dysfunction in a subset of young T1DM patients during acute DKA.

  9. Differential Expression of Serum MicroRNAs Supports CD4⁺ T Cell Differentiation into Th2/Th17 Cells in Severe Equine Asthma.

    Science.gov (United States)

    Pacholewska, Alicja; Kraft, Matthias F; Gerber, Vincent; Jagannathan, Vidhya

    2017-12-12

    MicroRNAs (miRNAs) regulate post-transcriptional gene expression and may be exported from cells via exosomes or in partnership with RNA-binding proteins. MiRNAs in body fluids can act in a hormone-like manner and play important roles in disease initiation and progression. Hence, miRNAs are promising candidates as biomarkers. To identify serum miRNA biomarkers in the equine model of asthma we investigated small RNA derived from the serum of 34 control and 37 asthmatic horses. These samples were used for next generation sequencing, novel miRNA identification and differential miRNA expression analysis. We identified 11 significantly differentially expressed miRNAs between case and control horses: eca-miR-128, eca-miR-744, eca-miR-197, eca-miR-103, eca-miR-107a, eca-miR-30d, eca-miR-140-3p, eca-miR-7, eca-miR-361-3p, eca-miR-148b-3p and eca-miR-215. Pathway enrichment using experimentally validated target genes of the human homologous miRNAs showed a significant enrichment in the regulation of epithelial-to-mesenchymal transition (key player in airway remodeling in asthma) and the phosphatidylinositol (3,4,5)-triphosphate (PIP3) signaling pathway (modulator of CD4⁺ T cell maturation and function). Downregulated miR-128 and miR-744 supports a Th2/Th17 type immune response in severe equine asthma.

  10. Differential Expression of Serum MicroRNAs Supports CD4+ T Cell Differentiation into Th2/Th17 Cells in Severe Equine Asthma

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    Alicja Pacholewska

    2017-12-01

    Full Text Available MicroRNAs (miRNAs regulate post-transcriptional gene expression and may be exported from cells via exosomes or in partnership with RNA-binding proteins. MiRNAs in body fluids can act in a hormone-like manner and play important roles in disease initiation and progression. Hence, miRNAs are promising candidates as biomarkers. To identify serum miRNA biomarkers in the equine model of asthma we investigated small RNA derived from the serum of 34 control and 37 asthmatic horses. These samples were used for next generation sequencing, novel miRNA identification and differential miRNA expression analysis. We identified 11 significantly differentially expressed miRNAs between case and control horses: eca-miR-128, eca-miR-744, eca-miR-197, eca-miR-103, eca-miR-107a, eca-miR-30d, eca-miR-140-3p, eca-miR-7, eca-miR-361-3p, eca-miR-148b-3p and eca-miR-215. Pathway enrichment using experimentally validated target genes of the human homologous miRNAs showed a significant enrichment in the regulation of epithelial-to-mesenchymal transition (key player in airway remodeling in asthma and the phosphatidylinositol (3,4,5-triphosphate (PIP3 signaling pathway (modulator of CD4+ T cell maturation and function. Downregulated miR-128 and miR-744 supports a Th2/Th17 type immune response in severe equine asthma.

  11. Differential Th17 response induced by the two clades of the pandemic ST258 Klebsiella pneumoniae clonal lineages producing KPC-type carbapenemase.

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    Ann Maria Clemente

    Full Text Available The spread of KPC-type carbapenemases is mainly attributed to the global dissemination of Klebsiella pneumoniae (KP strains belonging to the clonal group (CG 258, including sequence type (ST 258 and other related STs. Two distinct clades of CG258-KP have evolved, which differ mainly for the composition of their capsular polysaccharides, and recent studies indicate that clade 1 evolved from an ancestor of clade 2 by recombination of a genomic fragment carrying the capsular polysaccharide (cps locus. In this paper, we investigated the ability of two ST258-KP strains, KKBO-1 and KK207-1, selected as representatives of ST258-KP clade 2 and clade 1, respectively, to activate an adaptive immune response using ex vivo-stimulation of PBMC from normal donors as an experimental model. Our data showed that KKBO-1 (clade 2 induces a Th17 response more efficiently than KK207-1 (clade 1: the percentage of CD4+IL17+ cells and the production of IL-17A were significantly higher in cultures with KKBO-1 compared to cultures with KK207-1. While no differences in the rate of bacterial internalization or in the bacteria-induced expression of CD86 and HLA-DR by monocytes and myeloid dendritic cells were revealed, we found that the two strains significantly differ in inducing the production of cytokines involved in the adaptive immune response, as IL-1β, IL-23 and TNF-α, by antigen-presenting cells, with KKBO-1 being a more efficient inducer than KK207-1. The immune responses elicited by KK207-1 were comparable to those elicited by CIP 52.145, a highly virulent K. pneumoniae reference strain known to escape immune-inflammatory responses. Altogether, present results suggest that CG258-KP of the two clades are capable of inducing a different response of adaptive immunity in the human host.

  12. Immunological and pathological investigations in equine experimental uveitis.

    Science.gov (United States)

    Simeonova, Galina P; Krastev, Svetozar Z; Simeonov, Radostin S

    2016-12-01

    The pathogenic mechanism of equine recurrent uveitis (ERU) is still poorly defined and many variations between experimental animal models and spontaneous disease exist. The aim of our study was to investigate if Th17 cell-mediated response plays role in the pathogenesis of the used experimental model in horses and to reveal its pathological findings. Experimental uveitis was induced in 6 healthy horses. The concentrations of retinal autoantigen CRALBP and IL-17 were measured using ELISA in aqueous humor and vitreous body of the 12 inflamed eyes as well as in 12 control non-inflamed eyes taken from 6 horses in slaughter house. After centrifugation of the two eye media, smears were prepared and cytological investigation was performed. Tissue specimens were taken from all eye globes and were submitted to histopathological investigation. CRALBP and IL-17 concentrations were significantly elevated in eye media of horses with experimental uveitis in comparison with controls. Cytological and histopathological findings corresponded to the changes characteristic of chronic immune-mediated inflammation with mononuclear cell infiltration of uvea, choroid, retina, and eye media as well as severe retinal destruction. Our study demonstrated the involvement of the retinal autoantigen CRALBP as well as IL-17 in the pathogenesis of experimental uveitis in horses. These findings suggests that this experimental uveitis in horses may serve as a suitable animal model for investigation of IL-17- mediated immune response during spontaneous autoimmune uveitis in horses as well as in humans.

  13. Effects of excimer laser irradiation on the expression of Th17, Treg, TGF-beta1, and IL-6 in patients with psoriasis vulgaris

    Science.gov (United States)

    Xiong, Guo-Xin; Li, Xin-Zhong

    2017-11-01

    The effects of laser irradiation on the expression of T helper 17 (Th17) and regulatory T (Treg) cells and their related cytokines, transforming growth factor beta 1 (TGF-β1) and interleukin-6 (IL-6), respectively, in the peripheral blood of patients with psoriasis vulgaris were investigated. 38 patients with psoriasis vulgaris in the stable state were selected as the treatment group that was treated twice a week for eight weeks. Another 38 healthy persons were chosen as the control group. Before and after treatment, the percentages of Th17 cells and Treg cells in the patients’ peripheral blood were detected using flow cytometry, the content of TGF-β1 and IL-6 in the patients’ sera were detected using enzyme-linked immunosorbent assay, and the extent and severity of lesions were determined by weighing the psoriasis area and severity index (PASI). After laser treatment, the percentage of Th17 cells, the Th17/Treg cell ratio and the level of IL-6 in the peripheral blood of patients with psoriasis in the treatment group were significantly lower than those of the same patients before the treatment (P  psoriasis vulgaris was 84.21%, and the PASI score was significantly lower (P  psoriasis vulgaris.

  14. The levels of IL-17A and of the cytokines involved in Th17 cell commitment are increased in patients with chronic immune thrombocytopenia

    Science.gov (United States)

    Rocha, Andreia Maria Camargos; Souza, Cláudia; Rocha, Gifone Aguiar; de Melo, Fabrício Freire; Clementino, Nelma Cristina Diogo; Marino, Marília Campos Abreu; Bozzi, Adriana; Silva, Maria Luiza; Martins Filho, Olindo Assis; Queiroz, Dulciene Maria Magalhães

    2011-01-01

    Th17 cells have been associated with immune-mediated diseases in humans but it has still not been determined whether they play a role in immune thrombocytopenia. We evaluated representative cytokines of the Th17, Th1, Th2 and Treg cell commitment in the serum of patients with chronic immune thrombocytopenia, as well as the cell source of IL-17A. Higher levels of IL-17A and Th17-related cytokines, and an increased percentage of IL-17A producing CD4+ and neutrophils were observed in patients. The levels of cytokines involved in Th1 cell commitment IFN-γ, IL-2, IL12-p70 and the percentages of Th1 cells were also increased, but IL-4 was not detected. Although the concentrations of IL-10 were higher, the levels of TGF-β were similar in both groups. In conclusion, our results point to a putative role for Th-17 cells/IL-17A cytokine in the pathogenesis of chronic immune thrombocytopenia. PMID:21972211

  15. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells.

    Science.gov (United States)

    Withers, David R; Hepworth, Matthew R; Wang, Xinxin; Mackley, Emma C; Halford, Emily E; Dutton, Emma E; Marriott, Clare L; Brucklacher-Waldert, Verena; Veldhoen, Marc; Kelsen, Judith; Baldassano, Robert N; Sonnenberg, Gregory F

    2016-03-01

    RAR-related orphan receptor-γt (ROR-γt) directs differentiation of proinflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases. However, ROR-γt-dependent group 3 innate lymphoid cells ILC3s provide essential immunity and tissue protection in the intestine, suggesting that targeting ROR-γt could also result in impaired host defense after infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 but not ILCs in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Temporal deletion of Rorc (encoding ROR-γt) in mature ILCs also did not impair cytokine response in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation and reduced the frequency of TH17 cells but not ILCs isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell and ILC3 responses and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation.

  16. Neisseria gonorrhoeae selectively suppresses the development of Th1 and Th2 cells, and enhances Th17 cell responses, through TGF-β-dependent mechanisms

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    Liu, Yingru; Islam, Epshita A.; Jarvis, Gary A.; Gray-Owen, Scott D.; Russell, Michael W.

    2012-01-01

    Infection with Neisseria gonorrhoeae does not induce specific immunity or immune memory. Our previous studies in a murine model of vaginal gonococcal infection showed that innate immunity governed by Th17 cells was a critical aspect of the immune response elicited by this pathogen. Herein we show that N. gonorrhoeae selectively inhibited Th1 and Th2 cells and enhanced Th17 cell development through the induction of TGF-β. Whereas Th17 responses depended on gonococcal lipooligosaccharide acting through TLR4, the inhibitory effect of N. gonorrhoeae on Th1/Th2 responses involved gonococcal Opa proteins. In vitro Th17 responses to N. gonorrhoeae could be diverted to Th1/Th2 by blockade of TGF-β, but not by blockade of IL-17. The results reveal that N. gonorrhoeae suppresses Th1/Th2-mediated adaptive immune response through mechanisms dependent on TGF-β, and that this effect can be manipulated to promote the development of adaptive immunity. PMID:22354319

  17. Generation of IL-23 Producing Dendritic Cells (DCs) by Airborne Fungi Regulates Fungal Pathogenicity via the Induction of TH-17 Responses

    Science.gov (United States)

    Chamilos, Georgios; Ganguly, Dipyaman; Lande, Roberto; Gregorio, Josh; Meller, Stephan; Goldman, William E.; Gilliet, Michel; Kontoyiannis, Dimitrios P.

    2010-01-01

    Interleukin-17 (IL-17) producing T helper cells (TH-17) comprise a newly recognized T cell subset with an emerging role in adaptive immunity to a variety of fungi. Whether different airborne fungi trigger a common signaling pathway for TH-17 induction, and whether this ability is related to the inherent pathogenic behavior of each fungus is currently unknown. Here we show that, as opposed to primary pathogenic fungi (Histoplasma capsulatum), opportunistic fungal pathogens (Aspergillus and Rhizopus) trigger a common innate sensing pathway in human dendritic cells (DCs) that results in robust production of IL-23 and drives TH-17 responses. This response requires activation of dectin-1 by the fungal cell wall polysaccharide b-glucan that is selectively exposed during the invasive growth of opportunistic fungi. Notably, unmasking of b-glucan in the cell wall of a mutant of Histoplasma not only abrogates the pathogenicity of this fungus, but also triggers the induction of IL-23 producing DCs. Thus, b-glucan exposure in the fungal cell wall is essential for the induction of IL-23/TH-17 axis and may represent a key factor that regulates protective immunity to opportunistic but not pathogenic fungi. PMID:20886035

  18. Inactive Gingipains fromP. gingivalisSelectively Skews T Cells toward a Th17 Phenotype in an IL-6 Dependent Manner.

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    Glowczyk, Izabela; Wong, Alicia; Potempa, Barbara; Babyak, Olena; Lech, Maciej; Lamont, Richard J; Potempa, Jan; Koziel, Joanna

    2017-01-01

    Gingipain cysteine proteases are considered key virulence factors of Porphyromonas gingivalis . They significantly influence antibacterial and homeostatic functions of macrophages, neutrophils, the complement system, and cytokine networks. Recent data indicate the role of P. gingivalis in T cell differentiation; however, the involvement of gingipains in this process remains elusive. Therefore, the aim of this study was to investigate the contribution of danger signals triggered by the gingipains on the generation of Th17 cells, which play a key role in protection against bacterial diseases but may cause chronic inflammation and bone resorption. To this end we compared the effects of the wild-type strain of P. gingivalis (W83) with its isogenic mutant devoid of gingipain activity (ΔKΔRAB), and bacterial cells pretreated with a highly-specific inhibitor of gingipains activity (KYTs). Antigen presenting cells (APCs), both professional (dendritic cells), and non-professional (gingival keratinocytes), exposed to viable bacteria expressed high amounts of cytokines (IL-6, IL-21, IL-23). These cytokines are reported to either stimulate or balance the Th17-dependent immune response. Surprisingly, cells infected with P. gingivalis devoid of gingipain activity showed increased levels of all tested cytokines compared to bacteria with fully active enzymes. The effect was dependent on both the reduction of cytokine proteolysis and the lack of cross-talk with other bacterial virulence factors, including LPS and fimbriae that induce de novo synthesis of cytokines. The profile of lymphocyte T differentiation from naive T cells showed enhanced generation of Th17 in response to bacteria with inactive gingipains. Moreover, we found that gingipain-dependent induction of Th17 cells was highly specific, since other T cell-subsets remained unchanged. Finally, inhibition of IL-6 signaling in dendritic cells led to a significant depletion of the Th17 population. Cumulatively, this study

  19. Significance of the balance between regulatory T (Treg and T helper 17 (Th17 cells during hepatitis B virus related liver fibrosis.

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    Jing Li

    Full Text Available BACKGROUND: Hepatitis B virus-related liver fibrosis (HBV-LF always progresses from inflammation to fibrosis. However, the relationship between these two pathological conditions is not fully understood. Here, it is postulated that the balance between regulatory T (Treg cells and T helper 17 (Th17 cells as an indicator of inflammation may predict fibrosis progression of HBV-LF. METHODOLOGY/PRINCIPAL FINDINGS: The frequencies and phenotypes of peripheral Treg and Th17 cells of seventy-seven HBeAg-positive chronic hepatitis B (CHB patients who underwent liver biopsies and thirty healthy controls were determined by flow cytometry. In the periphery of CHB patients, both Treg and Th17 frequencies were significantly increased and correlated, and a lower Treg/Th17 ratio always indicated more liver injury and fibrosis progression. To investigate exact effects of Treg and Th17 cells during HBV-LF, a series of in vitro experiments were performed using purified CD4(+, CD4(+CD25(+, or CD4(+CD25(- cells from the periphery, primary human hepatic stellate cells (HSCs isolated from healthy liver specimens, human recombinant interleukin (IL-17 cytokine, anti-IL-17 antibody and HBcAg. In response to HBcAg, CD4(+CD25(+ cells significantly inhibited cell proliferation and cytokine production (especially IL-17 and IL-22 by CD4(+CD25(- cells in cell-contact and dose-dependent manners. In addition, CD4(+ cells from CHB patients, compared to those from HC subjects, dramatically promoted proliferation and activation of human HSCs. Moreover, in a dramatically dose-dependent manner, CD4(+CD25(+ cells from CHB patients inhibited, whereas recombinant IL-17 response promoted the proliferation and activation of HSCs. Finally, in vivo evidence about effects of Treg/Th17 balance during liver fibrosis was obtained in concanavalin A-induced mouse fibrosis models via depletion of CD25(+ or IL-17(+ cells, and it's observed that CD25 depletion promoted, whereas IL-17 depletion

  20. Th17 cells and IL-17 promote the skin and lung inflammation and fibrosis process in a bleomycin-induced murine model of systemic sclerosis.

    Science.gov (United States)

    Lei, Ling; Zhao, Cheng; Qin, Fang; He, Zhi-Yi; Wang, Xu; Zhong, Xiao-Ning

    2016-01-01

    Systemic sclerosis (SSc) is characterised by fibrosis of the skin and internal organs, such as the lungs. Enhanced Th17 responses are associated with skin fibrosis in patients with SSc, however, whether they are associated with lung fibrosis has not been clarified. This study aimed to investigate the potential association of Th17 responses with the skin and pulmonary fibrosis as well as the potential mechanisms in a mouse bleomycin (BLM) model of SSc. BALB/c mice were injected subcutaneously with phosphate buffered saline (PBS) (control) or BLM for 28 days and the skin and pulmonary inflammation and fibrosis were characterized by histology. The percentages of circulating, skin and pulmonary infiltrating Th17 cells and the contents of collagen in mice were analysed. The levels of RORγt, IL-17A, IL-6 and TGF-β1 mRNA transcripts in the skin and lungs were determined by quantitative RTPCR and the levels of serum IL-17A, IL-6 and TGF-β1 were determined by ELISA. Furthermore, the effect of rIL-17A on the proliferation of pulmonary fibroblasts and their cytokine expression was analysed. The potential association of Th17 responses with the severity of skin and lung fibrosis was analysed. In comparison with the control mice, significantly increased skin and pulmonary inflammation and fibrosis and higher levels of hydroxyproline were detected in the BLM mice. Significantly higher frequency of circulating, skin and lung infiltrating Th17 cells and higher levels of serum, skin and lung IL-17A, TGF-β1, IL-6 and RORγt were detected in the BLM mice. The concentrations of serum IL-17A were correlated positively with the percentages of Th17 cells and the contents of skin hydroxyproline in the BLM mice. The levels of IL-17A expression were positively correlated with the skin and lung inflammatory scores as well as the skin fibrosis in the BLM mice. In addition, IL-17A significantly enhanced pulmonary fibroblast proliferation and their type I collagen, TGF-β and IL-6 expression

  1. IL-23 actived γδ T cells affect Th17 cells and regulatory T cells by secreting IL-21 in children with primary nephrotic syndrome.

    Science.gov (United States)

    Zhang, Li; Yan, Junli; Yang, Baohui; Zhang, Gaofu; Wang, Mo; Dong, Shifang; Liu, Wei; Yang, Haiping; Li, Qiu

    2017-11-09

    This study (1) analyzed the percentage of γδ T cells, γδ T cell subsets, Th17 cells, and regulatory T cells (Treg cells), and (2) determined the role of IL-23 in primary nephrotic syndrome (PNS) patients with active disease and in remission. Eighty-four PNS patients and 51 healthy age-matched controls were included in this study. The percentage of γδ T cells, γδ T cell subsets, Th17 cells, and Treg cells in peripheral blood mononuclear cells (PBMCs) were analyzed by fluorescence-activated cell sorting. PMBCs from PNS patients with active disease were cultured in the presence of IL-23, IL-23 and an IL-23 antagonist, or IL23 and an anti-IL-21 monoclonal antibody (mAb). The percentage of γδT cells, IL-23R+ γδ T cells, and IL-17+ γδ T cells were significantly increased in PNS patients with active disease. There was a positive correlation between the percentage of γδ T cells, IL-23R+ γδ T cells, IL-17+ γδ T cells, and the Th17/Treg ratio. IL-23 increased the percentage of γδ T cells and Th17 cells and decreased the percentage of Treg cells in PBMCs isolated from PNS patients with active disease. Anti-IL-21 mAb reduced the percentage of γδ T cells and Th17 cells, but increased the percentage of Treg cells. γδ T cells, IL-17+ γδ T cells, and IL-23R+ γδ T cells may be involved in the pathogenesis of pediatric PNS by modulating the balance of Th17/Treg cells. γδT cells may cause an imbalance in Th17/Treg cells by secreting IL-21 in the presence of IL-23. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  2. Elevated Levels of Cytokines Associated with Th2 and Th17 Cells in Vitreous Fluid of Proliferative Diabetic Retinopathy Patients.

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    Masaru Takeuchi

    Full Text Available Macrophages are involved in low-grade inflammation in diabetes, and play pathogenic roles in proliferative diabetic retinopathy (PDR by producing proinflammatory cytokines. T cells as well as other cells are also activated by proinflammatory cytokines, and infiltration into the vitreous of patients with PDR has been shown. In this study, we measured helper T (Th cell-related cytokines in the vitreous of PDR patients to define the characteristics of Th-mediated immune responses associated with PDR. The study group consisted of 25 type 2 diabetic patients (25 eyes with PDR. The control group consisted of 27 patients with epiretinal membrane (ERM, 26 patients with idiopathic macular hole (MH, and 26 patients with uveitis associated with sarcoidosis. Vitreous fluid was obtained at the beginning of vitrectomy, and centrifuging for cellular removals was not performed. Serum was also collected from PDR patients. IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble sCD40L, and TNFα in the vitreous and serum samples were measured. Both percent detectable and levels of IL-4, IL-6, IL-17A, IL-21, IL-22, and TNFα in the vitreous were significantly higher than those in the serum in PDR patients. Vitreous levels of these cytokines and IL-31 were significantly higher in PDR than in ERM or MH patients. Vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFα in PDR patients were also significantly higher than those of sarcoidosis patients. In PDR patients, vitreous IL-17A level correlated significantly with vitreous levels of IL-22 and IL-31, and especially with IL-4 and TNFα. Although it is unclear whether these cytokines play facilitative roles or inhibitory roles for the progression of PDR, the present study indicated that Th2- and Th17-related immune responses are involved in the pathogenesis of PDR.

  3. Elevated Levels of Cytokines Associated with Th2 and Th17 Cells in Vitreous Fluid of Proliferative Diabetic Retinopathy Patients

    Science.gov (United States)

    Takeuchi, Masaru; Sato, Tomohito; Tanaka, Atsushi; Muraoka, Tadashi; Taguchi, Manzo; Sakurai, Yutaka; Karasawa, Yoko; Ito, Masataka

    2015-01-01

    Macrophages are involved in low-grade inflammation in diabetes, and play pathogenic roles in proliferative diabetic retinopathy (PDR) by producing proinflammatory cytokines. T cells as well as other cells are also activated by proinflammatory cytokines, and infiltration into the vitreous of patients with PDR has been shown. In this study, we measured helper T (Th) cell-related cytokines in the vitreous of PDR patients to define the characteristics of Th-mediated immune responses associated with PDR. The study group consisted of 25 type 2 diabetic patients (25 eyes) with PDR. The control group consisted of 27 patients with epiretinal membrane (ERM), 26 patients with idiopathic macular hole (MH), and 26 patients with uveitis associated with sarcoidosis. Vitreous fluid was obtained at the beginning of vitrectomy, and centrifuging for cellular removals was not performed. Serum was also collected from PDR patients. IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble sCD40L, and TNFα in the vitreous and serum samples were measured. Both percent detectable and levels of IL-4, IL-6, IL-17A, IL-21, IL-22, and TNFα in the vitreous were significantly higher than those in the serum in PDR patients. Vitreous levels of these cytokines and IL-31 were significantly higher in PDR than in ERM or MH patients. Vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFα in PDR patients were also significantly higher than those of sarcoidosis patients. In PDR patients, vitreous IL-17A level correlated significantly with vitreous levels of IL-22 and IL-31, and especially with IL-4 and TNFα. Although it is unclear whether these cytokines play facilitative roles or inhibitory roles for the progression of PDR, the present study indicated that Th2- and Th17-related immune responses are involved in the pathogenesis of PDR. PMID:26352837

  4. Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.

    Science.gov (United States)

    Wu, Xin; Dou, Yannong; Yang, Yan; Bian, Difei; Luo, Jinque; Tong, Bei; Xia, Yufeng; Dai, Yue

    2015-08-15

    Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro, arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. CD4+ Th17 cells discriminate clinical types and constitute a third subset of non Th1, Non Th2 T cells in human leprosy.

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    Chaman Saini

    Full Text Available BACKGROUND: Patients with localized tuberculoid and generalized lepromatous leprosy show respectively Th1 and Th2 cytokine profile. Additionally, other patients in both types of leprosy also show a non discriminating Th0 cytokine profile with both interferon-γ and IL-4. The present study investigated the role of Th17 cells which appear to be a distinct subtype of Th subtypes in 19 tuberculoid and 18 lepromatous leprosy patients. Five healthy subjects with long term exposure to infection and 4 skin biopsies from healthy subjects undergoing cosmetic surgery were used as controls. METHODOLOGY/PRINCIPLE FINDINGS: An array of Th17 related primers for cytokines, chemokines and transcription factors was used in real time reverse transcribed PCR to evaluate gene expression, ELISA for cytokine secretion in the supernatants of antigen stimulated PBMC cultures and flow cytometry for establishing the phenotype of the IL-17, IL-21 producing cells. CONCLUSIONS/SIGNIFICANCE: IL-17 isoforms showed significantly higher expression and release in supernatants of antigen stimulated PBMC cultures and dermal lesions of healthy contacts and tuberculoid leprosy as compared to lepromatous leprosy (p<0.003. This was further confirmed by Th17 associated transcription factor RORC, cytokines IL-21, IL-22, and IL-23, chemokines MMP13, CCL20, CCL22. Of interest was the association of IL-23R and not IL-6R with IL-17(+ cells. The Th17 cells were CD4(+ CCR6(+ confirming their effector cell lineage. Polarized Th1 cytokines were seen in 3/7 tuberculoid and Th2 cytokines in 5/10 lepromatous leprosy patients. Of importance was the higher association of Th17 pathway factors with the non-polarized Th0 types as compared to the polarized Th1 and Th2 (p<0.01. Our study draws attention to a third type of effector Th cell that may play a role in leprosy.

  6. Ocotillol, a Majonoside R2 Metabolite, Ameliorates 2,4,6-Trinitrobenzenesulfonic Acid-Induced Colitis in Mice by Restoring the Balance of Th17/Treg Cells.

    Science.gov (United States)

    Lee, Sang-Yun; Jeong, Jin-Ju; Le, Thi Hong Van; Eun, Su-Hyeon; Nguyen, Minh Duc; Park, Jeong Hill; Kim, Dong-Hyun

    2015-08-12

    In a preliminary experiment, majonoside R2 (MR2), isolated from Vietnamese ginseng (Panax vietnamensis Ha et Grushv.), inhibited differentiation to Th17 cells and was metabolized to ocotillol via pseudoginsenoside RT4 (PRT4) by gut microbiota. Therefore, we examined the inhibitory effects of MR2 and its metabolites PRT4 and ocotillol against Th17 cell differentiation. These ginsenosides significantly suppressed interleukin (IL)-6/tumor growth factor beta-induced differentiation of splenic CD4(+) T cells into Th17 cells and expression of IL-17 in vitro. Among these ginsenosides, ocotillol showed the highest inhibitory effect. We also examined the anti-inflammatory effect of ocotillol in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. Oral administration of ocotillol significantly suppressed TNBS-induced colon shortening, macroscopic score, myeloperoxidase activity, and production of nitric oxide and prostaglandin E2. Ocotillol treatment increased TNBS-suppressed expression of tight junction proteins ZO-1, occludin, and claudin-1 in the colon. Treatment with ocotillol inhibited TNBS-induced expression of tumor necrosis factor (TNF)-α and IL-1β, as well as activation of NF-κB and MAPKs. Moreover, treatment with ocotillol inhibited TNBS- induced differentiation to Th17 cells in the lamina propria of colon, as well as expression of T-bet, RORγt, IL-17, and IL-23. Ocotillol treatment also increased Treg cell differentiation and Foxp3 and IL-10 expression. These findings suggest that orally administered MR2 may be metabolized to ocotillol in the intestine by gut microbiota and the transformed ocotillol may ameliorate inflammatory diseases such as colitis by restoring the balance of Th17/Treg cells.

  7. Possible neuroimmunomodulation therapy in T-cell-mediated oral diseases

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    Tsuyoshi Sato

    2015-01-01

    Full Text Available Introduction: Recurrent aphthous stomatitis and oral lichen planus are local chronic inflammatory diseases which are implicated in T cell-mediated immunity. According to the systematic review, there is insufficient evidence to support any specific treatment for T-cell mediated oral diseases. The hypothesis: In this paper, we propose a hypothesis that recurrent aphthous stomatitis and oral lichen planus can be treated with selective α7 subunit of nicotinic acetylcholine receptor (α7 -nAChR agonists. Our hypothesis is supported by the following two facts. First, the pathophysiological conditions, T h 1/T h 17 cell activation and autonomic nervous system dysfunction, are observed in T-cell mediated oral diseases as well as in T-cell mediated systemic diseases such as rheumatoid arthritis. Second, the cholinergic anti-inflammatory pathway is inhibited in systemic T-cell mediated chronic inflammatory diseases. On the other hand, treatment with α7 -nAChR agonists which activate the cholinergic anti-inflammatory pathway suppresses neuroinflammation via inhibition of T h 1/T h 17 responses in animal model of systemic T-cell mediated chronic inflammatory diseases. We thus expect that selective α7 -nAChR agonists will be effective for the treatment of T-cell mediated oral diseases. Evaluation of the hypothesis: To test our hypothesis, we need to develop in vivo mouse model of T-cell mediated oral diseases. To evaluate the therapeutic effect of a selective α7 -nAChR agonist, we choose ABT-107 because of its safety and tolerability. We believe that the selective α7 -nAChR agonist, especially ABT-107, may be a therapeutic drug to treat T-cell mediated oral diseases.

  8. Defining T-Cell-Mediated Immune Responses in Rotavirus-Infected Juvenile Rhesus Macaques

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    Sestak, K.; McNeal, M M; Choi, A.; Cole, M. J.; Ramesh, G.; Alvarez, X.; Aye, P. P.; Bohm, R P; Mohamadzadeh, M.; Ward, R. L.

    2004-01-01

    The appearance of virus-specific CD4+ and/or CD8+ T lymphocytes in peripheral blood of captive juvenile rhesus macaques (Macaca mulatta) was observed following rotavirus infection. These cell-mediated immune responses were measured following experimental or natural infection after rotavirus was isolated from stool specimens of asymptomatic animals. The virus isolated was a new strain of simian rotavirus that we named TUCH (for Tulane University and Cincinnati Children's Hospital). Restimulati...

  9. Innate PI3K p110δ regulates Th1/Th17 development and microbiota-dependent colitis.

    Science.gov (United States)

    Steinbach, Erin C; Kobayashi, Taku; Russo, Steven M; Sheikh, Shehzad Z; Gipson, Gregory R; Kennedy, Samantha T; Uno, Jennifer K; Mishima, Yoshiyuki; Borst, Luke B; Liu, Bo; Herfarth, Hans; Ting, Jenny P Y; Sartor, R Balfour; Plevy, Scott E

    2014-04-15

    The p110δ subunit of class IA PI3K modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110δ subunit (p110δ(KD)) develop spontaneous colitis. Macrophages contributed to the Th1/Th17 cytokine bias in p110δ(KD) mice through increased IL-12 and IL-23 expression. In this study, we show that the enteric microbiota is required for colitis development in germfree p110δ(KD) mice. Colonic tissue and macrophages from p110δ(KD) mice produce significantly less IL-10 compared with wild-type mice. p110δ(KD) APCs cocultured with naive CD4+ Ag-specific T cells also produce significantly less IL-10 and induce more IFN-γ- and IL-17A-producing CD4+ T cells compared with wild-type APCs. Illustrating the importance of APC-T cell interactions in colitis pathogenesis in vivo, Rag1(-/-)/p110δ(KD) mice develop mild colonic inflammation and produced more colonic IL-12p40 compared with Rag1(-/-) mice. However, CD4+ CD45RB(high/low) T cell Rag1(-/-)/p110δ(KD) recipient mice develop severe colitis with increased percentages of IFN-γ- and IL-17A-producing lamina propria CD3+D4+ T cells compared with Rag1(-/-) recipient mice. Intestinal tissue samples from patients with Crohn's disease reveal significantly lower expression of PIK3CD compared with intestinal samples from non-inflammatory bowel disease control subjects (p < 0.05). PIK3CD expression inversely correlates with the ratio of IL12B:IL10 expression. In conclusion, the PI3K subunit p110δ controls homeostatic APC-T cell interactions by altering the balance between IL-10 and IL-12/23. Defects in p110δ expression and/or function may underlie the pathogenesis of human inflammatory bowel disease and lead to new therapeutic strategies.

  10. Changes of serum cytokines-related Th1/Th2/Th17 concentration in patients with postmenopausal osteoporosis.

    Science.gov (United States)

    Zhang, Jing; Fu, Qin; Ren, Zhaozhou; Wang, Yanjun; Wang, Chenchen; Shen, Tao; Wang, Guangbin; Wu, Lina

    2015-03-01

    Postmenopausal osteoporosis is now hypothetically considered to be an autoimmune and inflammatory process in which many pro-inflammatory and T cell-derived cytokines play important roles in the loss of bone mass. For instance, interleukin-2 (IL-2), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) secreted by Th1 and IL-6, IL-4, and IL-10 secreted by Th2 have been shown to be involved in the pathogenesis of osteoporosis. Interleukin-17 (IL-17) is a characteristic cytokine secreted by Th17 cells of the CD4 + subgroup. Although IL-17 has been shown to enhance bone resorption in ovariectomized mouse model, bone cells and genetic research, human-related studies of IL-17 are few. According to WHO classification of osteoporosis by the T scores of BMD, the subjects were divided into the postmenopausal osteoporosis group (T scores≤-2.5), the postmenopausal osteopenia group (-2.5 osteoporosis group than in the postmenopausal osteopenia group and the postmenopausal normal BMD group, but the difference between the postmenopausal osteopenia group and the postmenopausal normal BMD group had no statistical significance. IL-17A was negatively correlated with BMD. To our knowledge, we discovered for the first time that serum concentrations of IFN-γ and IL-4 were significantly lower in the postmenopausal osteoporosis group than in the postmenopausal normal BMD group; IFN-γ and IL-4 were positively correlated with BMD. In addition, we also determined that BMI was negatively correlated with BMD; IL-17A was positively correlated with serum calcium. However, no significant differences in IL-6, TNF-α, IL-2, and IL-10 were observed among the three groups; these three factors were not correlated with BMD. Our experiments have confirmed the roles of IL-17 in the pathogenesis of postmenopausal osteoporosis and in the promotion of bone resorption. Targeted therapy of IL-17, IFN-γ, and IL-4 may be beneficial in the treatment of patients with postmenopausal osteoporosis

  11. NOD-Like Receptor P3 Inflammasome Controls Protective Th1/Th17 Immunity against Pulmonary Paracoccidioidomycosis

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    Claudia Feriotti

    2017-07-01

    CD8+ T cells expressing IFN-γ and IL-17 whereas those producing IL-4 and TGF-β appeared in increased frequencies. Histopathological studies showed that all deficient mouse strains developed more severe lesions containing elevated numbers of budding yeast cells resulting in increased mortality rates. Altogether, these findings led us to conclude that the activation of the NLRP3 inflammasome has a crucial role in the immunoprotection against pulmonary PCM by promoting the expansion of Th1/Th17 immunity and reducing the suppressive control mediated by Treg cells.

  12. Microscopic colitis patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile.

    Science.gov (United States)

    Kumawat, Ashok Kumar; Strid, Hilja; Tysk, Curt; Bohr, Johan; Hörnquist, Elisabeth Hultgren

    2013-10-01

    Microscopic colitis (MC) is a chronic inflammatory bowel disorder of unknown aetiology comprising collagenous colitis (CC) and lymphocytic colitis (LC). Data on the local cytokine profile in MC is limited. This study investigated the T helper (Th) cell and cytotoxic T lymphocyte (CTL) mucosal cytokine profile at messenger and protein levels in MC patients. Mucosal biopsies from CC (n=10), LC (n=5), and CC or LC patients in histopathological remission (CC-HR, n=4), (LC-HR, n=6), ulcerative colitis (UC, n=3) and controls (n=10) were analysed by real-time PCR and Luminex for expression/production of IL-1β, -4, -5, -6, -10, -12, -17, -21, -22, -23, IFN-γ, TNF-α, T-bet and RORC2. Mucosal mRNA but not protein levels of IFN-γ and IL-12 were significantly up regulated in CC, LC as well as UC patients compared to controls. Transcription of the Th1 transcription factor T-bet was significantly enhanced in CC but not LC patients. mRNA levels for IL-17A, IL-21, IL-22 and IL-6 were significantly up regulated in CC and LC patients compared to controls, albeit less than in UC patients. Significantly enhanced IL-21 protein levels were noted in both CC and LC patients. IL-6 protein and IL-1β mRNA levels were increased in CC and UC but not LC patients. Increased mucosal mRNA levels of IFN-γ, IL-21 and IL-22 were correlated with higher clinical activity, recorded as the number of bowel movements per day, in MC patients. Although at lower magnitude, IL-23A mRNA was upregulated in CC and LC, whereas TNF-α protein was increased in CC, LC as well as in UC patients. Neither mRNA nor protein levels of IL-4, IL-5 or IL-10 were significantly changed in any of the colitis groups. LC-HR and especially CC-HR patients had normalized mRNA and protein levels of the above cytokines compared to LC and CC patients. No significant differences were found between LC and CC in cytokine expression/production. LC and CC patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile

  13. Bordetella pertussis infection induces a mucosal IL-17 response and long-lived Th17 and Th1 immune memory cells in nonhuman primates.

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    Warfel, J M; Merkel, T J

    2013-07-01

    Despite near universal vaccine coverage, the bacterial pathogen Bordetella pertussis has re-emerged as a major public health concern. We recently developed a baboon (Papio anubis) model of pertussis that provides an excellent model of human pertussis. Using this model, the immune response to pertussis was characterized by measuring cytokines in the nasopharyngeal mucosa of infected baboons. Notably, we observed mucosal expression of interleukin-17 (IL-17) as well as IL-6, IL-23, and several cytokines and chemokines that are orchestrated by IL-17 immune responses. We also found substantial populations of circulating B. pertussis-specific Th17 and Th1 cells in convalescent animals >2 years post-infection consistent with a role in immunological memory to pertussis. Collectively, these data shed important light on the innate and adaptive immune responses to pertussis in a primate infection model and suggest that Th17 and Th1 immune responses contribute to the immunity conferred by natural pertussis infection.

  14. Pre-Vaccination Frequencies of Th17 Cells Correlate with Vaccine-Induced T-Cell Responses to Survivin-Derived Peptide Epitopes

    DEFF Research Database (Denmark)

    Køllgaard, Tania; Ugurel-Becker, Selma; Idorn, Manja

    2015-01-01

    as well as clinical outcome in metastatic melanoma patients vaccinated with survivin-derived peptides. Notably, we observed dysfunctional Th1 and cytotoxic T cells, i.e. down-regulation of the CD3ζchain (p=0.001) and an impaired IFNγ-production (p=0.001) in patients compared to healthy donors, suggesting......Various subsets of immune regulatory cells are suggested to influence the outcome of therapeutic antigen-specific anti-tumor vaccinations. We performed an exploratory analysis of a possible correlation of pre-vaccination Th17 cells, MDSCs, and Tregs with both vaccination-induced T-cell responses...... an altered activity of immune regulatory cells. Moreover, the frequencies of Th17 cells (p=0.03) and Tregs (p=0.02) were elevated as compared to healthy donors. IL-17-secreting CD4+ T cells displayed an impact on the immunological and clinical effects of vaccination: Patients characterized by high...

  15. The Circulating Treg/Th17 Cell Ratio Is Correlated with Relapse and Treatment Response in Pulmonary Sarcoidosis Patients after Corticosteroid Withdrawal.

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    Yongzhe Liu

    Full Text Available Pulmonary sarcoidosis is an immune-mediated disease, and some patients can be effectively treated with corticosteroids. However, nearly half of all sarcoidosis patients relapse after corticosteroid withdrawal. Different subsets of CD4+ helper T cells participate in the immunopathogenesis of sarcoidosis. Thus, the aims of our study were to investigate whether the circulating subsets of CD4+ helper T cells were associated with sarcoidosis relapse and with its remission after retreatment. Additionally, we identified a useful biomarker for predicting the relapse and remission of sarcoidosis patients.Forty-two patients were enrolled in the present study who had previously been diagnosed with pulmonary sarcoidosis and treated with corticosteroids. The patients were allocated into either a stable group if they exhibited sustained remission (n = 22 or a relapse group if they experienced clinical or radiological recurrence after treatment withdrawal (n = 20. Peripheral blood cells were collected from these patients and analyzed to determine the frequencies of subsets of circulating CD4+ helper T cells by flow cytometry. The patients in the relapse group were retreated with corticosteroids and immunosuppressive agents and were then reevaluated to determine the frequencies of dynamic subsets of circulating CD4+ helper T cells after remission.The frequencies of circulating Tregs were significantly increased concomitant with a decrease in the circulating Th17 cell frequency in the relapsed patients compared with the stable patients. The Treg/Th17 ratio was negatively correlated with sarcoidosis activity and was sensitive to retreatment. In addition, the percentage of isolated CD45RO+Ki67+ Tregs was higher in the patients who were stable and in those who recovered after retreatment than in those who relapsed.An imbalance between Tregs and Th17 cells is associated with pulmonary sarcoidosis relapse after corticosteroid withdrawal. The circulating Treg/Th17

  16. Coincident diabetes mellitus modulates Th1-, Th2-, and Th17-cell responses in latent tuberculosis in an IL-10- and TGF-β-dependent manner.

    Science.gov (United States)

    Kumar, Nathella Pavan; Moideen, Kadar; George, Parakkal Jovvian; Dolla, Chandrakumar; Kumaran, Paul; Babu, Subash

    2016-02-01

    Type 2 diabetes mellitus (DM) is a risk factor for the development of active tuberculosis (TB), although its role in the TB-induced responses in latent TB (LTB) is not well understood. Since Th1, Th2, and Th17 responses are important in immunity to LTB, we postulated that coincident DM could alter the function of these CD4(+) T-cell subsets. To this end, we examined mycobacteria-induced immune responses in the whole blood of individuals with LTB-DM and compared them with responses of individuals without DM (LTB-NDM). T-cell responses from LTB-DM are characterized by diminished frequencies of mono- and dual-functional CD4(+) Th1, Th2, and Th17 cells at baseline and following stimulation with mycobacterial antigens-purified protein derivative, early secreted antigen-6, and culture filtrate protein-10. This modulation was at least partially dependent on IL-10 and TGF-β, since neutralization of either cytokine resulted in significantly increased frequencies of Th1 and Th2 cells but not Th17 cells in LTB-DM but not LTB individuals. LTB-DM is therefore characterized by diminished frequencies of Th1, Th2, and Th17 cells, indicating that DM alters the immune response in latent TB leading to a suboptimal induction of protective CD4(+) T-cell responses, thereby providing a potential mechanism for increased susceptibility to active disease. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. [Effect of montelukast sodium intervention on airway remodeling and percentage of Th17 cells/CD4+CD25+ regulatory T cells in asthmatic mice].

    Science.gov (United States)

    Li, Li; Lou, Chun-Yan; Li, Min; Zhang, Jian-Bo; Chen, Jie

    2016-11-01

    To study the dynamic changes in the percentage of Th17 cells/CD4(+)CD25(+) regulatory T cells after intervention with montelukast sodium, a leukotriene receptor antagonist, in asthmatic mice and the association between them. Balb/c mice were randomly divided into blank group, asthma group, and montelukast sodium group. The asthmatic mouse model of airway remodeling was established by sensitization with intraperitoneal injection of chicken ovalbumin (OVA) and aluminum hydroxide suspension and aerosol inhalation of OVA. The mice in the blank group were given normal saline, and those in the montelukast sodium group were given montelukast sodium by gavage before aerosol inhalation. Eight mice were randomly sacrificed within 24 hours after 2, 4, and 8 weeks of aerosol inhalation. The pathological sections of lung tissue were used to observe the degree of airway remodeling. Flow cytometry was used to measure the percentages of Th17 cells and CD4(+)CD25(+) regulatory T cells in CD4(+) T cells. The asthma group and the montelukast sodium group had significantly higher bronchial wall thickness and smooth muscle thickness at all time points compared with the blank group (Pmontelukast sodium group had significantly greater improvements in the above changes compared with the asthma group (Pmontelukast sodium group had significant increases in Th17 cells (positively correlated with airway remodeling) and significant reductions in CD4(+)CD25(+) regulatory T cells (negatively correlated to airway remodeling) at all time points (Pmontelukast sodium group had a significant reduction in the number of Th17 cells and a significant increase in the number of CD4(+)CD25(+) regulatory T cells compared with the asthma group (PMontelukast sodium intervention can alleviate airway remodeling and achieve better improvements over the time of intervention. The possible mechanism may be related to the improvement of immunologic derangement of CD4(+)CD25(+) regulatory T cells and inhibition of

  18. Systemic Inflammation in Progressive Multiple Sclerosis Involves Follicular T-Helper, Th17- and Activated B-Cells and Correlates with Progression

    DEFF Research Database (Denmark)

    Romme Christensen, Jeppe; Börnsen, Lars; Ratzer, Rikke

    2013-01-01

    Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (TFH...... a pathogenic role of systemic inflammation in progressive MS. These observations may have implications for the treatment of progressive MS....

  19. T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation. | Center for Cancer Research

    Science.gov (United States)

    The process by which self-reactive CD4+ T cells infiltrate the central nervous system (CNS) and trigger neuroinflammation is not fully understood. Lazarevic and colleagues show that NKp46+innate lymphoid cells dependent on the transcription factor T-bet are critical mediators in facilitating the entry of autoreactive CD4+ cells of the TH17 subset of helper T cells into the CNS, which leads to autoimmunity. Artwork by Lewis Long.

  20. TLR2 Expression in Peripheral CD4+ T Cells Promotes Th17 Response and Is Associated with Disease Aggravation of Hepatitis B Virus-Related Acute-On-Chronic Liver Failure

    Directory of Open Access Journals (Sweden)

    Chunli Xu

    2017-11-01

    Full Text Available Th17 responses have been shown to play crucial roles in the pathogenesis of hepatitis B virus (HBV-associated acute-on-chronic liver failure (ACLF. The mechanism underlying the enhanced Th17 responses in these patients remains largely unclear. Here we investigated toll-like receptors (TLRs expression in peripheral T cells and their roles in Th17 cell differentiation and disease aggravation in ACLF patients. 18 healthy subjects (HS, 20 chronic HBV-infected (CHB patients, and 26 ACLF patients were enrolled and examined for TLRs expression in peripheral blood mononuclear cells (PBMCs. The correlations of T cell TLR2 expression with the antigen non-specific Th17 responses and disease aggravation, as well as the Th17 response to TLR2 ligand stimulation were evaluated in ACLF patients. Compared to HS and CHB patients, ACLF patients showed a distinct TLRs expression pattern in PBMCs. Significantly increased TLR2 expression in T cells was observed in ACLF patients. The TLR2 expression in CD4+ T cells was correlated with the Th17 responses and the clinical markers for disease aggravation in ACLF patients. Moreover, TLR2 ligands stimulation promoted Th17 cell differentiation and response in PBMCs of ACLF patients. These findings implicate that TLR2 signaling plays critical roles in Th17 cell differentiation and disease aggravation of HBV-related ACLF.

  1. A live Leishmania major vaccine containing CpG motifs induces the de novo generation of Th17 cells in C57BL/6 mice.

    Science.gov (United States)

    Wu, Wenhui; Huang, Lu; Mendez, Susana

    2010-09-01

    Cutaneous leishmaniasis produces open sores that lead to scarring and disfiguration. We have reported that vaccination of C57BL/6 mice with live Leishmania major plus CpG DNA (Lm/CpG) prevents lesion development and provides long-term immunity. Our current study aims to characterize the components of the adaptive immune response that are unique to Lm/CpG. We find that this vaccine enhances the proliferation of CD4(+) Th17 cells, which contrasts with the highly polarized Th1 response caused by L. major alone; the Th17 response is dependent upon release of vaccine-induced IL-6. Neutralization of IFN-gamma and, in particular, IL-17 caused increased parasite burdens in Lm/CpG-vaccinated mice. IL-17R-deficient Lm/CpG-vaccinated mice develop lesions, and display decreased IL-17 and IFN-gamma, despite normal IL-12, production. Neutrophil accumulation is also decreased in the IL-17R-deficient Lm/CpG-vaccinated mice but Treg numbers are augmented. Our data demonstrate that activation of immune cells through CpG DNA, in the presence of live L. major, causes the specific induction of Th17 cells, which enhances the development of a protective cellular immunity against the parasite. Our study also demonstrates that vaccines combining live pathogens with immunomodulatory molecules may strikingly modify the natural immune response to infection in an alternative manner to that induced by killed or subunit vaccines.

  2. Effects of exposure to extremely low-frequency electromagnetic fields on the differentiation of Th17 T cells and regulatory T cells.

    Science.gov (United States)

    Lee, Yun-Jung; Hyung, Kyeong Eun; Yoo, Jong-Sun; Jang, Ye Won; Kim, Soo Jeong; Lee, Do Ik; Lee, Sang Joon; Park, So-Young; Jeong, Ji Hoon; Hwang, Kwang Woo

    2016-10-01

    The potential risks that electromagnetic fields (EMF) pose to human physiology have been debated for several decades, especially considering that EMF is almost omnipresent and some occupations involve regular exposure to particularly strong fields. In the present study, the effects of 60 Hz 0.3 mT EMF on CD4+ T cells were evaluated. Production of T cell related cytokines, IFN-γ and IL-2, was not altered in CD4+ T cells that were exposed to EMF, and cell proliferation was also unaffected. The expression of genes present in a subset of Th17 cells was upregulated following EMF exposure, and the production of effector cytokines of the IL-17A subset also increased. To determine signaling pathways that underlie these effects, phosphorylation of STAT3 and SMAD3, downstream molecules of cytokines critical for Th17 induction, was analyzed. Increased SMAD3 phosphorylation level in cells exposed to EMF, suggesting that SMAD3 may be at least in part causing the increased Th17 cell production. Differentiation of Treg, another CD4+ T cell subset induced by SMAD3 signaling, was also elevated following EMF exposure. These results suggest that 60 Hz 0.3 mT EMF exposure amplifies TGF-β signaling and increases the generation of specific T cell subsets.

  3. The Effects of Aloe Vera on TNF-a Levels, the Percentage of Nk Cells and Th 17 Cells in Rat That Received Izoniazid and Rifampycin.

    Science.gov (United States)

    Mawarti, Herin; Rajin, Mukhamad; Asumta, Zulfikar

    2017-10-01

    The present study was undertaken to investigate the hepatoprotective effect of Aloe vera against side effect of antituberculosis drug. Twenty-five rats will be divided into five groups, namely the control group (without any treatment), the group of rats treated with anti-tuberculosis drugs, and a group of rats were treated antituberculosis drugs and got Aloe vera extract at a dose of 40; 80; and 120 mg/kg body weight. Antituberculosis drugs are isoniazid and rifampicin a dose of 50 mg/kg body weight. Antituberculosis treated group showed significantly increase levels of TNF-a, the percentage of NK cells and the number of Th17 cells compared with the control group (p Aloe vera reduce levels of TNF-a compared with the antituberculosis group (p 0.05). Aloe vera at first and the third dose lower the number of NK cells compared to the antituberculosis group, although it has not yet reached a significant difference (p > 0.05). The first dose of Aloe vera was significantly decreased the percentage of Th17 cells compared to the antituberculosis drug group (p 0.05). It was concluded that administration of Aloe vera can suppress the production of TNF-a and the percentage of Th17 cells as a result of antituberculosis drug administration. Thus, Aloe vera can be a useful alternative to natural materials in the successful treatment of tuberculosis through the inhibition of side effect.

  4. The Mincle-activating adjuvant TDB induces MyD88-dependent Th1 and Th17 responses through IL-1R signaling.

    Directory of Open Access Journals (Sweden)

    Christiane Desel

    Full Text Available Successful vaccination against intracellular pathogens requires the generation of cellular immune responses. Trehalose-6,6-dibehenate (TDB, the synthetic analog of the mycobacterial cord factor trehalose-6,6-dimycolate (TDM, is a potent adjuvant inducing strong Th1 and Th17 immune responses. We previously identified the C-type lectin Mincle as receptor for these glycolipids that triggers the FcRγ-Syk-Card9 pathway for APC activation and adjuvanticity. Interestingly, in vivo data revealed that the adjuvant effect was not solely Mincle-dependent but also required MyD88. Therefore, we dissected which MyD88-dependent pathways are essential for successful immunization with a tuberculosis subunit vaccine. We show here that antigen-specific Th1/Th17 immune responses required IL-1 receptor-mediated signals independent of IL-18 and IL-33-signaling. ASC-deficient mice had impaired IL-17 but intact IFNγ responses, indicating partial independence of TDB adjuvanticity from inflammasome activation. Our data suggest that the glycolipid adjuvant TDB triggers Mincle-dependent IL-1 production to induce MyD88-dependent Th1/Th17 responses in vivo.

  5. Intercellular Interactomics of Human Brain Endothelial Cells and Th17 Lymphocytes: A Novel Strategy for Identifying Therapeutic Targets of CNS Inflammation

    Directory of Open Access Journals (Sweden)

    Arsalan S. Haqqani

    2011-01-01

    Full Text Available Leukocyte infiltration across an activated brain endothelium contributes to the neuroinflammation seen in many neurological disorders. Recent evidence shows that IL-17-producing T-lymphocytes (e.g., Th17 cells possess brain-homing capability and contribute to the pathogenesis of multiple sclerosis and cerebral ischemia. The leukocyte transmigration across the endothelium is a highly regulated, multistep process involving intercellular communications and interactions between the leukocytes and endothelial cells. The molecules involved in the process are attractive therapeutic targets for inhibiting leukocyte brain migration. We hypothesized and have been successful in demonstrating that molecules of potential therapeutic significance involved in Th17-brain endothelial cell (BEC communications and interactions can be discovered through the combination of advanced membrane/submembrane proteomic and interactomic methods. We describe elements of this strategy and preliminary results obtained in method and approach development. The Th17-BEC interaction network provides new insights into the complexity of the transmigration process mediated by well-organized, subcellularly localized molecular interactions. These molecules and interactions are potential diagnostic, therapeutic, or theranostic targets for treatment of neurological conditions accompanied or caused by leukocyte infiltration.

  6. Chronic mucocutaneous candidiasis: characterization of a family with STAT-1 gain-of-function and development of an ex-vivo assay for Th17 deficiency of diagnostic utility.

    Science.gov (United States)

    Dhalla, F; Fox, H; Davenport, E E; Sadler, R; Anzilotti, C; van Schouwenburg, P A; Ferry, B; Chapel, H; Knight, J C; Patel, S Y

    2016-05-01

    Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent and persistent superficial infections, with Candida albicans affecting the mucous membranes, skin and nails. It can be acquired or caused by primary immune deficiencies, particularly those that impair interleukin (IL)-17 and IL-22 immunity. We describe a single kindred with CMC and the identification of a STAT1 GOF mutation by whole exome sequencing (WES). We show how detailed clinical and immunological phenotyping of this family in the context of WES has enabled revision of disease status and clinical management. Together with analysis of other CMC cases within our cohort of patients, we used knowledge arising from the characterization of this family to develop a rapid ex-vivo screening assay for the detection of T helper type 17 (Th17) deficiency better suited to the routine diagnostic setting than established in-vitro techniques, such as intracellular cytokine staining and enzyme-linked immunosorbent assay (ELISA) using cell culture supernatants. We demonstrate that cell surface staining of unstimulated whole blood for CCR6⁺ CXCR3⁻ CCR4⁺ CD161⁺ T helper cells generates results that correlate with intracellular cytokine staining for IL-17A, and is able to discriminate between patients with molecularly defined CMC and healthy controls with 100% sensitivity and specificity within the cohort tested. Furthermore, removal of CCR4 and CD161 from the antibody staining panel did not affect assay performance, suggesting that the enumeration of CCR6⁺ CXCR3⁻ CD4⁺ T cells is sufficient for screening for Th17 deficiency in patients with CMC and could be used to guide further investigation aimed at identifying the underlying molecular cause. © 2016 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.

  7. Bordetella pertussis commits human dendritic cells to promote a Th1/Th17 response through the activity of adenylate cyclase toxin and MAPK-pathways.

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    Giorgio Fedele

    Full Text Available The complex pathology of B. pertussis infection is due to multiple virulence factors having disparate effects on different cell types. We focused our investigation on the ability of B. pertussis to modulate host immunity, in particular on the role played by adenylate cyclase toxin (CyaA, an important virulence factor of B. pertussis. As a tool, we used human monocyte derived dendritic cells (MDDC, an ex vivo model useful for the evaluation of the regulatory potential of DC on T cell immune responses. The work compared MDDC functions after encounter with wild-type B. pertussis (BpWT or a mutant lacking CyaA (BpCyaA-, or the BpCyaA- strain supplemented with either the fully functional CyaA or a derivative, CyaA*, lacking adenylate cyclase activity. As a first step, MDDC maturation, cytokine production, and modulation of T helper cell polarization were evaluated. As a second step, engagement of Toll-like receptors (TLR 2 and TLR4 by B. pertussis and the signaling events connected to this were analyzed. These approaches allowed us to demonstrate that CyaA expressed by B. pertussis strongly interferes with DC functions, by reducing the expression of phenotypic markers and immunomodulatory cytokines, and blocking IL-12p70 production. B. pertussis-treated MDDC promoted a mixed Th1/Th17 polarization, and the activity of CyaA altered the Th1/Th17 balance, enhancing Th17 and limiting Th1 expansion. We also demonstrated that Th1 effectors are induced by B. pertussis-MDDC in the absence of IL-12p70 through an ERK1/2 dependent mechanism, and that p38 MAPK is essential for MDDC-driven Th17 expansion. The data suggest that CyaA mediates an escape strategy for the bacterium, since it reduces Th1 immunity and increases Th17 responses thought to be responsible, when the response is exacerbated, for enhanced lung inflammation and injury.

  8. Mesenchymal stem cell-mediated functional tooth regeneration in swine.

    Science.gov (United States)

    Sonoyama, Wataru; Liu, Yi; Fang, Dianji; Yamaza, Takayoshi; Seo, Byoung-Moo; Zhang, Chunmei; Liu, He; Gronthos, Stan; Wang, Cun-Yu; Wang, Songlin; Shi, Songtao

    2006-12-20

    Mesenchymal stem cell-mediated tissue regeneration is a promising approach for regenerative medicine for a wide range of applications. Here we report a new population of stem cells isolated from the root apical papilla of human teeth (SCAP, stem cells from apical papilla). Using a minipig model, we transplanted both human SCAP and periodontal ligament stem cells (PDLSCs) to generate a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This work integrates a stem cell-mediated tissue regeneration strategy, engineered materials for structure, and current dental crown technologies. This hybridized tissue engineering approach led to recovery of tooth strength and appearance.

  9. Mesenchymal stem cell-mediated functional tooth regeneration in swine.

    Directory of Open Access Journals (Sweden)

    Wataru Sonoyama

    2006-12-01

    Full Text Available Mesenchymal stem cell-mediated tissue regeneration is a promising approach for regenerative medicine for a wide range of applications. Here we report a new population of stem cells isolated from the root apical papilla of human teeth (SCAP, stem cells from apical papilla. Using a minipig model, we transplanted both human SCAP and periodontal ligament stem cells (PDLSCs to generate a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This work integrates a stem cell-mediated tissue regeneration strategy, engineered materials for structure, and current dental crown technologies. This hybridized tissue engineering approach led to recovery of tooth strength and appearance.

  10. Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells

    Science.gov (United States)

    Gomez-Rodriguez, Julio; Wohlfert, Elizabeth A.; Handon, Robin; Meylan, Françoise; Wu, Julie Z.; Anderson, Stacie M.; Kirby, Martha R.; Belkaid, Yasmine

    2014-01-01

    A proper balance between Th17 and T regulatory cells (Treg cells) is critical for generating protective immune responses while minimizing autoimmunity. We show that the Tec family kinase Itk (IL2-inducible T cell kinase), a component of T cell receptor (TCR) signaling pathways, influences this balance by regulating cross talk between TCR and cytokine signaling. Under both Th17 and Treg cell differentiation conditions, Itk−/− CD4+ T cells develop higher percentages of functional FoxP3+ cells, associated with increased sensitivity to IL-2. Itk−/− CD4+ T cells also preferentially develop into Treg cells in vivo. We find that Itk-deficient T cells exhibit reduced TCR-induced phosphorylation of mammalian target of rapamycin (mTOR) targets, accompanied by downstream metabolic alterations. Surprisingly, Itk−/− cells also exhibit reduced IL-2–induced mTOR activation, despite increased STAT5 phosphorylation. We demonstrate that in wild-type CD4+ T cells, TCR stimulation leads to a dose-dependent repression of Pten. However, at low TCR stimulation or in the absence of Itk, Pten is not effectively repressed, thereby uncoupling STAT5 phosphorylation and phosphoinositide-3-kinase (PI3K) pathways. Moreover, Itk-deficient CD4+ T cells show impaired TCR-mediated induction of Myc and miR-19b, known repressors of Pten. Our results demonstrate that Itk helps orchestrate positive feedback loops integrating multiple T cell signaling pathways, suggesting Itk as a potential target for altering the balance between Th17 and Treg cells. PMID:24534190

  11. Exposure to Candida albicans polarizes a T-cell driven arthritis model towards Th17 responses, resulting in a more destructive arthritis.

    Directory of Open Access Journals (Sweden)

    Renoud J Marijnissen

    Full Text Available BACKGROUND: Fungal components have been shown very effective in generating Th17 responses. We investigated whether exposure to a minute amount of C. albicans in the arthritic joint altered the local cytokine environment, leading to enhanced Th17 expansion and resulting in a more destructive arthritis. METHODOLOGY: Chronic SCW arthritis was induced by repeated injection with Streptococcus pyogenes (SCW cell wall fragments into the knee joint of C57Bl/6 mice, alone or in combination with the yeast of C. albicans or Zymosan A. During the chronic phase of the arthritis, the cytokine levels, mRNA expression and histopathological analysis of the joints were performed. To investigate the phenotype of the IL-17 producing T-cells, synovial cells were isolated and analyzed by flowcytometry. PRINCIPAL FINDINGS: Intra-articular injection of either Zymosan A or C. albicans on top of the SCW injection both resulted in enhanced joint swelling and inflammation compared to the normal SCW group. However, only the addition of C. albicans during SCW arthritis resulted in severe chondrocyte death and enhanced destruction of cartilage and bone. Additionally, exposure to C. albicans led to increased IL-17 in the arthritic joint, which was accompanied by an increased synovial mRNA expression of T-bet and RORγT. Moreover, the C. albicans-injected mice had significantly more Th17 cells in the synovium, of which a large population also produced IFN-γ. CONCLUSION: This study clearly shows that minute amounts of fungal components, like C. albicans, are very potent in interfering with the local cytokine environment in an arthritic joint, thereby polarizing arthritis towards a more destructive phenotype.

  12. TLR2 and TLR4 co-activation utilizes distinct signaling pathways for the production of Th1/Th2/Th17 cytokines in neonatal immune cells.

    Science.gov (United States)

    Sugitharini, V; Shahana, P; Prema, A; Berla Thangam, E

    2016-09-01

    Co-activation of TLR2 and TLR4 by gram negative and gram positive bacterial ligands induces a robust pro-inflammatory response in inflammatory cells. In order to understand the signaling mechanism, we aimed to delineate the signaling molecules involved in TLR2 and TLR4 co-activation in neonatal immune cells for the production of Th1/Th2/Th17 inflammatory cytokines. For this, we pretreated cord blood and peripheral blood mononuclear and human mast cells with specific signaling molecule inhibitors such as BAY117082, PD98059 and LY294002 and then stimulated with LPS and PGN and assayed for cytokines IL-6, IL-12/IL-23p40 (Th1), IL-13 (Th2), IL-23 (Th17) and RANTES secretion. We found that upon co-stimulation the phosphorylation of NFκBp65, ERK1/2 and Akt was found to be higher than when stimulated with individual ligands in CBMCs. Also, when compared to adult cells, neonatal cells were more potent in the activation of ERK and Akt through TLR2 and TLR4 co-activation. In addition, neonatal cells possess similar capacity to activate NFκB as that of adult cells for IL-6 secretion. Furthermore, all three signaling molecules were found to be involved in the production of Th17 cytokines which is detrimental during inflammation induced by infection in neonates whereas NFκB is mainly involved in the induction of pro-inflammatory response and Th2 cytokines production. In conclusion, different signaling molecules were utilized for the production of different cytokines in immune cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Norisoboldine ameliorates collagen-induced arthritis through regulating the balance between Th17 and regulatory T cells in gut-associated lymphoid tissues

    Energy Technology Data Exchange (ETDEWEB)

    Tong, Bei; Dou, Yannong; Wang, Ting; Yu, Juntao; Wu, Xin; Lu, Qian [Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009 (China); Chou, Guixin; Wang, Zhengtao [Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Kong, Lingyi [Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009 (China); Dai, Yue, E-mail: yuedaicpu@hotmail.com [Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009 (China); Xia, Yufeng, E-mail: yfxiacpu@126.com [Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009 (China)

    2015-01-01

    Norisoboldine (NOR), the main active ingredient of the dry root of Lindera aggregata, was previously proven to have substantial therapeutic effects on collagen-induced arthritis (CIA) in mice by oral administration. However, it exhibited a very poor bioavailability in normal rats. The pharmacokinetic–pharmacodynamics disconnection attracts us to explore its anti-arthritic mechanism in more detail. In this study, NOR, administered orally, markedly attenuated the pathological changes in CIA rats, which was accompanied by the down-regulation of pro-inflammatory cytokines and the up-regulation of anti-inflammatory cytokine IL-10. Pharmacokinetic studies demonstrated that the plasma concentration of NOR was moderately elevated in CIA rats compared with normal rats, but it was still far lower than the minimal effective concentration required for inhibiting the proliferation and activation of T lymphocytes in vitro. Interestingly, NOR was shown to regulate the balance between Th17 and regulatory T (Treg) cells in the intestinal lymph nodes more strikingly than in other tissues. It could increase the expression of Foxp3 mRNA in both gut and joints, and markedly up-regulate the number of integrin α4β7 (a marker of gut source)-positive Foxp3{sup +} cells in the joints of CIA rats. These results suggest that the gut might be the primary action site of NOR, and NOR exerts anti-arthritis effect through regulating the balance between Th17 and Treg cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from the gut to joint. The findings of the present study also provide a plausible explanation for the anti-arthritic effects of poorly absorbed compounds like NOR. - Highlights: • Norisoboldine, administered orally, markedly attenuates the clinical signs of CIA. • Norisoboldine regulates the balance of Th17/Treg cells in the intestinal lymph node. • Norisoboldine induces the migration of Treg cells from the gut to joint.

  14. Differential expression of circulating Th1/ Th2/ Th17 cytokines in serum of Chlamydia trachomatis-infected women undergoing incomplete spontaneous abortion.

    Science.gov (United States)

    Prasad, Priya; Singh, Namita; Das, Banashree; Raisuddin, Sheikh; Dudeja, Mridu; Rastogi, Sangita

    2017-09-01

    The study aimed to elucidate role of Th1/Th2/Th17 cytokines in the immunopathogenesis of spontaneous abortion in Chlamydia trachomatis (Ct)-positive first-trimester aborters. Endometrial curettage tissue and serum were collected from 145 aborters (spontaneous abortion (SA) group, n = 85; recurrent miscarriage (RM) group, n = 60) and 120 controls attending Department of Obstetrics & Gynecology at Safdarjung hospital, New Delhi (India). Polymerase chain reaction was used to detect Ct plasmid/MOMP, while commercial cytometric bead array kit was utilized to estimate circulating serum cytokines. 13.7% aborters were Ct-positive, however, none was found to be infected among controls. IFN-γ, TNF-α, IL-2, IL-6 and IL-17A cytokines were significantly increased in SA group/RM group (Ct-infected) versus controls. IL-4 showed no difference between groups, while IL-10 was significantly elevated in controls versus Ct-infected subjects in SA group/RM group. Furthermore, IFN-γ, TNF-α, IL-6, IL-17A cytokines were significantly elevated in Ct-positive RM group versus Chlamydia-infected SA group. However, IL-2, IL-4 and IL-10 cytokines showed no significant difference between Ct-positive SA group versus infected RM group. Positive correlation was found between few cytokines (TNF-α and IFN-γ/IL-17A; IL-17A and IFN-γ/IL-6) in Ct-positive aborters. Our study clearly established the role of Th1/Th2/Th17 cytokines in the pathogenesis of spontaneous abortion in Ct-infected subjects and found that Chlamydia-positive recurrent aborters had a predominant Th1/Th17 bias. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Cathepsin S Is Involved in Th17 Differentiation Through the Upregulation of IL-6 by Activating PAR-2 after Systemic Exposure to Lipopolysaccharide from Porphyromonas gingivalis

    Directory of Open Access Journals (Sweden)

    Masato Dekita

    2017-07-01

    Full Text Available Positive links have been found between periodontitis and numerous diseases in humans via persistent inflammation throughout the body. However, the main factors responsible for maintaining this pro-inflammatory condition are poorly understood. The spleen, the largest secondary immune organ, is a central hub regulating the immune response/inflammation due to the dendritic cell (DC response to CD4+ T cell subtype differentiation, and lysosomal proteinase cathepsin S (CatS is known to be involved in DC functions. In the present study, we found that CatS-induced IL-6 production by splenic DCs subsequently promotes Th17 differentiation, in response to systemic exposure to lipopolysaccharide derived from Porphyromonas gingivalis (PgLPS. The population of CD11c+ DCs was significantly increased in the splenic marginal zone (MZ locally of wild-type (DBA/2 mice with splenomegaly but not in that of CatS deficient (CatS-/- mice after systemic exposure to PgLPS for 7 consecutive days (5 mg/kg/day, intraperitoneal. Similarly, the population of Th17+CD4+ T cells was also significantly increased in the splenic MZ of wild-type mice but not in that of CatS-/- mice after PgLPS exposure. Furthermore, the increase in the Th17+ CD4+ T cell population paralleled increases in the levels of CatS and IL-6 in CD11c+ cells in the splenic MZ. In isolated primary splenic CD11c+ cells, the mRNA expression and the production of IL-6 was dramatically increased in wild-type mice but not in CatS-/- mice after direct stimulation with PgLPS (1 μg/ml, and this PgLPS-induced increase in the IL-6 expression was completely abolished by pre-treatment with Z-Phe-Leu-COCHO (Z-FL, the specific inhibitor of CatS. The PgLPS activated protease-activated receptor (PAR 2 in the isolated splenic CD11c+ cells was also significantly inhibited by CatS deficiently. In addition, the PgLPS-induced increase in the IL-6 production by splenic CD11c+ cells was completely abolished by pre-treatment with

  16. Athymic nude rat. III natural cell mediated cytotoxicity.

    NARCIS (Netherlands)

    W.H. de Jong; P.A. Steerenberg; P.S. Ursem; A.D.M.E. Osterhaus (Albert); J.G. Vos (Joseph); E.J. Ruitenberg (Joost)

    1980-01-01

    textabstractHomozygous rnu/rnu and heterozygous +/rnu rats were investigated and compared with each other for the existence of natural cell-mediated cytotoxicity. Investigated were total, adherent, and nonadherent cell populations from spleen, peritoneal cavity, and mesenteric lymph node. The

  17. The Major Players in Adaptive Immunity-Cell-mediated Immunity

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 14; Issue 6. The Major Players in Adaptive Immunity - Cell-mediated Immunity. Asma Ahmed Banishree Saha Anand Patwardhan Shwetha Shivaprasad Dipankar Nandi. General Article Volume 14 Issue 6 June 2009 pp 610-621 ...

  18. IL-17 producing innate lymphoid cells 3 (ILC3) but not Th17 cells might be the potential danger factor for preeclampsia and other pregnancy associated diseases.

    Science.gov (United States)

    Barnie, Prince A; Lin, Xin; Liu, Yueqin; Xu, Huaxi; Su, Zhaoliang

    2015-01-01

    In pregnancy, the immunologic system plays an important role that ensures normal pregnancy development and can as well promote the development of complications. Pregnancy success appears to rely on a discrete balance between the Th cytokines, which are involved in fetal growth and development. Preeclampsia and gestational diabetes are known complications associated with pregnancy. However, the source of the increased IL-17 cytokine in preeclampsia and other pregnancy associated diseases still remains unclear amidst numerous inconsistencies. The recent identification of innate lymphoid cells (ILC) has raised more doubts about the sources of most of the Th associated cytokines. We investigated the source of peripheral IL-17 levels in preeclamptic, gestational diabetics and chronic diabetics compared to healthy pregnancy subjects. To evaluate the source of the increased IL-17 cytokine among preeclampsia, chronic diabetic and gestational diabetic patients we investigated the proportion of Th17 cell populations in peripheral blood mononuclear cells using flow cytometry as well as analyzing levels of IFN-γ, IL-17, IL-1β and HMGB1. This study found that the Th17 cell populations in peripheral blood of preeclamptic, gestational nor chronic diabetes during pregnancy did not correlate with the increased IL-17. We report that the increased IL-17 levels observed in patients with preeclampsia, gestational diabetes and chronic diabetes are associated with innate lymphoid cells 3 (ILC3) and may pose threats to the fetus if disregulated.

  19. Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway.

    Science.gov (United States)

    Espinosa, Alexander; Dardalhon, Valerie; Brauner, Susanna; Ambrosi, Aurelie; Higgs, Rowan; Quintana, Fransisco J; Sjöstrand, Maria; Eloranta, Maija-Leena; Ní Gabhann, Joan; Winqvist, Ola; Sundelin, Birgitta; Jefferies, Caroline A; Rozell, Björn; Kuchroo, Vijay K; Wahren-Herlenius, Marie

    2009-08-03

    Ro52/Trim21 is targeted as an autoantigen in systemic lupus erythematosus and Sjögren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52-null mice (Ro52(-/-)), which appear phenotypically normal if left unmanipulated. However, Ro52(-/-) mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52(-/-) mice conferred protection from skin disease and systemic autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and systemic autoimmunity through the IL-23-Th17 pathway.

  20. Bone marrow transplantation alters lung antigen-presenting cells to promote TH17 response and the development of pneumonitis and fibrosis following gammaherpesvirus infection.

    Science.gov (United States)

    Zhou, X; Loomis-King, H; Gurczynski, S J; Wilke, C A; Konopka, K E; Ptaschinski, C; Coomes, S M; Iwakura, Y; van Dyk, L F; Lukacs, N W; Moore, B B

    2016-05-01

    Hematopoietic stem cell transplantation (HSCT) efficacy is limited by numerous pulmonary complications. We developed a model of syngeneic bone marrow transplantion (BMT) followed by infection with murine gamma herpesvirus-68 that results in pneumonitis and fibrosis and mimics human "noninfectious" HSCT complications. BMT mice experience increased early lytic replication, but establish viral latency by 21 days post infection. CD4 T cells in BMT mice are skewed toward interleukin (IL)-17A rather than interferon (IFN)-γ production. Transplantation of bone marrow from Il-17a(-/-) donors or treatment with anti-IL-17A neutralization antibodies at late stages attenuates pneumonitis and fibrosis in infected BMT mice, suggesting that hematopoietic-derived IL-17A is essential for development of pathology. IL-17A directly influences activation and extracellular matrix production by lung mesenchymal cells. Lung CD11c+ cells of BMT mice secrete more transforming growth factor beta-β1, and pro-TH17 mRNAs for IL-23 and IL-6, and less TH1-promoting cytokine mRNA for IFN-γ but slightly more IL-12 mRNA in response to viral infection. Adoptive transfer of non-BMT lung CD11c-enriched cells restores robust TH1 response and suppresses aberrant TH17 response in BMT mice to improve lung pathology. Our data suggest that "noninfectious" HSCT lung complications may reflect preceding viral infections and demonstrate that IL-17A neutralization may offer therapeutic advantage even after disease onset.

  1. A chitin-like component on sclerotic cells of Fonsecaea pedrosoi inhibits Dectin-1-mediated murine Th17 development by masking β-glucans.

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    Bilin Dong

    Full Text Available Fonsecaea pedrosoi (F. pedrosoi, a major agent of chromoblastomycosis, has been shown to be recognized primarily by C-type lectin receptors (CLRs in a murine model of chromoblastomycosis. Specifically, the β-glucan receptor, Dectin-1, mediates Th17 development and consequent recruitment of neutrophils, and is evidenced to have the capacity to bind to saprophytic hyphae of F. pedrosoi in vitro. However, when embedded in tissue, most etiological agents of chromoblastomycosis including F. pedrosoi will transform into the sclerotic cells, which are linked to the greatest survival of melanized fungi in tissue. In this study, using immunocompetent and athymic (nu/nu murine models infected subcutaneously or intraperitoneally with F. pedrosoi, we demonstrated that T lymphocytes play an active role in the resolution of localized footpad infection, and there existed a significantly decreased expression of Th17-defining transcription factor Rorγt and inefficient recruitment of neutrophils in chronically infected spleen where the inoculated mycelium of F. pedrosoi transformed into the sclerotic cells. We also found that Dectin-1-expressing histocytes and neutrophils participated in the enclosure of transformed sclerotic cells in the infectious foci. Furthermore, we induced the formation of sclerotic cells in vitro, and evidenced a significantly decreased binding capacity of human or murine-derived Dectin-1 to the induced sclerotic cells in comparison with the saprophytic mycelial forms. Our analysis of β-glucans-masking components revealed that it is a chitin-like component, but not the mannose moiety on the sclerotic cells, that interferes with the binding of β-glucans by human or murine Dectin-1. Notably, we demonstrated that although Dectin-1 contributed to the development of IL-17A-producing CD3+CD4+ murine splenocytes upon in vitro-stimulation by saprophytic F. pedrosoi, the masking effect of chitin components partly inhibited Dectin-1-mediated Th

  2. Th17 transcription factor RORC2 is inversely correlated with FOXP3 expression in the joints of children with juvenile idiopathic arthritis.

    Science.gov (United States)

    Olivito, Biagio; Simonini, Gabriele; Ciullini, Sara; Moriondo, Maria; Betti, Letizia; Gambineri, Eleonora; Cantarini, Luca; De Martino, Maurizio; Azzari, Chiara; Cimaz, Rolando

    2009-09-01

    To investigate the relationship between interleukin 17 (IL-17) producing T cells (Th17) and CD4+CD25+FOXP3+ regulatory T cells (Tregs) in blood and synovial fluid (SF) of patients with juvenile idiopathic arthritis (JIA). Sixty-five children with JIA (18 males and 47 females, median age 6.2 yrs; 45 with oligoarticular and 20 with polyarticular course) and 75 age- and sex-matched healthy controls were studied. Flow cytometry was used to analyze the forkhead box P3 (FOXP3)-positive Treg cells in peripheral blood (PB) and synovial fluid mononuclear cells (SFMC). FOXP3 and retinoic-acid related orphan receptor C isoform 2 (RORC2) messenger RNA (mRNA) were assessed by real-time polymerase chain reaction analysis. Cytokines (IL-17 and Th1/Th2 related cytokines) were measured in culture supernatants of 11 paired PBMC and SFMC activated with PMA and ionomycin. FOXP3+ T cells and FOXP3 mRNA amounts were significantly lower in PB of children with JIA as compared with controls (p = 0.0002 and p = 0.001, respectively) and a higher percentage of Treg cells with concomitant higher level of FOXP3 transcript levels were observed in SF when compared with their PB counterparts (both p < 0.0001). SF CD4+FOXP3+ T cells were characterized by higher amounts of FOXP3 protein per cell when compared with peripheral CD4+FOXP3+ T cells, as revealed by the difference in FOXP3 median fluorescence intensity (median +/- SD, arbitrary units, 54 +/- 22.6 vs 19.5 +/- 4.2; p < 0.001). RORC2 transcript levels were higher in JIA joints when compared with matched PB samples (median fold increase 3.9, p < 0.0001) but negatively correlated with FOXP3 mRNA levels (r = -0.623, p = 0.04). Stimulated SFMC displayed an impaired ability to produce IL-17 when compared with PBMC and, interestingly, an inverse relationship between IL-17 levels and the percentage of CD4+CD25+FOXP3+ SF T cells (r = -0.510, p = 0.047) was seen. We demonstrated for the first time an increased synovial expression of the transcription

  3. Th17-skewed immune response and cluster of differentiation 40 ligand expression in canine steroid-responsive meningitis-arteritis, a large animal model for neutrophilic meningitis.

    Science.gov (United States)

    Freundt-Revilla, Jessica; Maiolini, Arianna; Carlson, Regina; Beyerbach, Martin; Rentmeister, Kai; Flegel, Thomas; Fischer, Andrea; Tipold, Andrea

    2017-01-23

    Steroid-responsive meningitis-arteritis (SRMA) is an immune-mediated disorder characterized by neutrophilic pleocytosis and an arteritis particularly in the cervical leptomeninges. Previous studies of the disease have shown increased levels of IL-6 and TGF-ß1 in cerebrospinal fluid (CSF). In the presence of these cytokines, naive CD4+ cells differentiate into Th17 lymphocytes which synthesize interleukin 17 (IL-17). It has been shown that IL-17 plays an active role in autoimmune diseases, it induces and mediates inflammatory responses and has an important role in recruitment of neutrophils. The hypothesis of a Th17-skewed immune response in SRMA should be supported by evaluating IL-17 and CD40L, inducing the vasculitis. An enzyme-linked immunosorbent assay (ELISA) was performed to measure IL-17 and CD40L in serum and CSF from a total of 79 dogs. Measurements of patients suffering from SRMA in the acute state (SRMA A) were compared with levels of patients under treatment with steroids (SRMA T), recurrence of the disease (SRMA R), other neurological disorders, and healthy dogs, using the two-part test. Additionally, secretion of IL-17 and interferon gamma (IFN-γ) from the peripheral blood mononuclear cells (PBMCs) was confirmed by an enzyme-linked immunospot (ELISpot) assay. Significant higher levels of IL-17 were found in CSF of dogs with SRMA A compared with SRMA T, other neurological disorders and healthy dogs (p < 0.0001). In addition, levels of CD40L in CSF in dogs with SRMA A and SRMA R were significantly higher than in those with SRMA T (p = 0.0004) and healthy controls (p = 0.014). Furthermore, CSF concentrations of IL-17 and CD40L showed a strong positive correlation among each other (rSpear = 0.6601; p < 0.0001) and with the degree of pleocytosis (rSpear = 0.8842; p < 0.0001 and rSpear = 0.6649; p < 0.0001, respectively). IL-17 synthesis from PBMCs in SRMA patients was confirmed; however, IL-17 is mainly intrathecally

  4. Mesenchymal Stem Cell-Mediated Functional Tooth Regeneration in Swine

    OpenAIRE

    Wataru Sonoyama; Yi Liu; Dianji Fang; Takayoshi Yamaza; Byoung-Moo Seo; Chunmei Zhang; He Liu; Stan Gronthos; Cun-Yu Wang; Songlin Wang; Songtao Shi

    2006-01-01

    Mesenchymal stem cell-mediated tissue regeneration is a promising approach for regenerative medicine for a wide range of applications. Here we report a new population of stem cells isolated from the root apical papilla of human teeth (SCAP, stem cells from apical papilla). Using a minipig model, we transplanted both human SCAP and periodontal ligament stem cells (PDLSCs) to generate a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This wo...

  5. Extracellular vesicles, especially derived from Gram-negative bacteria, in indoor dust induce neutrophilic pulmonary inflammation associated with both Th1 and Th17 cell responses.

    Science.gov (United States)

    Kim, Y-S; Choi, E-J; Lee, W-H; Choi, S-J; Roh, T-Y; Park, J; Jee, Y-K; Zhu, Z; Koh, Y-Y; Gho, Y S; Kim, Y-K

    2013-04-01

    Many bacterial components in indoor dust can evoke inflammatory pulmonary diseases. Bacteria secrete nanometre-sized vesicles into the extracellular milieu, but it remains to be determined whether bacteria-derived extracellular vesicles in indoor dust are pathophysiologically related to inflammatory pulmonary diseases. To evaluate whether extracellular vesicles (EV) in indoor air are related to the pathogenesis of pulmonary inflammation and/or asthma. Indoor dust was collected from a bed mattress in an apartment. EV were prepared by sequential ultrafiltration and ultracentrifugation. Innate and adaptive immune responses were evaluated after airway exposure of EV. Repeated intranasal application of indoor-dust-induced neutrophilic pulmonary inflammation accompanied by lung infiltration of both Th1 and Th17 cells. EV 50-200 nm in diameter were present (102.5 μg protein concentration/g dust) in indoor dust. These vesicles were internalized by airway epithelial cells and alveolar macrophages, and this process was blocked by treatment of polymyxin B (an antagonist of lipopolysaccharide, an outer-membrane component of Gram-negative bacteria). Intranasal application of 0.1 or 1 μg of these vesicles for 4 weeks elicited neutrophilic pulmonary inflammation. This phenotype was accompanied by lung infiltration of both Th1 and Th17 cells, which were reversed by treatment of polymyxin B. Serum dust EV-reactive IgG1 levels were significantly higher in atopic children with asthma than in atopic healthy children and those with rhinitis or dermatitis. Indoor dust EV, especially derived from Gram-negative bacteria, is a possible causative agent of neutrophilic airway diseases. © 2013 Blackwell Publishing Ltd.

  6. Lactobacillus rhamnosus GG supernatant promotes intestinal barrier function, balances Treg and TH17 cells and ameliorates hepatic injury in a mouse model of chronic-binge alcohol feeding.

    Science.gov (United States)

    Chen, Rui-Cong; Xu, Lan-Man; Du, Shan-Jie; Huang, Si-Si; Wu, He; Dong, Jia-Jia; Huang, Jian-Rong; Wang, Xiao-Dong; Feng, Wen-Ke; Chen, Yong-Ping

    2016-01-22

    Impaired intestinal barrier function plays a critical role in alcohol-induced hepatic injury, and the subsequent excessive absorbed endotoxin and bacterial translocation activate the immune response that aggravates the liver injury. Lactobacillus rhamnosus GG supernatant (LGG-s) has been suggested to improve intestinal barrier function and alleviate the liver injury induced by chronic and binge alcohol consumption, but the underlying mechanisms are still not clear. In this study, chronic-binge alcohol fed model was used to determine the effects of LGG-s on the prevention of alcoholic liver disease in C57BL/6 mice and investigate underlying mechanisms. Mice were fed Lieber-DeCarli diet containing 5% alcohol for 10 days, and one dose of alcohol was gavaged on Day 11. In one group, LGG-s was supplemented along with alcohol. Control mice were fed isocaloric diet. Nine hours later the mice were sacrificed for analysis. Chronic-binge alcohol exposure induced an elevation in liver enzymes, steatosis and morphology changes, while LGG-s supplementation attenuated these changes. Treatment with LGG-s significantly improved intestinal barrier function reflected by increased mRNA expression of tight junction (TJ) proteins and villus-crypt histology in ileum, and decreased Escherichia coli (E. coli) protein level in liver. Importantly, flow cytometry analysis showed that alcohol reduced Treg cell population while increased TH17 cell population as well as IL-17 secretion, which was reversed by LGG-s administration. In conclusion, our findings indicate that LGG-s is effective in preventing chronic-binge alcohol exposure-induced liver injury and shed a light on the importance of the balance of Treg and TH17 cells in the role of LGG-s application. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Associations of Functional MicroRNA Binding Site Polymorphisms in IL23/Th17 Inflammatory Pathway Genes with Gastric Cancer Risk

    Directory of Open Access Journals (Sweden)

    Kaiyan Dong

    2017-01-01

    Full Text Available IL23/Th17 axis acts as an inflammatory pathway in gastric carcinogenesis. MicroRNA- (miRNA- binding site single-nucleotide polymorphisms (SNPs of inflammatory genes may alter gastric cancer (GC susceptibility. In this study, four miRNA binding site SNPs (rs3748067 of IL17A, rs887796, rs1468488 of IL17RA, and rs10889677 of IL23R were genotyped from 500 patients and 500 controls. Unconditional logistic regression analyses and multifactor dimensionality reduction software were used to evaluate the relationships of SNPs with GC and gene-environment interactions, respectively. Quantitative real-time PCR, Western blot analysis, and luciferase report gene assay were applied for function verification. We found that CT (ORadj = 0.59; 95% CI: 0.44–0.79, CT + TT (ORadj = 0.58; 95% CI: 0.43–0.77 genotypes, and T allele (ORadj = 0.77; 95% CI: 0.47–0.80 of rs3748067 reduced GC risk; the rs10889677 CC genotype (ORadj = 2.22; 95% CI: 1.27–3.87 and C allele (ORadj = 1.24; 95% CI: 1.02–1.52 increased GC risk. A meaningful interaction among ever smoked, family history of GC, and rs3748068 could intensify GC risk by 2.25-fold. Functional tests demonstrated the inhibitory effect of miR-10a-3p on IL17A expression in SGC-7901 cells. These results suggested that miRNA binding site SNPs within IL23/Th17 inflammatory pathway genes and their interactions with environmental factors could be associated with GC risk.

  8. Cytotoxic Th1 and Th17 cells infiltrate the intestinal mucosa of Behcet patients and exhibit high levels of TNF-α in early phases of the disease

    Science.gov (United States)

    Emmi, Giacomo; Silvestri, Elena; Bella, Chiara Della; Grassi, Alessia; Benagiano, Marisa; Cianchi, Fabio; Squatrito, Danilo; Cantarini, Luca; Emmi, Lorenzo; Selmi, Carlo; Prisco, Domenico; D’Elios, Mario Milco

    2016-01-01

    Abstract Background: Gastrointestinal involvement is one of the most serious in Behçet disease, potentially leading to severe complications. Aim of this study was to investigate at mucosal level the T-cell responses in Behçet patients with early intestinal involvement. Methods: We isolated T cells from intestinal mucosa of 8 patients with intestinal symptoms started within 6 months. T lymphocytes were cloned and analyzed for surface phenotype and cytokines production. Results: We obtained 382 T-cell clones: 324 were CD4+ and 58 were CD8+. Within the 324 CD4+ clones, 195 were able to secrete IFN-γ and TNF-α, but not IL-4, nor IL-17 thus showing a polarized Th1 profile, whereas CD4 clones producing both IFN-γ and IL-17 (Th1/Th17 profile) were 79. Likewise, the number of CD8 clones producing type 1 cytokines was higher than those of CD8 clones producing both type 1 and 2 cytokines. Almost all intestinal-derived T-cell clones expressed perforin-mediated cytotoxicity and Fas–Fas Ligand-mediated pro-apoptotic activity. Conclusions: Our results indicate that in the early stages of the disease, both Th1 and Th17 cells drive inflammation leading to mucosal damage via abnormal and long-lasting cytokines production as well as via both perforin- and Fas–Fas ligand-mediated cytotoxicity. Finally, all the T cells at mucosal level were able to produce large amount of TNF-α, suggesting that its production is a property of intestinal T cells of patients with early active intestinal disease. These results support the therapy with anti-TNF-α agents and suggest the use of anti-IL-17 monoclonal antibodies in Behçet patients with early intestinal involvement. PMID:27930541

  9. Distinct Roles of Th17 and Th1 Cells in Inflammatory Responses Associated with the Presentation of Paucibacillary Leprosy and Leprosy Reactions.

    Science.gov (United States)

    Santos, M B; de Oliveira, D T; Cazzaniga, R A; Varjão, C S; Dos Santos, P L; Santos, M L B; Correia, C B; Faria, D R; Simon, M do V; Silva, J S; Dutra, W O; Reed, S G; Duthie, M S; de Almeida, R P; de Jesus, A R

    2017-07-01

    It is well established that helper T cell responses influence resistance or susceptibility to Mycobacterium leprae infection, but the role of more recently described helper T cell subsets in determining severity is less clear. To investigate the involvement of Th17 cells in the pathogenesis of leprosy, we determined the immune profile with variant presentations of leprosy. Firstly, IL-17A, IFN-γ and IL-10 were evaluated in conjunction with CD4 + T cell staining by confocal microscopy of lesion biopsies from tuberculoid (TT) and lepromatous leprosy (LL) patients. Secondly, inflammatory cytokines were measured by multiplex assay of serum samples from Multibacillary (MB, n = 28) and Paucibacillary (PB, n = 23) patients and household contacts (HHC, n = 23). Patients with leprosy were also evaluated for leprosy reaction occurrence: LR+ (n = 8) and LR- (n = 20). Finally, peripheral blood mononuclear cells were analysed by flow cytometry used to determine the phenotype of cytokine-producing cells. Lesions from TT patients were found to have more CD4 + IL-17A + cells than those from LL patients. Higher concentrations of IL-17A and IL-1β were observed in serum from PB than MB patients. The highest serum IFN-γ concentrations were, however, detected in sera from MB patients that developed leprosy reactions (MB LR + ). Together, these results indicate that Th1 cells were associated with both the PB presentation and also with leprosy reactions. In contrast, Th17 cells were associated with an effective inflammatory response that is present in the PB forms but were not predictive of leprosy reactions in MB patients. © 2017 The Foundation for the Scandinavian Journal of Immunology.

  10. Doxycycline and Benznidazole Reduce the Profile of Th1, Th2, and Th17 Chemokines and Chemokine Receptors in Cardiac Tissue from Chronic Trypanosoma cruzi-Infected Dogs

    Directory of Open Access Journals (Sweden)

    Guilherme de Paula Costa

    2016-01-01

    Full Text Available Chemokines (CKs and chemokine receptors (CKR promote leukocyte recruitment into cardiac tissue infected by the Trypanosoma cruzi. This study investigated the long-term treatment with subantimicrobial doses of doxycycline (Dox in association, or not, with benznidazole (Bz on the expression of CK and CKR in cardiac tissue. Thirty mongrel dogs were infected, or not, with the Berenice-78 strain of T. cruzi and grouped according their treatments: (i two months after infection, Dox (50 mg/kg 2x/day for 12 months; (ii nine months after infection, Bz (3,5 mg/kg 2x/day for 60 days; (iii Dox + Bz; and (iv vehicle. After 14 months of infection, hearts were excised and processed for qPCR analysis of Th1 (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL11, Th2 (CCL1, CCL17, CCL24, and CCL26, Th17 (CCL20 CKs, Th1 (CCR5, CCR6, and CXCR3, and Th2/Th17 (CCR3, CCR4, and CCR8 CKR, as well as IL-17. T. cruzi infection increases CCL1, CCL2, CCL4, CCL5, CCL17, CXCL10, and CCR5 expression in the heart. Dox, Bz, or Dox + Bz treatments cause a reversal of CK and CKR and reduce the expression of CCL20, IL-17, CCR6, and CXCR3. Our data reveal an immune modulatory effect of Dox with Bz, during the chronic phase of infection suggesting a promising therapy for cardiac protection.

  11. Evidence for a role for interleukin-17, Th17 cells and iron homeostasis in protective immunity against tuberculosis in cynomolgus macaques.

    Directory of Open Access Journals (Sweden)

    Alice S Wareham

    Full Text Available Tuberculosis (TB remains a major global public health problem. The only vaccine, BCG, gives variable protection, especially in adults, so several new vaccines are in clinical trials. There are no correlates of protective immunity to TB; therefore vaccines progress through lengthy and expensive pre-clinical assessments and human trials. Correlates of protection could act as early end-points during clinical trials, accelerating vaccine development and reducing costs. A genome-wide microarray was utilised to identify potential correlates of protection and biomarkers of disease induced post-BCG vaccination and post-Mycobacterium tuberculosis challenge in PPD-stimulated peripheral blood mononuclear cells from cynomolgus macaques where the outcome of infection was known. Gene expression post BCG-vaccination and post challenge was compared with gene expression when the animals were naïve. Differentially expressed genes were identified using a moderated T test with Benjamini Hochberg multiple testing correction. After BCG vaccination and six weeks post-M. tuberculosis challenge, up-regulation of genes related to a Th1 and Th17 response was observed in disease controllers. At post-mortem, RT-PCR revealed an up-regulation of iron regulatory genes in animals that developed TB and down-regulation of these genes in disease controllers, indicating the ability to successfully withhold iron may be important in the control of TB disease. The induction of a balanced Th1 and Th17 response, together with expression of effector cytokines, such as IFNG, IL2, IL17, IL21 and IL22, could be used as correlates of a protective host response.

  12. The altered expression of inflammation-related microRNAs with microRNA-155 expression correlates with Th17 differentiation in patients with acute coronary syndrome.

    Science.gov (United States)

    Yao, Rui; Ma, Yulan; Du, Youyou; Liao, Mengyang; Li, Huanhuan; Liang, Wei; Yuan, Jing; Ma, Zhijun; Yu, Xian; Xiao, Hong; Liao, Yuhua

    2011-11-01

    MicroRNAs (miRNAs) are a novel class of small, non-coding RNAs that play a significant role in both inflammatory and cardiovascular diseases. Immune cells, especially T helper (Th) cells, are critical in the development of atherosclerosis and the onset of acute coronary syndrome (ACS). To assess whether inflammation-related miRNAs (such as miR-155, 146a, 21, 125a-5p, 125b, 31) are involved in the imbalance of Th cell subsets in patients with ACS, we measured the expression of related miRNAs in patients with acute myocardial infarction (AMI), unstable angina (UA), stable angina (SA) and chest pain syndrome (CPS); analyzed the relationship between miRNA expression and the frequency of Th cell subsets; and observed the co-expression of miR-155 and IL-17A in peripheral blood mononuclear cells (PBMCs) of patients with ACS. The results showed that the expression of miR-155 in the PBMCs of patients with ACS was decreased by approximately 60%, while the expression of both miR-21 and miR-146a was increased by approximately twofold. The expression patterns of miRNAs in plasma correlated with those in PBMCs, except for miR-21, which was increased by approximately sixfold in the AMI group and showed no significant difference between the UA group and the CPS group. We also found that the expression of miR-155 inversely correlated with the frequency of Th17 cells (r=-0.896, Pinflammation-related miRNAs in patients with ACS and found that miR-155 may be associated with Th17 cell differentiation.

  13. Topical application of Moringa oleifera leaf extract ameliorates experimentally induced atopic dermatitis by the regulation of Th1/Th2/Th17 balance.

    Science.gov (United States)

    Choi, Eun-Ju; Debnath, Trishna; Tang, Yujiao; Ryu, Young-Bae; Moon, Sang-Ho; Kim, Eun-Kyung

    2016-12-01

    Moringa oleifera (M. oleifera) is widely cultivated in tropical and subtropical regions and has been used as a vegetable and in traditional medicine. In this study, the anti-atopic dermatitis activity of the ethanol extract of M. oleifera leaf was investigated in vitro and in vivo. For the in vitro study, HaCaT human keratinocytes were used for cytokines and MAPKinase assay. In the in vivo study, M. oleifera leaf ethanolic extract (MO) was topically applied to BALB/c mice with Dermatophagoides farinae extract (DFE; house dust mite extract)- and 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD). The expression of TNF-α, CCL17, IL-1β, IL-6 pro-inflammatory cytokine-related mRNA, and mitogen-activated protein kinases (MAPKs) in TNF-α/IFN-γ-induced HaCaT keratinocytes were reduced by MO. Epidermal and dermal ear thickness, mast cell infiltration, serum immunoglobulin levels, as well as gene expression of various cytokines in the ear tissue, lymph nodes, and splenocytes were improved by treatment with MO. In addition, MO reduced the expression of retinoic acid-related orphan receptor γT (RORγT), thymic stromal lymphopoietin (TSLP), and mannose receptor (CD206) mRNA in the ear tissue and improved cervical lymph node size. The results of this study strongly suggest the beneficial effects of MO on AD via the regulation of inflammatory responses. Copyright © 2016. Published by Elsevier Masson SAS.

  14. Therapeutic Treatment of Arthritic Mice with 15-Deoxy Δ12,14-Prostaglandin J2 (15d-PGJ2 Ameliorates Disease through the Suppression of Th17 Cells and the Induction of CD4+CD25−FOXP3+ Cells

    Directory of Open Access Journals (Sweden)

    Vanessa Carregaro

    2016-01-01

    Full Text Available The prostaglandin, 15-deoxy Δ12,14-prostaglandin J2 (15d-PGJ2, is a lipid mediator that plays an important role in the control of chronic inflammatory disease. However, the role of prostanoid in rheumatoid arthritis (RA is not well determined. We demonstrated the therapeutic effect of 15d-PGJ2 in an experimental model of arthritis. Daily administration of 15d-PGJ2 attenuated the severity of CIA, reducing the clinical score, pain, and edema. 15d-PGJ2 treatment was associated with a marked reduction in joint levels of proinflammatory cytokines. Although the mRNA expression of ROR-γt was profoundly reduced, FOXP3 was enhanced in draining lymph node cells from 15d-PGJ2-treated arthritic mice. The specific and polyclonal CD4+ Th17 cell responses were limited during the addition of prostaglandin to cell culture. Moreover, in vitro 15d-PGJ2 increased the expression of FOXP3, GITR, and CTLA-4 in the CD4+CD25− population, suggesting the induction of Tregs on conventional T cells. Prostanoid addition to CD4+CD25− cells selectively suppressed Th17 differentiation and promoted the enhancement of FOXP3 under polarization conditions. Thus, 15d-PGJ2 ameliorated symptoms of collagen-induced arthritis by regulating Th17 differentiation, concomitant with the induction of Tregs, and, consequently, protected mice from diseases aggravation. Altogether, these results indicate that 15d-PGJ2 may represent a potential therapeutic strategy in RA.

  15. Defining T-cell-mediated immune responses in rotavirus-infected juvenile rhesus macaques.

    Science.gov (United States)

    Sestak, K; McNeal, M M; Choi, A; Cole, M J; Ramesh, G; Alvarez, X; Aye, P P; Bohm, R P; Mohamadzadeh, M; Ward, R L

    2004-10-01

    The appearance of virus-specific CD4(+) and/or CD8(+) T lymphocytes in peripheral blood of captive juvenile rhesus macaques (Macaca mulatta) was observed following rotavirus infection. These cell-mediated immune responses were measured following experimental or natural infection after rotavirus was isolated from stool specimens of asymptomatic animals. The virus isolated was a new strain of simian rotavirus that we named TUCH (for Tulane University and Cincinnati Children's Hospital). Restimulation of peripheral T lymphocytes by inactivated double- or triple-layered TUCH rotavirus particles containing either VP6 or VP4 and VP7 on their respective surfaces resulted in increased quantities of interleukin-6 (IL-6) and IL-12 in cell culture supernatants. Recall responses to rotavirus by CD4(+) and CD8(+) T lymphocytes were associated with accumulation of intracellular IL-6 and gamma interferon. Antigen presentation of TUCH rotavirus to lymphocytes was mediated via differentiated cultures of monocyte-derived dendritic (HLA-DR(+)) cells. This is the first report demonstrating cell-mediated immune responses to rotavirus in nonhuman primates. Further exploration of rhesus macaques in vaccine trials with human rotavirus vaccine candidates is the major objective of future studies.

  16. Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation.

    Science.gov (United States)

    Brasseit, Jennifer; Kwong Chung, Cheong K C; Noti, Mario; Zysset, Daniel; Hoheisel-Dickgreber, Nina; Genitsch, Vera; Corazza, Nadia; Mueller, Christoph

    2018-01-01

    Aberrant interferon gamma (IFNγ) expression is associated with the pathogenesis of numerous autoimmune- and inflammatory disorders, including inflammatory bowel diseases (IBD). However, the requirement of IFNγ for the pathogenesis of chronic intestinal inflammation remains controversial. The aim of this study was thus to investigate the role of IFNγ in experimental mouse models of innate and adaptive immune cell-mediated intestinal inflammation using genetically and microbiota-stabilized hosts. While we find that IFNγ drives acute intestinal inflammation in the anti-CD40 colitis model in an innate lymphoid cell (ILC)-dependent manner, IFNγ secreted by both transferred CD4 T cells and/or cells of the lymphopenic Rag1 -/- recipient mice was dispensable for CD4 T cell-mediated colitis. In the absence of IFNγ, intestinal inflammation in CD4 T cell recipient mice was associated with enhanced IL17 responses; consequently, targeting IL17 signaling in IFNγ-deficient mice reduced T cell-mediated colitis. Intriguingly, in contrast to the anti-CD40 model of colitis, depletion of ILC in the Rag1 -/- recipients of colitogenic CD4 T cells did not prevent induction of colonic inflammation. Together, our findings demonstrate that IFNγ represents an essential, or a redundant, pro-inflammatory cytokine for the induction of intestinal inflammation, depending on the experimental mouse model used and on the nature of the critical disease inducing immune cell populations involved.

  17. Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell-mediated liver regeneration

    DEFF Research Database (Denmark)

    Jelnes, Peter; Santoni-Rugiu, Eric; Rasmussen, Morten

    2007-01-01

    The experimental protocols used in the investigation of stem cell-mediated liver regeneration in rodents are characterized by activation of the hepatic stem cell compartment in the canals of Hering followed by transit amplification of oval cells and their subsequent differentiation along hepatic...... the molecular phenotypes of oval cells in several of the most commonly used protocols of stem cell-mediated liver regeneration-namely, treatment with 2-acetylaminofluorene and partial (70%) hepatectomy (AAF/PHx); a choline-deficient, ethionine-supplemented (CDE) diet; a 3,5-diethoxycarbonyl-1,4-dihydro......-collidin (DDC) diet; and N-acetyl-paraaminophen (APAP). Reproducibly, oval cells showing reactivity for cytokeratins (CKs), muscle pyruvate kinase (MPK), the adenosine triphosphate-binding cassette transporter ABCG2/BCRP1 (ABCG2), alpha-fetoprotein (AFP), and delta-like protein 1/preadipocyte factor 1 (Dlk...

  18. Detection of IFN-γ+IL-17+ cells in salivary glands of patients with Sjögren's syndrome and Mikulicz's disease: Potential role of Th17•Th1 in the pathogenesis of autoimmune diseases.

    Science.gov (United States)

    Nanke, Yuki; Kobashigawa, Tsuyoshi; Yago, Toru; Kawamoto, Manabu; Yamanaka, Hisashi; Kotake, Shigeru

    2016-01-01

      Objective: Th17 cells, which mainly produce interleukin (IL)-17, have been suggested to play a critical role in the pathogenesis of autoimmune diseases. The plasticity of Th17 cells, in which these cells shift to a Th1 phenotype in the presence of IL-12, has recently been reported. However, the role of IL-17 in Sjögren's syndrome (SS) and Mikulicz's disease (MD) currently remains unknown. The submandibular salivary gland and lymph node of a MD patient and the salivary glands of 15 SS patients were collected. IFN-γ+ cells, IL-17+ cells, and IFN-γ+IL-17+ cells were detected by immunohistochemical staining. IFN-γ+ cells, IL-17+ cells, and IFN-γ+IL-17+ cells were detected in the submandibular salivary gland and lymph node of the MD patient and salivary glands of the 15 SS patients. IFN-γ+IL-17+cells in the salivary glands of patients were speculated to be Th1/Th17 cells in the present study. Th1/Th17 cells are known to be derived from Th17 cells and differentiate into Th1 cells, and IL-17-derived Th1 cells have been suggested to induce the deterioration of juvenile idiopathic arthritis (JIA). Thus, Th1/Th17 cells may play an important role in the pathogenesis of SS and MD. IFN-γ+, IFN-γ+IL-17+, and IL-17+ cells were detected in the submandibular salivary gland and lymph node of a MD patient and the salivary glands of 15 SS patients.

  19. Resident Bacteria-Stimulated Interleukin-10-Secreting B Cells Ameliorate T-Cell-Mediated Colitis by Inducing T-Regulatory-1 Cells That Require Interleukin-27 SignalingSummary

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    Yoshiyuki Mishima

    2015-05-01

    Full Text Available Background & Aims: The regulatory roles of interleukin-10 (IL10-producing B cells in colitis are not fully understood, so we explored the molecular mechanisms by which these cells modulate mucosal homeostasis. Methods: CD4+ T cells from wild-type (WT, Il10−/−, or Il27ra−/− mice were cotransferred with B cells from specific pathogen-free (SPF or germ-free (GF WT or Il10−/− mice into Rag2−/−Il10−/−(double-knockout mice, and the severity of colitis and intestinal regulatory T-cell populations were characterized. In vitro, WT or Il10−/− B cells were cocultured with unfractionated, naïve or regulatory T cells plus Il10−/− antigen-presenting cells and stimulated with cecal bacterial lysate (CBL with or without IL27 or anti-IL10R blockade. Gene expressions, cytokines in the supernatant and cell populations were assessed. Results: WT but not Il10−/− B cells attenuated T helper cell TH1/TH17-mediated colitis in double-knockout mice that also received WT but not Il10−/− T cells. In vitro, CBL-stimulated WT B cells secrete abundant IL10 and suppress interferon-γ (IFNγ and IL17a-production by T cells without requiring cell contact. Although both WT and Il10−/− B cells induced Foxp3+CD4+ T-regulatory cells, only WT B cells induced IL10-producing (Foxp3-negative T regulatory-1 (Tr-1 cells both in vivo and in vitro. However, IL10-producing B cells did not attenuate colitis or induce Tr-1 cells in the absence of T cell IL27 signaling in vivo. WT B cell-dependent Tr-1 induction and concomitant decreased IFNγ-secretion were also mediated by T-cell IL27-signaling in vitro. Conclusions: IL10-secreting B cells activated by physiologically relevant bacteria ameliorate T-cell-mediated colitis and contribute to intestinal homeostasis by suppressing effector T cells and inducing Tr-1 cells via IL27-signaling on T cells. Keywords: Experimental

  20. Salmonella Typhimurium, the major causative agent of foodborne illness inactivated by a phage lysis system provides effective protection against lethal challenge by induction of robust cell-mediated immune responses and activation of dendritic cells.

    Science.gov (United States)

    Won, Gayeon; Lee, John Hwa

    2017-10-25

    Salmonella Typhimurium infection via foodborne transmission remains a major public health threat even in developed countries. Vaccines have been developed to reduce the disease burden at the pre-harvest stage, but the cell-mediated immune response against intracellular invasion of the pathogen is not sufficiently elicited by conventional killed Salmonella vaccines, which are safer than live vaccines. In this study, we developed a genetically inactivated vaccine candidate by introducing lysis plasmid pJHL454 harboring the λ phage holin-endolysin system into S. Typhimurium; we designated this vaccine JOL1950. In vitro expression of endolysin was validated by immunoblotting, and complete inactivation of JOL1950 cells was observed following 36 h of the lysis. Electron microscopic examinations by scanning electron microscopy and immunogold labeling transmission EM revealed conserved surface antigenic traits of the JOL1950 cells after lysis. An in vivo immunogenicity study in mice immunized with lysed cells showed significantly increased serum IgG, IgG1, and IgG2a levels. Further, we observed markedly increased in vitro cell proliferation and upregulation of Th1, Th2, and Th17 cytokines in the repulsed splenic T-cells of immunized mice. In dendritic cells (DCs) treated with lysed JOL1950, we observed a significant increase in dendritic cell activation, co-stimulatory molecule production, and levels of immunomodulatory cytokines. In addition, Th1 and Th17 cytokines were also released by naïve CD4+ T-cells pulsed with primed DCs. Lysed JOL1950 also protected against lethal challenge in immunized mice. Together, these results indicate that our vaccine candidate has great potential to induce cell-mediated immunity against S. Typhimurium by facilitating the activation of DCs.

  1. NLRP3 suppresses NK cell-mediated responses to carcinogen-induced tumors and metastases.

    Science.gov (United States)

    Chow, Melvyn T; Sceneay, Jaclyn; Paget, Christophe; Wong, Christina S F; Duret, Helene; Tschopp, Jürg; Möller, Andreas; Smyth, Mark J

    2012-11-15

    The NLRP3 inflammasome acts as a danger signal sensor that triggers and coordinates the inflammatory response upon infectious insults or tissue injury and damage. However, the role of the NLRP3 inflammasome in natural killer (NK) cell-mediated control of tumor immunity is poorly understood. Here, we show in a model of chemical-induced carcinogenesis and a series of experimental and spontaneous metastases models that mice lacking NLRP3 display significantly reduced tumor burden than control wild-type (WT) mice. The suppression of spontaneous and experimental tumor metastases and methylcholanthrene (MCA)-induced sarcomas in mice deficient for NLRP3 was NK cell and IFN-γ-dependent. Focusing on the amenable B16F10 experimental lung metastases model, we determined that expression of NLRP3 in bone marrow-derived cells was necessary for optimal tumor metastasis. Tumor-driven expansion of CD11b(+)Gr-1(intermediate) (Gr-1(int)) myeloid cells within the lung tumor microenvironment of NLRP3(-/-) mice was coincident with increased lung infiltrating activated NK cells and an enhanced antimetastatic response. The CD11b(+)Gr-1(int) myeloid cells displayed a unique cell surface phenotype and were characterized by their elevated production of CCL5 and CXCL9 chemokines. Adoptive transfer of this population into WT mice enhanced NK cell numbers in, and suppression of, B16F10 lung metastases. Together, these data suggested that NLRP3 is an important suppressor of NK cell-mediated control of carcinogenesis and metastases and identify CD11b(+)Gr-1(int) myeloid cells that promote NK cell antimetastatic function. ©2012 AACR.

  2. Augmentation of humoral and cell mediated immune responses by Thujone.

    Science.gov (United States)

    Siveen, K S; Kuttan, Girija

    2011-12-01

    Thujone, a naturally occurring monoterpene, was found to enhance the total WBC count, bone marrow cellularity, number of α-esterase positive cells, number of plaque forming cells in spleen and circulating antibody titer in Balb/c mice (1mg/kg body weight, intraperitoneally for 5 days). Thujone treatment enhanced proliferation of splenocytes and thymocytes, both in the presence and absence of specific mitogens. Administration of Thujone was found to stimulate the cell-mediated immunological response in normal and tumor bearing Balb/c mice. A significant enhancement in natural killer (NK) cell mediated cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent complement mediated cytotoxicity (ACC) in both normal as well as tumor-bearing animals was observed after the administration of Thujone. Production of cytokines such as IL-2 and IFN-γ was significantly enhanced by the administration of Thujone. The stimulatory effect of Thujone on cytotoxic T lymphocyte (CTL) generation was determined by Winn's neutralization assay using CTL sensitive EL4 thymoma cells. Thujone treatment showed a significant increase in CTL production in both the in vivo and in vitro models, as indicated by a significant increase in the life span of tumor bearing animals. All these results indicate that administration of Thujone could enhance the immune response of mice. There was a significant reduction in solid tumor development, mediated by the presence of alert immune responses during Thujone administration. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Engineering PTEN-L for Cell-Mediated Delivery.

    Science.gov (United States)

    Lavictoire, Sylvie J; Gont, Alexander; Julian, Lisa M; Stanford, William L; Vlasschaert, Caitlyn; Gray, Douglas A; Jomaa, Danny; Lorimer, Ian A J

    2018-06-15

    The tumor suppressor PTEN is frequently inactivated in glioblastoma. PTEN-L is a long form of PTEN produced by translation from an alternate upstream start codon. Unlike PTEN, PTEN-L has a signal sequence and a tract of six arginine residues that allow PTEN-L to be secreted from cells and be taken up by neighboring cells. This suggests that PTEN-L could be used as a therapeutic to restore PTEN activity. However, effective delivery of therapeutic proteins to treat CNS cancers such as glioblastoma is challenging. One method under evaluation is cell-mediated therapy, where cells with tumor-homing abilities such as neural stem cells are genetically modified to express a therapeutic protein. Here, we have developed a version of PTEN-L that is engineered for enhanced cell-mediated delivery. This was accomplished by replacement of the native leader sequence of PTEN-L with a leader sequence from human light-chain immunoglobulin G (IgG). This version of PTEN-L showed increased secretion and an increased ability to transfer to neighboring cells. Neural stem cells derived from human fibroblasts could be modified to express this version of PTEN-L and were able to deliver catalytically active light-chain leader PTEN-L (lclPTEN-L) to neighboring glioblastoma cells.

  4. PLGA nano/micro particles encapsulated with pertussis toxoid (PTd) enhances Th1/Th17 immune response in a murine model.

    Science.gov (United States)

    Li, Pan; Asokanathan, Catpagavalli; Liu, Fang; Khaing, Kyi Kyi; Kmiec, Dorota; Wei, Xiaoqing; Song, Bing; Xing, Dorothy; Kong, Deling

    2016-11-20

    Poly(lactic-co-glycolic acid) (PLGA) based nano/micro particles were investigated as a potential vaccine platform for pertussis antigen. Presentation of pertussis toxoid as nano/micro particles (NP/MP) gave similar antigen-specific IgG responses in mice compared to soluble antigen. Notably, in cell line based assays, it was found that PLGA based nano/micro particles enhanced the phagocytosis of fluorescent antigen-nano/micro particles by J774.2 murine monocyte/macrophage cells compared to soluble antigen. More importantly, when mice were immunised with the antigen-nano/micro particles they significantly increased antigen-specific Th1 cytokines INF-γ and IL-17 secretion in splenocytes after in vitro re-stimulation with heat killed Bordetalla pertussis, indicating the induction of a Th1/Th17 response. Also, presentation of pertussis antigen in a NP/MP formulation is able to provide protection against respiratory infection in a murine model. Thus, the NP/MP formulation may provide an alternative to conventional acellular vaccines to achieve a more balanced Th1/Th2 immune response. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Oral administration of apple condensed tannins delays rheumatoid arthritis development in mice via downregulation of T helper 17 (Th17) cell responses.

    Science.gov (United States)

    Nakamura, Kosuke; Matsuoka, Hideki; Nakashima, Syohei; Kanda, Tomomasa; Nishimaki-Mogami, Tomoko; Akiyama, Hiroshi

    2015-07-01

    Apples are known to contain high concentrations of phenolic compounds such as condensed tannins. Consumption of condensed tannins has been reported to reduce the risk of many types of chronic diseases including allergies. However, their therapeutic effectiveness and potential in treating autoimmune disease remain controversial. Here, the effect of oral administration of apple condensed tannins (ACT) prepared from apples (Malus pumila cv. Fuji) on bovine type II collagen (CII)-induced arthritis in DBA1/J mice, a well-established murine model of human rheumatoid arthritis (RA), was evaluated. As compared to the control (without ACT administration) group, RA development was delayed and a significant reduction in the RA clinical score was observed in the ACT-administered group. Using cultured splenocytes isolated from CII-immunized mice, ACT-administration was shown to decrease the CII-induced increases in IL-17 expression and production in vitro. We propose that downregulation of T helper (Th) 17 cells is responsible for the ACT-induced RA suppression. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH17 cytokine interleukin-22

    Science.gov (United States)

    Hughes, Tiffany; Becknell, Brian; McClory, Susan; Briercheck, Edward; Freud, Aharon G.; Zhang, Xiaoli; Mao, Hsiaoyin; Nuovo, Gerard; Yu, Jianhua

    2009-01-01

    Considerable functional heterogeneity within human natural killer (NK) cells has been revealed through the characterization of distinct NK-cell subsets. Accordingly, a small subset of CD56+NKp44+NK cells, termed NK-22 cells, was recently described within secondary lymphoid tissue (SLT) as IL-22− when resting, with a minor fraction of this population becoming IL-22+ when activated. Here we discover that the vast majority of stage 3 immature NK (iNK) cells in SLT constitutively and selectively express IL-22, a TH17 cytokine important for mucosal immunity, whereas earlier and later stages of NK developmental intermediates do not express IL-22. These iNK cells have a surface phenotype of CD34−CD117+CD161+CD94−, largely lack expression of NKp44 and CD56, and do not produce IFN-γ or possess cytolytic activity. In summary, stage 3 iNK cells are highly enriched for IL-22 and IL-26 messenger RNA, and IL-22 protein production, but do not express IL-17A or IL-17F. PMID:19244159

  7. Plasma Interleukin-37 Is Elevated in Patients with Rheumatoid Arthritis: Its Correlation with Disease Activity and Th1/Th2/Th17-Related Cytokines

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    Ting Xia

    2015-01-01

    Full Text Available Interleukin- (IL- 37 is a novel anti-inflammatory cytokine that suppresses immune response and inflammation. This study was performed to determine whether IL-37 was elevated in patients with rheumatoid arthritis (RA and investigate the correlation between IL-37 level and disease activity and the concentration of Th1/Th2/Th17-related cytokines. Clinical parameters of disease activity, including the 28-joint disease activity score (DAS28 and C-reactive protein (CRP, were collected in 34 RA patients and 34 age- and sex-matched healthy controls. Plasma IL-37 was measured by ELISA. Plasma levels of TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, IFN-γ, MCP-1, and MIP-1β were analyzed using the Bio-Plex suspension array system. It was found that IL-37 levels were elevated markedly in RA patients and almost undetectable in healthy controls. In addition, IL-37 levels in patients with active RA were significantly enhanced as compared with those in patients of remission. More importantly, IL-37 showed a significant correlation with disease activity (DAS28 and IL-4, IL-7, IL-10, IL-12, and IL-13 concentrations in RA patients. These findings suggest that IL-37 plays an important role in the pathogenesis of RA and may prove to be a potential biomarker of active RA.

  8. B-cell anergy induces a Th17 shift in a novel B lymphocyte transgenic NOD mouse model, the 116C-NOD mouse.

    Science.gov (United States)

    Carrascal, Jorge; Carrillo, Jorge; Arpa, Berta; Egia-Mendikute, Leire; Rosell-Mases, Estela; Pujol-Autonell, Irma; Planas, Raquel; Mora, Conchi; Mauricio, Dídac; Ampudia, Rosa Maria; Vives-Pi, Marta; Verdaguer, Joan

    2016-03-01

    Autoreactive B lymphocytes play a key role as APCs in diaebetogenesis. However, it remains unclear whether B-cell tolerance is compromised in NOD mice. Here, we describe a new B lymphocyte transgenic NOD mouse model, the 116C-NOD mouse, where the transgenes derive from an islet-infiltrating B lymphocyte of a (8.3-NODxNOR) F1 mouse. The 116C-NOD mouse produces clonal B lymphocytes with pancreatic islet beta cell specificity. The incidence of T1D in 116C-NOD mice is decreased in both genders when compared with NOD mice. Moreover, several immune selection mechanisms (including clonal deletion and anergy) acting on the development, phenotype, and function of autoreactive B lymphocytes during T1D development have been identified in the 116C-NOD mouse. Surprisingly, a more accurate analysis revealed that, despite their anergic phenotype, 116C B cells express some costimulatory molecules after activation, and induce a T-cell shift toward a Th17 phenotype. Furthermore, this shift on T lymphocytes seems to occur not only when both T and B cells contact, but also when helper T (Th) lineage is established. The 116C-NOD mouse model could be useful to elucidate the mechanisms involved in the generation of Th-cell lineages. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Phenome-wide association study using research participants' self-reported data provides insight into the Th17 and IL-17 pathway.

    Science.gov (United States)

    Ehm, Margaret G; Aponte, Jennifer L; Chiano, Mathias N; Yerges-Armstrong, Laura M; Johnson, Toby; Barker, Jonathan N; Cook, Suzanne F; Gupta, Akanksha; Hinds, David A; Li, Li; Nelson, Matthew R; Simpson, Michael A; Tian, Chao; McCarthy, Linda C; Rajpal, Deepak K; Waterworth, Dawn M

    2017-01-01

    A phenome-wide association study of variants in genes in the Th17 and IL-17 pathway was performed using self-reported phenotypes and genetic data from 521,000 research participants of 23andMe. Results replicated known associations with similar effect sizes for autoimmune traits illustrating self-reported traits can be a surrogate for clinically assessed conditions. Novel associations controlling for a false discovery rate of 5% included the association of the variant encoding p.Ile684Ser in TYK2 with increased risk of tonsillectomy, strep throat occurrences and teen acne, the variant encoding p.Arg381Gln in IL23R with a decrease in dandruff frequency, the variant encoding p.Asp10Asn in TRAF3IP2 with risk of male-pattern balding, and the RORC regulatory variant (rs4845604) with protection from allergies. This approach enabled rapid assessment of association with a wide variety of traits and investigation of traits with limited reported associations to overlay meaningful phenotypic context on the range of conditions being considered for drugs targeting this pathway.

  10. Human dendritic cells activated via dectin-1 are efficient at priming Th17, cytotoxic CD8 T and B cell responses.

    Directory of Open Access Journals (Sweden)

    Sudhanshu Agrawal

    Full Text Available BACKGROUND: Dendritic cells capture antigens through PRRs and modulate adaptive immune responses. The type of adaptive immune T cell response generated is dependent upon the type of PRR activated by the microbes. Dectin-1 is a C-type lectin receptor present on dendritic cells. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that selective dectin-1 agonist Curdlan can activate human DCs and induce the secretion of large amounts of IL-23, IL-1β, IL-6 and low levels of IL-12p70 as determined by ELISA. The Curdlan-stimulated DCs are efficient at priming naïve CD4 cells to differentiate into Th17 and Th1 cells. Furthermore, these CD4 T cells induce differentiation of B cells to secrete IgG and IgA. In addition, Curdlan-stimulated DCs promote the expansion and differentiation of Granzyme and perforin expressing cytotoxic T lymphocyte that display high cytolytic activity against target tumor cells in vitro. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that DCs stimulated through Dectin-1 can generate efficient Th, CTL and B cell responses and can therefore be used as effective mucosal and systemic adjuvants in humans.

  11. Prospective study in a porcine model of sarcoptes scabiei indicates the association of Th2 and Th17 pathways with the clinical severity of scabies.

    Directory of Open Access Journals (Sweden)

    Kate E Mounsey

    2015-03-01

    Full Text Available BACKGROUND: Understanding of scabies immunopathology has been hampered by the inability to undertake longitudinal studies in humans. Pigs are a useful animal model for scabies, and show clinical and immunologic changes similar to those in humans. Crusted scabies can be readily established in pigs by treatment with the glucocorticoid dexamethasone (Dex. METHODOLOGY/ PRINCIPAL FINDINGS: Prospective study of 24 pigs in four groups: a Scabies+/Dex+, b Scabies+/Dex-, c Scabies-/Dex+ and d Scabies-/Dex-. Clinical symptoms were monitored. Histological profiling and transcriptional analysis of skin biopsies was undertaken to compare changes in cell infiltrates and representative cytokines. A range of clinical responses to Sarcoptes scabiei were observed in Dex treated and non-immunosuppressed pigs. An association was confirmed between disease severity and transcription of the Th2 cytokines IL-4 and IL-13, and up-regulation of the Th17 cytokines IL-17 and IL-23 in pigs with crusted scabies. Immunohistochemistry revealed marked infiltration of lymphocytes and mast cells, and strong staining for IL-17. CONCLUSIONS/ SIGNIFICANCE: While an allergic Th2 type response to scabies has been previously described, these results suggest that IL-17 related pathways may also contribute to immunopathology of crusted scabies. This may lead to new strategies to protect vulnerable subjects from contracting recurrent crusted scabies.

  12. Phenome-wide association study using research participants' self-reported data provides insight into the Th17 and IL-17 pathway.

    Directory of Open Access Journals (Sweden)

    Margaret G Ehm

    Full Text Available A phenome-wide association study of variants in genes in the Th17 and IL-17 pathway was performed using self-reported phenotypes and genetic data from 521,000 research participants of 23andMe. Results replicated known associations with similar effect sizes for autoimmune traits illustrating self-reported traits can be a surrogate for clinically assessed conditions. Novel associations controlling for a false discovery rate of 5% included the association of the variant encoding p.Ile684Ser in TYK2 with increased risk of tonsillectomy, strep throat occurrences and teen acne, the variant encoding p.Arg381Gln in IL23R with a decrease in dandruff frequency, the variant encoding p.Asp10Asn in TRAF3IP2 with risk of male-pattern balding, and the RORC regulatory variant (rs4845604 with protection from allergies. This approach enabled rapid assessment of association with a wide variety of traits and investigation of traits with limited reported associations to overlay meaningful phenotypic context on the range of conditions being considered for drugs targeting this pathway.

  13. The IL23R A/Gln381 allele promotes IL-23 unresponsiveness in human memory T-helper 17 cells and impairs Th17 responses in psoriasis patients.

    Science.gov (United States)

    Di Meglio, Paola; Villanova, Federica; Napolitano, Luca; Tosi, Isabella; Terranova Barberio, Manuela; Mak, Rose K; Nutland, Sarah; Smith, Catherine H; Barker, Jonathan N W N; Todd, John A; Nestle, Frank O

    2013-10-01

    We and others have shown that the minor, nonconserved allele Gln381 of the Arg381Gln single-nucleotide polymorphism (rs11209026G>A) of the IL-23 receptor gene (IL23R) protects against psoriasis. Moreover, we have recently shown impaired IL-23-induced IL-17A production and STAT-3 phosphorylation in Th17 cells generated in vitro from healthy individuals heterozygous for the protective A allele (GA). However, the biological effect of this variant has not been determined in homozygous carriers of the protective A allele (AA), nor in psoriatic patients. Here we expand our functional investigation of the IL23R Arg381Gln gene variant to include AA homozygous individuals. By using isolated memory CD4+ T cells, we found attenuated IL-23-induced Th17 response in heterozygous individuals. Moreover, we found that AA homozygous individuals were strikingly unresponsive to IL-23, with minimal or no IL-17A and IL-17F production and failure of human memory Th17 cell survival/expansion. Finally, IL-23-induced Th17 response was also attenuated in age- and sex-matched GA versus GG psoriatic patients undergoing systemic treatment. Taken together, our data provide evidence for an allele-dosage effect for IL-23R Gln381 and indicate that common gene alleles associated with complex diseases might have biological effects of considerable magnitude in homozygous carriers.

  14. Establishment of Stable, Cell-Mediated Immunity that Makes "Susceptible" Mice Resistant to Leishmania major

    Science.gov (United States)

    Bretscher, Peter A.; Wei, Guojian; Menon, Juthika N.; Bielefeldt-Ohmann, Helle

    1992-07-01

    Cell-mediated, but not antibody-mediated, immune responses protect humans against certain pathogens that produce chronic diseases such as leishmaniasis. Effective vaccination against such pathogens must therefore produce an immunological "imprint" so that stable, cell-mediated immunity is induced in all individuals after natural infection. BALB/c mice "innately susceptible" to Leishmania major produce antibodies after substantial infection. In the present study, "susceptible" mice injected with a small number of parasites mounted a cell-mediated response and acquired resistance to a larger, normally pathogenic, challenge. This vaccination strategy may be applicable in diseases in which protection is dependent on cell-mediated immunity.

  15. Antibody-dependent cell-mediated effects in bancroftian filariasis.

    Science.gov (United States)

    Mehta, K; Sindhu, R K; Subrahmanyam, D; Hopper, K; Nelson, D S; Rao, C K

    1981-01-01

    The nature of immunoglobulin and effector cells involved in the antibody-dependent cell-mediated adhesion and cytotoxicity to Wuchereria bancrofti larvae has been investigated. Human neutrophils and eosinophils purified from peripheral blood by metrizamide gradients readily adhered to the parasites in presence of IgG fraction of sera from majority of elephantiasis cases with amicrofilaraemia and many of the endemic normals. The cells from normal, microfilariae and elephantiasis cases were equally effective inthe adhesion reaction. While the adhered neutrophils killed the larvae, eosinophils were ineffective in this respect. DEC treatment of elephantiasis cases results in a significant reduction in the ability of their sera to promote cellular adhesion. Images Figure 1 PMID:7019047

  16. Cell mediated immune response in human antirabies revaccination

    Directory of Open Access Journals (Sweden)

    Débora Regina Veiga

    1987-04-01

    Full Text Available The occurrence of secondary cell mediated immune response (CMI in human antirabies immunization was studied. The Puenzalida & Palácios vaccine was used because it is routinely used in Brazil. CMI was evaluated by lymphoblastic transformation indices obtained in whole blood culture in the presence of rabies and control (nervous tissue antigens. Eleven volunteers submitted to revaccination constituted the group under study, while three other volunteers submitted primo vaccination were utilized as control group. A clear secondary CMI to rabies antigen was detected in all the revaccinated volunteers who showed earlier and more intense response than the control group. Response to the control antigen, however, present in all the components of the first group was not detectable in two out of the three primovaccinated and very low in the third one.

  17. Social differences in oral health: Dental status of individuals buried in and around Trakai Church in Lithuania (16th-17th c.c.).

    Science.gov (United States)

    Miliauskienė, Žydrūnė; Jankauskas, Rimantas

    2015-01-01

    The evaluation of social differences in dental health is based on the assumption that individuals belonging to a higher social class consumed a different diet than a common people. The aim of our study was to analyse and compare dental health of 16(th) - 17(th) c. individuals, buried inside and around the Roman Catholic Church in Trakai (Lithuania). All material (189 adult individuals) was divided in two samples of a presumably different social status: the Churchyard (ordinary townsmen) and the Presbytery (elite). Dental status analysis included that of tooth loss, tooth wear, caries, abscesses and calculus. Results revealed higher prevalence of dental disease in the Churchyard sample compared to the Presbytery. Individuals buried around the church had statistically higher prevalence of caries, antemortem tooth loss and abscesses compared to those who were buried inside the church. The Churchyard sample was also characterised by a higher increase in severity of caries with age, and a more rapid tooth wear. Differences in dental health between the samples the most probably reflect different dietary habits of people from different social groups: poor quality carbohydrate based diet of laymen buried in the churchyard and more varied diet with proteins and of a better quality of local elite, buried inside the church. Substantial sex differences in dental health were found only in the Churchyard sample: males had statistically higher prevalence of abscesses and calculus, while females had higher prevalence of caries and AMTL (antemortem tooth loss). Females were also characterised by a higher increase in the number of dental decay and tooth loss with age and had higher prevalence of gross caries, which indicates a more rapid progression of the disease. Worse dental health of females could be a result of culturally based dietary differences between females (more carbohydrates) and males (more proteins) and different physiological demands (hormonal fluctuations and

  18. Dimethyl Fumarate Selectively Reduces Memory T Cells and Shifts the Balance between Th1/Th17 and Th2 in Multiple Sclerosis Patients.

    Science.gov (United States)

    Wu, Qi; Wang, Qin; Mao, Guangmei; Dowling, Catherine A; Lundy, Steven K; Mao-Draayer, Yang

    2017-04-15

    Dimethyl fumarate (DMF; trade name Tecfidera) is an oral formulation of the fumaric acid ester that is Food and Drug Administration approved for treatment of relapsing-remitting multiple sclerosis. To better understand the therapeutic effects of Tecfidera and its rare side effect of progressive multifocal leukoencephalopathy, we conducted cross-sectional and longitudinal studies by immunophenotyping cells from peripheral blood (particularly T lymphocytes) derived from untreated and 4-6 and 18-26 mo Tecfidera-treated stable relapsing-remitting multiple sclerosis patients using multiparametric flow cytometry. The absolute numbers of CD4 and CD8 T cells were significantly decreased and the CD4/CD8 ratio was increased with DMF treatment. The proportions of both effector memory T cells and central memory T cells were reduced, whereas naive T cells increased in treated patients. T cell activation was reduced with DMF treatment, especially among effector memory T cells and effector memory RA T cells. Th subsets Th1 (CXCR3 + ), Th17 (CCR6 + ), and particularly those expressing both CXCR3 and CD161 were reduced most significantly, whereas the anti-inflammatory Th2 subset (CCR3 + ) was increased after DMF treatment. A corresponding increase in IL-4 and decrease in IFN-γ and IL-17-expressing CD4 + T cells were observed in DMF-treated patients. DMF in vitro treatment also led to increased T cell apoptosis and decreased activation, proliferation, reactive oxygen species, and CCR7 expression. Our results suggest that DMF acts on specific memory and effector T cell subsets by limiting their survival, proliferation, activation, and cytokine production. Monitoring these subsets could help to evaluate the efficacy and safety of DMF treatment. Copyright © 2017 by The American Association of Immunologists, Inc.

  19. TGF-beta/atRA-induced Tregs express a selected set of microRNAs involved in the repression of transcripts related to Th17 differentiation.

    Science.gov (United States)

    Schiavinato, Josiane Lilian Dos Santos; Haddad, Rodrigo; Saldanha-Araujo, Felipe; Baiochi, João; Araujo, Amélia Goes; Santos Scheucher, Priscila; Covas, Dimas Tadeu; Zago, Marco Antonio; Panepucci, Rodrigo Alexandre

    2017-06-15

    Regulatory T cells (Tregs) are essential regulators of immune tolerance. atRA and TGF-β can inhibit the polarization of naïve T cells into inflammatory Th17 cells, favoring the generation of stable iTregs, however the regulatory mechanisms involved are not fully understood. In this context, the roles of individual microRNAs in Tregs are largely unexplored. Naïve T cells were immunomagnetically isolated from umbilical cord blood and activated with anti-human CD2/CD3/CD28 beads in the presence of IL-2 alone (CD4Med) or with the addition of TGF-β and atRA (CD4TGF/atRA). As compared to CD4Med, the CD4TGF/atRA condition allowed the generation of highly suppressive CD4(+)CD25(hi)CD127(-)FOXP3(hi) iTregs. Microarray profiling allowed the identification of a set of microRNAs that are exclusively expressed upon TGF-β/atRA treatment and that are predicted to target a set of transcripts concordantly downregulated. This set of predicted targets were enriched for central components of IL-6/JAK/STAT and AKT-mTOR signaling, whose inhibition is known to play important roles in the generation and function of regulatory lymphocytes. Finally, we show that mimics of exclusively expressed miRs (namely miR-1299 and miR-30a-5p) can reduce the levels of its target transcripts, IL6R and IL6ST (GP130), and increase the percentage of FoxP3(+) cells among CD4(+)CD25(+/hi) cells.

  20. Transcriptional profiling reveals molecular signatures associated with HIV permissiveness in Th1Th17 cells and identifies peroxisome proliferator-activated receptor gamma as an intrinsic negative regulator of viral replication.

    Science.gov (United States)

    Bernier, Annie; Cleret-Buhot, Aurélie; Zhang, Yuwei; Goulet, Jean-Philippe; Monteiro, Patricia; Gosselin, Annie; DaFonseca, Sandrina; Wacleche, Vanessa Sue; Jenabian, Mohammad-Ali; Routy, Jean-Pierre; Tremblay, Cécile; Ancuta, Petronela

    2013-12-21

    We previously demonstrated that primary Th1Th17 cells are highly permissive to HIV-1, whereas Th1 cells are relatively resistant. Molecular mechanisms underlying these differences remain unknown. Exposure to replication competent and single-round VSV-G pseudotyped HIV strains provide evidence that superior HIV replication in Th1Th17 vs. Th1 cells was regulated by mechanisms located at entry and post-entry levels. Genome-wide transcriptional profiling identified transcripts upregulated (n = 264) and downregulated (n = 235) in Th1Th17 vs. Th1 cells (p-value TNFSF13B, TNFSF25, PTPN13, MAP3K4, LTB, CTSH), transcription (PPARγ, RUNX1, ATF5, ARNTL), apoptosis (FASLG), and HIV infection (CXCR6, FURIN). Differential expression of CXCR6, PPARγ, ARNTL, PTPN13, MAP3K4, CTSH, SERPINB6, PTK2, and ISG20 was validated by RT-PCR, flow cytometry and/or confocal microscopy. The nuclear receptor PPARγ was preferentially expressed by Th1Th17 cells. PPARγ RNA interference significantly increased HIV replication at levels post-entry and prior HIV-DNA integration. Finally, the activation of PPARγ pathway via the agonist Rosiglitazone induced the nuclear translocation of PPARγ and a robust inhibition of viral replication. Thus, transcriptional profiling in Th1Th17 vs. Th1 cells demonstrated that HIV permissiveness is associated with a superior state of cellular activation and limited antiviral properties and identified PPARγ as an intrinsic negative regulator of viral replication. Therefore, triggering PPARγ pathway via non-toxic agonists may contribute to limiting covert HIV replication and disease progression during antiretroviral treatment.

  1. Dietary Indoles Suppress Delayed-Type Hypersensitivity by Inducing a Switch from Proinflammatory Th17 Cells to Anti-Inflammatory Regulatory T Cells through Regulation of MicroRNA.

    Science.gov (United States)

    Singh, Narendra P; Singh, Udai P; Rouse, Michael; Zhang, Jiajia; Chatterjee, Saurabh; Nagarkatti, Prakash S; Nagarkatti, Mitzi

    2016-02-01

    Aryl hydrocarbon receptor (AhR) has been shown to have profound influence on T cell differentiation, and use of distinct AhR ligands has shown that whereas some ligands induce regulatory T cells (Tregs), others induce Th17 cells. In the present study, we tested the ability of dietary AhR ligands (indole-3-carbinol [I3C] and 3,3'-diindolylmethane [DIM]) and an endogenous AhR ligand, 6-formylindolo(3,2-b)carbazole (FICZ), on the differentiation and functions of Tregs and Th17 cells. Treatment of C57BL/6 mice with indoles (I3C or DIM) attenuated delayed-type hypersensitivity (DTH) response to methylated BSA and generation of Th17 cells while promoting Tregs. In contrast, FICZ exacerbated the DTH response and promoted Th17 cells. Indoles decreased the induction of IL-17 but promoted IL-10 and Foxp3 expression. Also, indoles caused reciprocal induction of Tregs and Th17 cells only in wild-type (AhR(+/+)) but not in AhR knockout (AhR(-/-)) mice. Upon analysis of microRNA (miR) profile in draining lymph nodes of mice with DTH, treatment with I3C and DIM decreased the expression of several miRs (miR-31, miR-219, and miR-490) that targeted Foxp3, whereas it increased the expression of miR-495 and miR-1192 that were specific to IL-17. Interestingly, treatment with FICZ had precisely the opposite effects on these miRs. Transfection studies using mature miR mimics of miR-490 and miR-1192 that target Foxp3 and IL-17, respectively, or scrambled miR (mock) or inhibitors confirmed that these miRs specifically targeted Foxp3 and IL-17 genes. Our studies demonstrate, to our knowledge for the first time, that the ability of AhR ligands to regulate the differentiation of Tregs versus Th17 cells may depend on miR signature profile. Copyright © 2016 by The American Association of Immunologists, Inc.

  2. Staged development of long-lived T-cell receptor αβ TH17 resident memory T-cell population to Candida albicans after skin infection.

    Science.gov (United States)

    Park, Chang Ook; Fu, Xiujun; Jiang, Xiaodong; Pan, Youdong; Teague, Jessica E; Collins, Nicholas; Tian, Tian; O'Malley, John T; Emerson, Ryan O; Kim, Ji Hye; Jung, Yookyung; Watanabe, Rei; Fuhlbrigge, Robert C; Carbone, Francis R; Gebhardt, Thomas; Clark, Rachael A; Lin, Charles P; Kupper, Thomas S

    2017-11-09

    Candida albicans is a dimorphic fungus to which human subjects are exposed early in life, and by adulthood, it is part of the mycobiome of skin and other tissues. Neonatal skin lacks resident memory T (TRM) cells, but in adults the C albicans skin test is a surrogate for immunocompetence. Young adult mice raised under specific pathogen-free conditions are naive to C albicans and have been shown recently to have an immune system resembling that of neonatal human subjects. We studied the evolution of the adaptive cutaneous immune response to Candida species. We examined both human skin T cells and the de novo and memory immune responses in a mouse model of C albicans skin infection. In mice the initial IL-17-producing cells after C albicans infection were dermal γδ T cells, but by day 7, αβ TH17 effector T cells were predominant. By day 30, the majority of C albicans-reactive IL-17-producing T cells were CD4 TRM cells. Intravital microscopy showed that CD4 effector T cells were recruited to the site of primary infection and were highly motile 10 days after infection. Between 30 and 90 days after infection, these CD4 T cells became increasingly sessile, acquired expression of CD69 and CD103, and localized to the papillary dermis. These established TRM cells produced IL-17 on challenge, whereas motile migratory memory T cells did not. TRM cells rapidly clear an infectious challenge with C albicans more effectively than recirculating T cells, although both populations participate. We found that in normal human skin IL-17-producing CD4+ TRM cells that responded to C albicans in an MHC class II-restricted fashion could be identified readily. These studies demonstrate that C albicans infection of skin preferentially generates CD4+ IL-17-producing TRM cells, which mediate durable protective immunity. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  3. Association between aqueous humor and vitreous fluid levels of Th17 cell-related cytokines in patients with proliferative diabetic retinopathy.

    Science.gov (United States)

    Takeuchi, Masaru; Sato, Tomohito; Sakurai, Yutaka; Taguchi, Manzo; Harimoto, Kozo; Karasawa, Yoko; Ito, Masataka

    2017-01-01

    Inflammation is known to be involved in the progression of diabetic retinopathy. We have recently reported that vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFα are higher than the respective serum levels in proliferative diabetic retinopathy (PDR) patients, and that vitreous levels of these cytokines are higher in PDR than in other non-inflammatory vitreoretinal diseases or uveitis associated with sarcoidosis. In the present study, we investigated inflammatory cytokines including Th17 cell-related cytokines in aqueous humor samples obtained from eyes with PDR, and analyzed the association between the aqueous humor and vitreous fluid levels of individual cytokines. The study group consisted of 31 consecutive type 2 diabetic patients with PDR who underwent cataract surgery and vitrectomy for vitreous hemorrhage and/or tractional retinal detachment. Undiluted aqueous humor was collected during cataract surgery, and then vitreous fluid was obtained using a 25G vitreous cutter inserted into the mid-vitreous cavity at the beginning of vitrectomy. IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble CD40 ligand (sCD40L), and TNFα levels in the aqueous humor and vitreous fluid were measured using a beads-array system. Although IL-17A was detected in the aqueous humor of eyes with PDR and the level correlated with IL-17A level in the vitreous fluid, both percent detectable and level of IL-17A in the aqueous humor were significantly lower than those in the vitreous fluid. Vitreous IL-17A level was related significantly to IL-10, IL-22, and TNFα levels in aqueous humor as well as in vitreous fluid, On the other hand, aqueous IL-17A level was not related significantly to aqueous or vitreous levels of IL-10, IL-22 or TNFα level. The present study demonstrated that IL-17A level and detectable rate in the aqueous humor of patients with PDR are markedly lower than those in the vitreous fluid and aqueous IL-17A does not

  4. Cell-mediated mutagenesis and cell transformation by chemical carcinogens

    Energy Technology Data Exchange (ETDEWEB)

    Huberman, E.; Langenbach, R.

    1977-01-01

    Results are reported from studies that showed that mutagenesis of mammalian cells can be achieved by carcinogenic polycyclic hydrocarbons, nitrosamines, and aflatoxins when tested in the presence of fibroblasts and hepatocytes which are able to metabolize these carcinogens. Further, we have found that there is a relationship between the degree of mutant induction and the degree of carcinogenicity of the different chemicals tested. By simultaneously measuring the frequency of cell transformation and the frequency of mutation at one locus (ouabain resistance) in the same cell system, it was possible to estimate the genetic target site for cell transformation. The results indicated that the target site for transformation is approximately 20 times larger than that determined for ouabain resistance. The results suggest that cell transformation may be due to a mutational event and the mutation can occur in one out of a small number of the same or different genes, and that the cell-mediated mutagenesis approach may be a valuable means of detecting tissue-specific carcinogens.

  5. Human cell-mediated immune responses to chlamydial antigens.

    Science.gov (United States)

    Hanna, L; Schmidt, L; Sharp, M; Stites, D P; Jawetz, E

    1979-02-01

    A reproducible method was developed to determine the ability of chlamydial antigens to stimulate lymphocytes from volunteers. In tests repeated 4 to 14 times, the cells from a given volunteer gave a relatively narrow range of responses, but there were great differences in the mean response of different volunteers. In the entire group of 52 volunteers, lymphocyte stimulation was significantly associated with the presence of antibody, but in a given individual results of one test did not aid in predicting the results of the other. A majority of persons with either antichlamydial antibody or elevated lymphocyte stimulation, or both, did not have a history of signs or symptoms within a spectrum of chlamydial diseases. This may reflect the great frequency of asymptomatic infection with these organisms. The lymphocytes of some individuals were stimulated to a significantly greater degree by antigens of one chlamydial species (Chlamydia trachomatis or C. psittaci) than by the other. These and other cell-mediated reactions in human chlamydial infections, and their possible medical significance, are under continued study.

  6. Desequilíbrio imunológico periférico mediado por células Th17/Treg em pacientes com rinite alérgica

    Directory of Open Access Journals (Sweden)

    Xuekun Huang

    2014-04-01

    Full Text Available Introdução: A rinite alérgica (RA é uma doença não infecciosa da mucosa nasal mediada por IgE após o contato com alérgenos. Objetivo: Investigar as células Th17 periféricas e CD4 + CD25 + Foxp3 + células T reguladoras (Treg e a expressão sérica de citocinas em pacientes com RA. Métodos: De março a maio de 2012, foi coletado o sangue periférico de 14 pacientes com RA (grupo RA e seis indivíduos saudáveis (grupo controle. A detecção das células Th17 e células Treg foi realizada através da citometria de fluxo e os níveis séricos de IL -17 e TGF- β1. Foram medidos por ELISA. Resultados: A percentagem de células Th17 no grupo RA foi bem maior do que no grupo controle (p < 0,01. A proporção de células Treg no grupo RA também foi drasticamente menor quando comparada ao grupo controle (p < 0,01. No grupo RA, o nível sérico de IL-17 foi significativamente maior do que no grupo controle (p < 0,01. Conclusão: O desequilíbrio de células Th17/Treg periféricas desempenha um papel importante na patogênese da RA.

  7. Simultaneous analysis of multiple T helper subsets in leprosy reveals distinct patterns of Th1, Th2, Th17 and Tregs markers expression in clinical forms and reactional events.

    Science.gov (United States)

    Azevedo, Michelle de Campos Soriani; Marques, Heloisa; Binelli, Larissa Sarri; Malange, Mariana Silva Vieira; Devides, Amanda Carreira; Silva, Eliane Aparecida; Fachin, Luciana Raquel Vincenzi; Ghidella, Cassio Cesar; Soares, Cleverson Teixeira; Garlet, Gustavo Pompermaier; Rosa, Patrícia Sammarco; Belone, Andrea de Farias Fernandes; Trombone, Ana Paula Favaro

    2017-12-01

    Leprosy is a chronic infectious disease caused by Mycobacterium leprae. Previous studies have demonstrated that the difference among clinical forms of leprosy can be associated with the immune response of patients, mainly by T helper (Th) and regulatory T cells (Tregs). Then, aiming at clarifying the immune response, the expression of cytokines related to Th1, Th2, Th17 and Tregs profiles were evaluated by qPCR in 87 skin biopsies from leprosy patients. Additionally, cytokines and anti-PGL-1 antibodies were determined in serum by ELISA. The results showed that the expression of various targets (mRNA) related to Th1, Th2, Th17 and Tregs were significantly modulated in leprosy when compared with healthy individuals, suggesting the presence of a mixed profile. In addition, the targets related to Th1 predominated in the tuberculoid pole and side and Th2 and Tregs predominated in the lepromatous pole and side; however, Th17 targets showed a mixed profile. Concerning reactional events, Tregs markers were decreased and IL-15 was increased in reversal reaction and IL-17F, CCL20 and IL-8 in erythema nodosum leprosum, when compared with the respective non-reactional leprosy patients. Additionally, ELISA analysis demonstrated that IL-22, IL-6, IL-10 and anti-PGL-1 antibody levels were significantly higher in the serum of patients when compared with healthy individuals, and IL-10 and anti-PGL-1 antibodies were also increased in the lepromatous pole and side. Together, these results indicate that Th1, Th2 and Th17 are involved in the determination of clinical forms of leprosy and suggest that decreased Tregs activity may be involved in the pathogenesis of reactional events.

  8. Cell-mediated non-allergic rhinitis in children.

    Science.gov (United States)

    Maselli Del Giudice, Alessandro; Barbara, Michele; Russo, Giuseppe Maria; Fiocca Matthews, Emily; Cassano, Michele

    2012-12-01

    Non-allergic rhinitis is a heterogeneous disease whose etiology is largely unknown. Nasal cytology only allows us to recognize different non-allergic rhinitis forms on the basis of the prevalent inflammatory cell infiltrate: non-allergic rhinitis with eosinophils, with neutrophils, with mast-cells and with both eosinophils and mast-cells. The aim of this study is to define the incidence, clinical features and comorbidity of the different types of cell-mediated non-allergic rhinitis in a pediatric age group. One hundred and fourteen non-allergic children with chronic nasal obstruction and associated symptoms (rhinorrhea, sneezing and nasal itchiness) were retrospectively selected. All patients had been submitted to a clinical history, pediatric evaluation, anterior rhinoscopy and fiberendoscopy, rhinomanometry and nasal cytology. Non-allergic rhinitis with neutrophils was present in 46 (40.4%) children, non-allergic rhinitis with eosinophils in 53 (46.5%), non-allergic rhinitis with mast-cells in 12 (10.5%) and non-allergic rhinitis with both eosinophils and mast-cells in 3 (2.6%). Nasal obstruction was prevalent in non-allergic rhinitis with eosinophils and in non-allergic rhinitis with mast-cells patients (Pallergic rhinitis with eosinophils group showed a higher probability of asthma (Ppediatric age group the most frequent forms of non-allergic rhinitis are those with eosinophils or with neutrophils. A diagnosis of non-allergic rhinitis with eosinophils in children presumes more severe symptoms and a higher incidence of pulmonary disease and roncopathy. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  9. Role of macrophage inflammatory protein-1alpha in T-cell-mediated immunity to viral infection

    DEFF Research Database (Denmark)

    Madsen, Andreas N; Nansen, Anneline; Christensen, Jan P

    2003-01-01

    The immune response to lymphocytic choriomeningitis virus in mice lacking macrophage inflammatory protein-1alpha (MIP-1alpha) was evaluated. Generation of virus-specific effector T cells is unimpaired in MIP-1alpha-deficient mice. Furthermore, MIP-1alpha is not required for T-cell-mediated virus...... control or virus-induced T-cell-dependent inflammation. Thus, MIP-1alpha is not mandatory for T-cell-mediated antiviral immunity....

  10. Benzoxazepines Achieve Potent Suppression of IL-17 Release in Human T-Helper 17 (TH 17) Cells through an Induced-Fit Binding Mode to the Nuclear Receptor RORγ.

    Science.gov (United States)

    Olsson, Roine I; Xue, Yafeng; von Berg, Stefan; Aagaard, Anna; McPheat, Jane; Hansson, Eva L; Bernström, Jenny; Hansson, Pia; Jirholt, Johan; Grindebacke, Hanna; Leffler, Agnes; Chen, Rongfeng; Xiong, Yao; Ge, Hongbin; Hansson, Thomas G; Narjes, Frank

    2016-01-19

    RORγt, an isoform of the retinoic acid-related orphan receptor gamma (RORc, RORγ), has been identified as the master regulator of T-helper 17 (TH 17) cell function and development, making it an attractive target for the treatment of autoimmune diseases. Validation for this target comes from antibodies targeting interleukin-17 (IL-17), the signature cytokine produced by TH 17 cells, which have shown impressive results in clinical trials. Through focused screening of our compound collection, we identified a series of N-sulfonylated benzoxazepines, which displayed micromolar affinity for the RORγ ligand-binding domain (LBD) in a radioligand binding assay. Optimization of these initial hits resulted in potent binders, which dose-dependently decreased the ability of the RORγ-LBD to interact with a peptide derived from steroid receptor coactivator 1, and inhibited the release of IL-17 secretion from isolated and cultured human TH 17 cells with nanomolar potency. A cocrystal structure of inverse agonist 15 (2-chloro-6-fluoro-N-(4-{[3-(trifluoromethyl)phenyl]sulfonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide) bound to the RORγ-LBD illustrated that both hydrophobic interactions, leading to an induced fit around the substituted benzamide moiety of 15, as well as a hydrogen bond from the amide NH to His479 seemed to be important for the mechanism of action. This structure is compared with the structure of agonist 25 (N-(2-fluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-6-amine ) and structures of other known RORγ modulators. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Rola subpopulacji limfocytów pomocniczych Th1, Th17 i Treg w patogenezie reumatoidalnego zapalenia stawów z uwzględnieniem przeciwzapalnego działania cytokin Th1

    Directory of Open Access Journals (Sweden)

    Agata Kosmaczewska

    2011-06-01

    Full Text Available W patogenezie reumatoidalnego zapalenia stawów (RZS szczególną rolę przypisuje się zaburzeniom w funkcjonowaniu układu odpornościowego. Przewlekły charakter zapalenia w stawach sugeruje, że regulacja ze strony układu odpornościowego jest zaburzona, co wiąże się z nadmiernie rozwiniętą odpowiedzią zapalną, której towarzyszą nieprawidłowe mechanizmy kontroli zapalenia. Zaburzenia immunologiczne nie ograniczają się jedynie do miejsc zapalenia, ale mają również charakter systemowy i obejmują głównie komórki jednojądrzaste krwi obwodowej (PBMC, wydzielające w nieprawidłowych ilościach cytokiny pro- i przeciwzapalne. Limfocyty T pomocnicze (Th mogą się różnicować w zależności od środowiska cytokinowego w komórki Th1, Th2, Th17 lub Treg. Aktywna postać RZS może być wynikiem przesunięcia równowagi układu odpornościowego w kierunku subpopulacji limfocytów T prozapalnych (głównie Th17 na niekorzyść regulatorowych komórek działających przeciwzapalnie (Treg. Wykazano, że zaburzenia wytwarzania cytokin Th1 (IL-2 i IFN-gamma, stwierdzane w przebiegu RZS, sprzyjają zwiększonemu wytwarzaniu IL-17 i infiltracji tkanek w miejscu zapalenia komórkami Th17. Najnowsze badania dowodzą, że cytokiny Th1 o udowodnionym działaniu prozapalnym mogą odgrywać ważną rolę w utrzymaniu równowagi między limfocytami Treg a Th17 poprzez promowanie różnicowania limfocytów Th w kierunku Treg. W pracy przedstawiono także wpływ TNF-alfa i jego blokady na populacje limfocytów Th u chorych na RZS.

  12. Expresión de citoquinas Th17 y su correlación con periodontopatógenos y el área periodontal inflamada en pacientes con periodontitis crónica

    OpenAIRE

    Herane, A.; Chaparro, A.; Quintero, A.; Sanz, A; Hernández, M.; Gaedechens,D; Carrión,F; Inostroza, C.

    2013-01-01

    Antecedentes: La periodontitis es una enfermedad inflamatoria infecciosa que involucra una respuesta inmune del hospedero y se caracteriza por destrucción del hueso alveolar, el objetivo del estudio es analizar la expresión de citoquinas Th17 y su correlación con periodontopatógenos y el área periodontal inflamada en pacientes con periodontitis crónica. Método: Se realizó un estudio descriptivo exploratorio en el que se reclutaron 23 pacientes con diagnóstico de periodontitis crónica y un gru...

  13. CHARACTERISATION OF CELL-MEDIATED IMMUNE RESPONSE IN PIGS IN A CLINICAL CHALLENGE EXPERIMENT OF A VACCINE AGAINST MYCOPLASMA HYOSYNOVIAE

    DEFF Research Database (Denmark)

    Rasmussen, Josephine Skovgaard; Riber, Ulla; Lauritsen, Klara Tølbøll

    Mycoplasma hyosynoviae (Mhs) is an extracellular parasitizing bacterium that causes arthritis in swine. The infection is widespread in modern pig production. An effective immunoprophylaxis is not available. In an experimental infection study (Lauritsen, K. T., et al., 2009. 3rd EVIW Poster, Berlin...... (Germany) September 10-13, 2009), testing a new vaccine (formalin inactivated Mhs and EMULSIGEN-BCL® (MVP Laboratories)), cell-mediated immune response was measured in the vaccine group (n=13) and not in the placebo group (n=13). In an IFN-γ assay, where whole-blood was co-cultured with Mhs......-antigen and recombinant IL-18, significantly higher level of IFN-γ was produced in the vaccine group compared to the placebo group one day before challenge with Mhs. In contrast, significantly higher level of IFN-γ was measured in the placebo group compared to the vaccine group at day 6 after challenge. The latter could...

  14. Cell-mediated immune responses differentiate infections with Brucella suis from Yersinia enterocolitica serotype O : 9 in pigs

    DEFF Research Database (Denmark)

    Riber, Ulla; Jungersen, Gregers

    2007-01-01

    Due to almost identical lipopolysaccharide (LPS) O-antigens, infections with Yersinia enterocolitica serotype 0:9 (YeO:9) cause false positive serological reactions (FPSR) in tests for Brucella and thus cause problems in National Brucella surveillance programs. As LPS are strong inducers...... of antibody responses it was hypothesized that cell-mediated immune responses to non-LPS antigens of the two bacteria can be used to separate immune responses to these two biologically very different infections. Following subclinical experimental infections with Brucella suis biovar 2, high interferon......-gamma (IFN-gamma) assay responses with a commercial Brucella melitensis antigen preparation (Brucellergene OCB) preceded the development of antibodies. High IFN-gamma responses in the seven B. suis inoculated pigs with serological evidence of infection were consistent throughout a 20-week postinoculation...

  15. Cell-mediated immune response to Leishmania chagasi experimental infection of BALB/c immunosuppressed mice

    Directory of Open Access Journals (Sweden)

    JG Machado

    2010-01-01

    Full Text Available Leishmaniasis, a zoonosis of worldwide distribution, presents a significant impact on immunosupressed patients. This study aimed to evaluate Leishmania chagasi infection in BALB/c mice immunosuppressed with dexamethasone. Spleen cells stimulated or not with L. chagasi were cultured for cytokine quantification (IFN-γ, IL-2, IL-4 and IL-10 by sandwich ELISA. Parasite loads in the spleen and liver were determined by means of culture microtitration. Immunosuppressed groups showed statistically lower spleen weight and CD4-cell percentage in blood on the day of infection and produced Th1 and Th2 cytokines on other days of the study. The other infected groups, weather immunosupressed or not, also produced Th1 and Th2 cytokines. Parasite loads in the spleen and liver were not statistically different among the groups. It was concluded that L. chagasi infection was not affected by dexamethasone-induced immunosuppression, probably due the reversible effect of the treatment.

  16. The experimental study of genetic engineering human neural stem cells mediated by lentivirus to express multigene.

    Science.gov (United States)

    Cai, Pei-qiang; Tang, Xun; Lin, Yue-qiu; Martin, Oudega; Sun, Guang-yun; Xu, Lin; Yang, Yun-kang; Zhou, Tian-hua

    2006-02-01

    To explore the feasibility to construct genetic engineering human neural stem cells (hNSCs) mediated by lentivirus to express multigene in order to provide a graft source for further studies of spinal cord injury (SCI). Human neural stem cells from the brain cortex of human abortus were isolated and cultured, then gene was modified by lentivirus to express both green fluorescence protein (GFP) and rat neurotrophin-3 (NT-3); the transgenic expression was detected by the methods of fluorescence microscope, dorsal root ganglion of fetal rats and slot blot. Genetic engineering hNSCs were successfully constructed. All of the genetic engineering hNSCs which expressed bright green fluorescence were observed under the fluorescence microscope. The conditioned medium of transgenic hNSCs could induce neurite flourishing outgrowth from dorsal root ganglion (DRG). The genetic engineering hNSCs expressed high level NT-3 which could be detected by using slot blot. Genetic engineering hNSCs mediated by lentivirus can be constructed to express multigene successfully.

  17. IL-10 polymorphism and cell-mediated immune response to Chlamydia trachomatis

    DEFF Research Database (Denmark)

    Öhman, H.; Tiitinen, A; Halttunen, M.

    2006-01-01

    background. To study a relationship between interleukin-10 (IL-10) promoter -1082 polymorphism and cell-mediated immune response during C trachomatis infection in vitro, lymphocyte proliferation and cytokine (IL-10, IFN-gamma, TNF-alpha, IL-2, IL-4 and IL-5) secretion were analysed in subjects with different...... IL-10 genotypes. Enhanced IL-10 secretion and reduced antigen-specific lymphocyte proliferative and IFN-gamma responses were found in subjects with IL-10 -1082 GG genotype when compared to those with -1082 AA genotype. CD14+ monocytes were main source of IL-10 indicating that these cells...... are important regulators of the antigen-specific cell-mediated responses during active C trachomatis infection. We conclude that impaired cell-mediated response to C trachomatis is associated with IL-10 genotype in subjects with high IL-10 producing capacity. A comparison of immune markers between subjects...

  18. Nmunomodulación de Uncaria tomentosa sobre células dendríticas, il-12 y perfil TH1/TH2/TH17 en cáncer de mama

    Directory of Open Access Journals (Sweden)

    César Núñez

    Full Text Available Objetivos. Evaluar el efecto inmunomodulador del extracto estandarizado (5,03%, alcaloides oxindólicos pentacíclicos de Uncaria tomentosa (UT-POA sobre el inmunofenotipo de células dendríticas (DC y IL-12/Th1/Th2/Th17 en pacientes con cáncer de mama estadio II (BCII y mujeres sanas (H. Materiales y métodos. Se obtuvó sangre de 11 H y 7 BCII, se aislaron y cultivaron PBMC por 2 h con/sin distintas concentraciones de UT-POA y se estimularon o no con LPS por 24 h. Las PBMC fueron marcadas con anticuerpos específicos para DC y en el sobrenadante se midió las citoquinas Th1/Th2/Th17, ambos por citometría de flujo. Además, se midió IL-12 por ELISA. Resultados. UT-POA no alteró a las DC o la expresión de moléculas accesorias en BCII. Sin embargo, en H mostró una disminución en el porcentaje de DC mieloides (mDC con incremento de HLA-DR y CD86 a 1000 μg/mL. La secreción de IL-12 fue modificada solo en H, incrementando la subunidad p70 y disminuyendo la p40. UT-POA incremento Th1 (IFN-γ y IL-2, Th2 (IL-4 y Th17 (IL-17 en BCII y H. Conclusiones. UT-POA incrementa la producción de citoquinas relacionadas con la respuesta antitumoral a concentraciones entre el rango de 500-1000 μg/mL. Este efecto positivo debería ser evaluado no solo sistemicamente sino también en el microambiente tumoral. La UT-POA puede ser un fitoquímico útil en la quimioprevención y en el uso alternativo con terapias contra el cáncer

  19. Cytotoxic effector functions of T cells are not required for protective immunity against fatal Rickettsia typhi infection in a murine model of infection: Role of TH1 and TH17 cytokines in protection and pathology.

    Directory of Open Access Journals (Sweden)

    Kristin Moderzynski

    2017-02-01

    Full Text Available Endemic typhus caused by Rickettsia (R. typhi is an emerging febrile disease that can be fatal due to multiple organ pathology. Here we analyzed the requirements for protection against R. typhi by T cells in the CB17 SCID model of infection. BALB/c wild-type mice generate CD4+ TH1 and cytotoxic CD8+ T cells both of which are sporadically reactivated in persistent infection. Either adoptively transferred CD8+ or CD4+ T cells protected R. typhi-infected CB17 SCID mice from death and provided long-term control. CD8+ T cells lacking either IFNγ or Perforin were still protective, demonstrating that the cytotoxic function of CD8+ T cells is not essential for protection. Immune wild-type CD4+ T cells produced high amounts of IFNγ, induced the release of nitric oxide in R. typhi-infected macrophages and inhibited bacterial growth in vitro via IFNγ and TNFα. However, adoptive transfer of CD4+IFNγ-/- T cells still protected 30-90% of R. typhi-infected CB17 SCID mice. These cells acquired a TH17 phenotype, producing high amounts of IL-17A and IL-22 in addition to TNFα, and inhibited bacterial growth in vitro. Surprisingly, the neutralization of either TNFα or IL-17A in CD4+IFNγ-/- T cell recipient mice did not alter bacterial elimination by these cells in vivo, led to faster recovery and enhanced survival compared to isotype-treated animals. Thus, collectively these data show that although CD4+ TH1 cells are clearly efficient in protection against R. typhi, CD4+ TH17 cells are similarly protective if the harmful effects of combined production of TNFα and IL-17A can be inhibited.

  20. Chronic mucocutaneous candidiasis: characterization of a family with STAT‐1 gain‐of‐function and development of an ex‐vivo assay for Th17 deficiency of diagnostic utility

    Science.gov (United States)

    Fox, H.; Davenport, E. E.; Sadler, R.; Anzilotti, C.; van Schouwenburg, P. A.; Ferry, B.; Chapel, H.; Knight, J. C.; Patel, S. Y.

    2016-01-01

    Summary Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent and persistent superficial infections, with Candida albicans affecting the mucous membranes, skin and nails. It can be acquired or caused by primary immune deficiencies, particularly those that impair interleukin (IL)−17 and IL‐22 immunity. We describe a single kindred with CMC and the identification of a STAT1 GOF mutation by whole exome sequencing (WES). We show how detailed clinical and immunological phenotyping of this family in the context of WES has enabled revision of disease status and clinical management. Together with analysis of other CMC cases within our cohort of patients, we used knowledge arising from the characterization of this family to develop a rapid ex‐vivo screening assay for the detection of T helper type 17 (Th17) deficiency better suited to the routine diagnostic setting than established in‐vitro techniques, such as intracellular cytokine staining and enzyme‐linked immunosorbent assay (ELISA) using cell culture supernatants. We demonstrate that cell surface staining of unstimulated whole blood for CCR6+CXCR3–CCR4+CD161+ T helper cells generates results that correlate with intracellular cytokine staining for IL‐17A, and is able to discriminate between patients with molecularly defined CMC and healthy controls with 100% sensitivity and specificity within the cohort tested. Furthermore, removal of CCR4 and CD161 from the antibody staining panel did not affect assay performance, suggesting that the enumeration of CCR6+CXCR3–CD4+ T cells is sufficient for screening for Th17 deficiency in patients with CMC and could be used to guide further investigation aimed at identifying the underlying molecular cause. PMID:26621323

  1. Expression of T helper type 17 (Th17)-associated cytokines and toll-like receptor 4 and their correlation with Foxp3 positive cells in rectal biopsies of horses with clinical signs of inflammatory bowel disease.

    Science.gov (United States)

    Olofsson, Karin M; Hjertner, Bernt; Fossum, Caroline; Press, Charles M; Lindberg, Ronny

    2015-10-01

    Inflammatory bowel disease (IBD) in horses is an idiopathic disorder, encompassing different types of chronic intestinal inflammation. The pathogenesis of the disease remains to be established, but it has been suggested that an imbalance between regulatory T cells (Tregs) and T helper 17 (Th17)-associated cytokines and altered toll-like receptor 4 (TLR4) expression is associated with intestinal inflammation in other species. The aim of the present study was to quantify Tregs in rectal biopsies from horses affected with IBD by immunohistochemistry and to evaluate expression of genes encoding interleukin (IL)-12p40, IL-17A, IL-23p19 and TLR4 by real-time quantitative PCR. Rectal biopsies from 11 healthy horses and 11 horses with clinical signs of IBD, showing inflammation classified as chronic simple proctitis (CSP) or chronic active simple proctitis (CASP), were evaluated. Expression of IL-17A mRNA was greater in horses affected with CASP compared with horses with CSP or healthy horses. In contrast, expression of IL-12p40 was lower in horses with CSP compared with horses with CASP or healthy horses. TLR4 expression was greater in horses with CASP compared with healthy horses. A positive correlation was seen between the numbers of Tregs and expression of IL-17A and IL-23p19. An association was demonstrated between the histopathological pattern of inflammation, cytokine profile and number of infiltrating Tregs. The research findings suggest that Th17 cells are involved in active IBD, possibly through recruitment of neutrophils via IL-17A, in combination with inadequate suppression of the inflammatory response by Tregs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Inhibition of natural killer cell-mediated cytotoxicity by lipids extracted from Mycobacterium bovis BCG

    NARCIS (Netherlands)

    Roozemond, R. C.; Halperin, M.; Das, P. K.

    1985-01-01

    Several studies have demonstrated an augmentation of natural killer (NK) cell-mediated cytotoxicity by various adjuvants including BCG. Inhibitory effects of BCG have also been reported, particularly for relatively high doses. Because the cell wall of Mycobacterium bovis BCG contains a high

  3. Administration of Mycobacterium leprae rHsp65 aggravates experimental autoimmune uveitis in mice.

    Directory of Open Access Journals (Sweden)

    Eliana B Marengo

    Full Text Available The 60 kDa heat shock protein family, Hsp60, constitutes an abundant and highly conserved class of molecules that are highly expressed in chronic-inflammatory and autoimmune processes. Experimental autoimmune uveitis [EAU] is a T cell mediated intraocular inflammatory disease that resembles human uveitis. Mycobacterial and homologous Hsp60 peptides induces uveitis in rats, however their participation in aggravating the disease is poorly known. We here evaluate the effects of the Mycobacterium leprae Hsp65 in the development/progression of EAU and the autoimmune response against the eye through the induction of the endogenous disequilibrium by enhancing the entropy of the immunobiological system with the addition of homologous Hsp. B10.RIII mice were immunized subcutaneously with interphotoreceptor retinoid-binding protein [IRBP], followed by intraperitoneally inoculation of M. leprae recombinant Hsp65 [rHsp65]. We evaluated the proliferative response, cytokine production and the percentage of CD4(+IL-17(+, CD4(+IFN-gamma(+ and CD4(+Foxp3(+ cells ex vivo, by flow cytometry. Disease severity was determined by eye histological examination and serum levels of anti-IRBP and anti-Hsp60/65 measured by ELISA. EAU scores increased in the Hsp65 group and were associated with an expansion of CD4(+IFN-gamma(+ and CD4(+IL-17(+ T cells, corroborating with higher levels of IFN-gamma. Our data indicate that rHsp65 is one of the managers with a significant impact over the immune response during autoimmunity, skewing it to a pathogenic state, promoting both Th1 and Th17 commitment. It seems comprehensible that the specificity and primary function of Hsp60 molecules can be considered as a potential pathogenic factor acting as a whistleblower announcing chronic-inflammatory diseases progression.

  4. Cell-Mediated Immune Function and Cytokine Regulation During Space Flight

    Science.gov (United States)

    Sams, Clarence F.; Pierson, Duane L.; Paloski, W. H. (Technical Monitor)

    2000-01-01

    The changes in immune function which occur during space flight potentially expose the crews to an increased risk for development of illness. Decreased cellular immune function has been repeatedly documented after space flight and confirmed during flight by in vivo delayed-type hypersensitivity testing. However, correlation of immune changes with a clinically significant risk factor has not yet been performed. Our hypothesis is that space flight induces a decrease in cell-mediated immune function accompanied by a shift from a type 1 cytokine pattern (favoring cell-mediated immunity) to a type 2 cytokine pattern (favoring humoral immunity). We further hypothesize that reactivation of latent viruses will occur during space flight in association with the decreased cellular immunity. To test these hypotheses, we will determine the effects of space flight on cell-mediated immunity and viral reactivation. We will utilize delayed-type hypersensitivity testing as an in vivo measure of integrated cell-mediated immune function. The production of cytokines and immunoregulatory factors by lymphocytes and monocytes will be measured to determine whether changes in cytokine patterns are associated with the space flight-induced immune dysregulation. Correlation of antigen-specific immune changes with reactivation of latent herpes viruses will be determined by measuring peripheral levels of viral (CMV, VZV, EBV) antigen-specific T cells and comparing to the levels of EBV-infected B-cells by fluorescence in situ hybridization and flow cytometry. A comparison of cell-mediated immune function, cytokine regulation and viral reactivation will provide new insights into crew member health risks during flight.

  5. Humoral and cell mediated immune responses against Schistosoma spindale in BALB/c mice.

    Science.gov (United States)

    Prechatangkit, B; Dhaliwal, J S; Ambu, S

    1994-03-01

    (BALB/c mice were infected with cercariae of Schistosoma spindale by tail immersion technique and by dropping some cercariae from a pipet onto the outer surface of the pinna of the ears. Groups of mice were removed on Days 10, 20 and 30 and tested for humoral and cell mediated immune responses using either adult worm or cercarial antigen. On Day 50 the mice were sacrificed and the worm burden was determined for each mouse. This method resulted in an infectivity rate of 89.7%. There was a significant increase in antibody titer to the adult worm antigen while no significant increase was observed for cercarial antigen over the period of the study. Results obtained for cell mediated immunity were more dramatic. There was a significant increase in foot pad swelling for adult worm antigen compared to a significant decrease for cercarial antigen during the course of the infection.

  6. A role for NKG2D in NK cell-mediated resistance to poxvirus disease.

    Directory of Open Access Journals (Sweden)

    Min Fang

    2008-02-01

    Full Text Available Ectromelia virus (ECTV is an orthopoxvirus (OPV that causes mousepox, the murine equivalent of human smallpox. C57BL/6 (B6 mice are naturally resistant to mousepox due to the concerted action of innate and adaptive immune responses. Previous studies have shown that natural killer (NK cells are a component of innate immunity that is essential for the B6 mice resistance to mousepox. However, the mechanism of NK cell-mediated resistance to OPV disease remains undefined. Here we show that B6 mice resistance to mousepox requires the direct cytolytic function of NK cells, as well as their ability to boost the T cell response. Furthermore, we show that the activating receptor NKG2D is required for optimal NK cell-mediated resistance to disease and lethality. Together, our results have important implication towards the understanding of natural resistance to pathogenic viral infections.

  7. Role of T-cell-mediated inflammation in psoriasis: pathogenesis and targeted therapy

    OpenAIRE

    Conrad, Curdin; Flatz,

    2013-01-01

    Lukas Flatz, Curdin ConradDepartment of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, SwitzerlandAbstract: Psoriasis is one of the most common chronic, inflammatory, T-cell-mediated autoimmune diseases. Over the past decade, increased knowledge of disease pathogenesis has fundamentally changed psoriasis treatment, with the introduction of biologics, and this has led to a multitude of improved selective targets providing potential therapeutic options. Indeed, numerous pathogen...

  8. Cell-Mediated Cytotoxicity Toward Measles Virus-Infected Target Cells in Randomly Bred Syrian Hamsters

    OpenAIRE

    Cremer, Natalie E.; O'Keefe, Beatrice; Hagens, Shirley J.; Diggs, Janice

    1982-01-01

    Cell-mediated cytotoxicity (CMC) toward measles virus-infected cells was studied by a 51Cr release assay with spleen cells from hamsters inoculated with measles virus (strain Lec) or control antigen and with spleen cells from normal hamsters. Spleen cells from measles virus-inoculated hamsters showed greater CMC toward infected than toward noninfected target cells (designated specific CMC). Specific CMC was maximal 7 days after virus inoculation and was declining by 9 to 10 days. Effector cel...

  9. In-vitro monitoring of cell-mediated immunity to dinitrochlorobenzene.

    Science.gov (United States)

    Hamilton, D N; Ledger, V; Diamandopoulos, A

    1976-11-27

    A dinitrochlorobenzene (D.N.C.B.)/red-blood-cell conjugate inhibited migration of leucocytes which came from D.N.C.B. sensitised patients. This effect provided the basis for a rapid, sensitive, and quantitative in-vitro measure of D.N.C.B. sensitivity. Frequent serial measurement of cell-mediated immunity was possible with the test, provided D.N.C.B. sensitivity was maintained by occasional skin patch tests.

  10. Saos-2 cell-mediated mineralization on collagen gels: Effect of densification and bioglass incorporation.

    Science.gov (United States)

    Liu, Gengbo; Pastakia, Meet; Fenn, Michael B; Kishore, Vipuil

    2016-05-01

    Plastic compression is a collagen densification process that has been widely used for the development of mechanically robust collagen-based materials. Incorporation of bioglass within plastically compressed collagen gels has been shown to mimic the microstructural properties of native bone and enhance in vitro cell-mediated mineralization. The current study seeks to decouple the effects of collagen densification and bioglass incorporation to understand the interplay between collagen packing density and presence of bioglass on cell-mediated mineralization. Saos-2 cell-mediated mineralization was assessed as a measure of the osteoconductivity of four different collagen gels: (1) uncompressed collagen gel (UC), (2) bioglass incorporated uncompressed collagen gel (UC + BG), (3) plastically compressed collagen gel (PC), and (4) bioglass incorporated plastically compressed collagen gel (PC + BG). The results indicated that collagen densification enhanced mineralization as shown by SEM, increased alkaline phosphatase activity and produced significantly higher amounts of mineralized nodules on PC gels compared to UC gels. Further, the amount of nodule formation on PC gels was significantly higher compared to UC + BG gels indicating that increase in matrix stiffness due to collagen densification had a greater effect on cell-mediated mineralization compared to bioglass incorporation into loosely packed UC gels. Incorporation of bioglass into PC gels further enhanced mineralization as evidenced by significantly larger nodule size and higher amount of mineralization on PC + BG gels compared to PC gels. In conclusion, collagen densification via plastic compression improves the osteoconductivity of collagen gels. Further, incorporation of bioglass within PC gels has an additive effect and further enhances the osteoconductivity of collagen gels. © 2016 Wiley Periodicals, Inc.

  11. Cell-mediated immune response in rotavirus-infected calves: leucocyte migration inhibition assay.

    Science.gov (United States)

    Chauhan, R S; Singh, N P

    1992-07-01

    The cell-mediated immune (CMI) response was determined in rotavirus-infected calves by leucocyte migration inhibition assay with blood, spleen, mesenteric lymph node and intestinal lymphocytes. The inhibition of migration was more prominent in intestinal and mesenteric lymph node lymphocytes than in spleen and blood. In rotavirus-infected calves, the assay indicated the presence of CMI response which was more prominent at the local site of infection.

  12. Activation of cell-mediated immunity by Morinda citrifolia fruit extract and its constituents.

    Science.gov (United States)

    Murata, Kazuya; Abe, Yumi; Futamura-Masudaa, Megumi; Uwaya, Akemi; Isami, Fumiyuki; Matsuda, Hideaki

    2014-04-01

    Morinda citrifolia, commonly known as noni, is a traditional natural medicine in French Polynesia and Hawaii. Functional foods derived from M. citrifolia fruit have been marketed to help prevent diseases and promote good health. The objective of this study was to assess the effects of M. citrifolia fruit on cell-mediated immunity. In the picryl chloride-induced contact dermatitis test, M. citrifolia fruit extract (Noni-ext) inhibited the suppression of cell-mediated immunity by immunosuppressive substances isolated from freeze-dried ascites of Ehrlich carcinoma-bearing mice (EC-sup). In addition, Noni-ext inhibited reduction of IL-2 production in EC-sup-treated mice and activated natural killer cells in normal mice. These results suggest that Noni-ext has multiple effects on the recovery of cell-mediated immunity. Furthermore, we investigated the active principles of Noni-ext and identified an iridoid glycoside, deacetylasperulosidic acid. Oral administration of deacetylasperulosidic acid inhibited the reduction of ear swelling, and also cancelled the suppression of IL-2 production along with the activation of natural killer cells in the same manner as that of Noni-ext.

  13. Augmented primary humoral immune response and decreased cell-mediated immunity by Murraya koenigii in rats.

    Science.gov (United States)

    Kaur, Inderjit; Bhatia, Sneh; Bhati, Yogendra; Sharma, Vinay; Mediratta, Pramod K; Bhattacharya, Swapan K

    2014-05-01

    Murraya koenigii (Rutaceae) (curry patta: Hindi) of the family Rutaceae is used in the traditional Indian system of medicine for its immunomodulatory properties. The essential oil of the leaves of M. koenigii possesses antimicrobial, antifungal, and pesticidal activities and is used for the treatment of amebiasis, diabetes, and hepatitis. The present study was performed to evaluate the effect of M. koenigii on humoral and cell-mediated immune responses in rats. Aqueous extract of M. koenigii leaves was administered orally in a dose of 350 mg/kg. Cell-mediated immunity was assessed by measuring foot pad thickness following sensitization by injection of keyhole limpet hemocyanin and subsequent challenge by the same. Humoral immunity was assessed by measurement of hemagglutination titer to sheep red blood cells (SRBCs). In the humoral immune response, the administration of M. koenigii [350 mg/kg per os (p.o.)] from day 1 to day 7 after sensitization with SRBC on day 0 caused a significant increase in the primary anti-SRBC titer. However, the secondary immune response was decreased significantly (pkoenigii (350 mg/kg, p.o.), when administered for 14 days, produced a significant (pkoenigii augments primary humoral immune response and decreases cell-mediated immunity.

  14. Zinc aspartate suppresses T cell activation in vitro and relapsing experimental autoimmune encephalomyelitis in SJL/J mice.

    Science.gov (United States)

    Stoye, Diana; Schubert, Claudia; Goihl, Alexander; Guttek, Karina; Reinhold, Annegret; Brocke, Stefan; Grüngreiff, Kurt; Reinhold, Dirk

    2012-06-01

    Zinc is an essential trace element with a critical role in normal growth and development and in immune homeostasis. Zinc deficiency impairs both the innate and the adaptive immune system and can be normalized by zinc supplementation. On the other end of the spectrum, high dosages of zinc diminish immune cell functions similar to zinc deficiency. Here, we investigated the influence of zinc aspartate on proliferation and cytokine production of stimulated human T cells and mouse splenocytes in vitro. Furthermore, the effect of zinc aspartate was examined in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of Multiple Sclerosis (MS) with a Th1/Th17 T cell-mediated immunopathogenesis. Zinc aspartate suppressed proliferation as well as IL-2, IL-10 and IL-17 production in stimulated human T cells and mouse splenocytes. Importantly, administration of a medium range dose of 30 μg/day zinc aspartate [1.5 mg/kg body weight (BW)] in a therapeutic manner led to a significant reduction of the clinical severity of the EAE during the first relapse of the disease. A lower zinc aspartate dose (6 μg/day, 0.3 mg/kg BW) had no significant therapeutic effect on the severity of the EAE, while administration of higher zinc aspartate amounts (120 μg/day, 6 mg/kg BW) led to more severe disease. Taken together, our data suggest that zinc aspartate can modulate activation, proliferation and cytokine production of effector T cells in vitro and in vivo and that activated autoreactive T cells may be potential therapeutic targets of tightly controlled zinc supplementation in autoimmune diseases like MS.

  15. Th17 response and autophagy - main pathways implicated in the development of inflammatory bowel disease by genome-wide association studies: new factors involved in inflammatory bowel disease susceptibility

    Directory of Open Access Journals (Sweden)

    Roberto Díaz-Peña

    2015-09-01

    Full Text Available Inflammatory bowel disease (IBD is an entity that mainly includes ulcerative colitis (UC and Crohn's disease (CD. Improved health care, diet changes, and higher industrialization are associated with an increase in IBD prevalence. This supports the central role of environmental factors in the pathology of this disease. However, IBD also shows a relevant genetic component as shown by high heritability. Classic genetic studies showed relevant associations between IBD susceptibility and genes involved in the immune response. This is consistent with prior theories about IBD development. According to these, contact of the immune system with a high number of harmless antigens from the diet and the bacterial flora should originate tolerance while preserving response against pathogens. Failure to achieve this balance may originate the typical inflammatory response associated with IBD. Recently, genome-wide association studies (GWASs have confirmed the implication of the immune system, particularly the Th17 immune response, previously associated to other autoimmune diseases, and of autophagy. In this paper, the mechanisms involved in these two relevant pathways and their potential role in the pathogenesis of IBD are reviewed.

  16. Iodine-Rich Herbs and Potassium Iodate Have Different Effects on the Oxidative Stress and Differentiation of TH17 Cells in Iodine-Deficient NOD.H-2h4 Mice.

    Science.gov (United States)

    Gao, Cheng-Han; Qu, Jin-Qiao; Zhou, Xi-Yu; Gao, Tian-Shu

    2017-08-12

    Iodine-rich herbs such as seaweed, kelp, and sea tangle were widely used to treat various types of goiter with good effect and without any adverse side effects in China. When compared with potassium iodate (PI), iodine-rich herbs had a positive effect on the recovery of goiter resulting from iodine deficiency without any obvious harmful effects. In NOD.H-2h4 mice, an autoimmune thyroiditis-prone model, iodine excess can increase infiltration of lymphocytes and structural damage of the thyroid follicles, hence resulting in thyroiditis. Until now, there has been little research on the comparative effects of PI and iodine-rich herbs on thyroid in an autoimmune thyroiditis-prone model. This study was designed to compare the different effects of iodine-rich herbs and PI on the thyroid gland in iodine-deficient NOD.H-2h4 mice. Excessive intake of PI cause oxidative injury in the thyroid gland and increase the risk of autoimmune thyroiditis, while iodine-rich herbs cause less oxidative injury, significantly enhancing antioxidant capacity, and inhibit the high differentiation of Th17 cells in the thyroid glands of NOD.H-2h4 mice.

  17. Lnc-SGK1 induced by Helicobacter pylori infection and highsalt diet promote Th2 and Th17 differentiation in human gastric cancer by SGK1/Jun B signaling.

    Science.gov (United States)

    Yao, Yongliang; Jiang, Qingbo; Jiang, Lixing; Wu, Jianhong; Zhang, Qinghui; Wang, Jianjun; Feng, Huang; Zang, Panpan

    2016-04-12

    Serum and glucocorticoid-inducible kinase (SGK) 1can be triggered in several malignancies. Most research on SGK1has focused on its role in cancer cells, and we sought to investigate its potential upstream non-coding RNA nominated as Lnc-SGK1, and their expression and diagnostic value in T cells in human gastric cancer (GC). Excessive expression of Lnc-SGK1 and SGK1 were observed in T cell either within the tumor or peripheral T cells, and furthermore associated with Helicobacter pylori infection and high-salt diet (HSD). Within T cells, Helicobacter pylori (Hp) infection and high-salt dietcan up-regulated SGK1 expression and in turn enhance expression of Lnc-SGK1 through JunB activation. And expression of Lnc-SGK1 can further enhance transcription of SGK1 through cis regulatory mode. Lnc-SGK1 can induce Th2 and Th17 and reduce Th1 differentiation via SGK1/JunB signaling. Serum Lnc-SGK1 expression in combination with H. pylori infection and/or HSD in T cells was associated with poor prognosis of GC patients, and could be an ideal diagnostic index in human GC.

  18. Inhibition of Mast Cell-Mediated Allergic Responses by Arctii Fructus Extracts and Its Main Compound Arctigenin.

    Science.gov (United States)

    Kee, Ji-Ye; Hong, Seung-Heon

    2017-11-01

    The Arctium lappa seeds (Arctii Fructus) and its major active compound, arctigenin (ARC), are known to have anticancer, antiobesity, antiosteoporosis, and anti-inflammatory activities. However, the effect of Arctii Fructus and ARC on mast cell-mediated allergic inflammation and its associated mechanism have not been elucidated. Therefore, we attempted to investigate the antiallergic activity of Arctii Fructus and ARC on mast cells and experimental mouse models. Arctii Fructus water extract (AFW) or ethanol extract (AFE) and ARC reduced the production of histamine and pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, and TNF-α in mast cells. AFW, AFE, and ARC inhibited phosphorylation of MAPKs and NF-κB in activated mast cells. Moreover, IgE-mediated passive cutaneous anaphylaxis and compound 48/80-induced anaphylactic shock were suppressed by AFW, AFE, and ARC administration. These results suggest that Arctii Fructus and ARC are potential therapeutic agents against allergic inflammatory diseases.

  19. Tumor Necrosis Factor (TNF Bioactivity at the Site of an Acute Cell-Mediated Immune Response Is Preserved in Rheumatoid Arthritis Patients Responding to Anti-TNF Therapy

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    Rachel Byng-Maddick

    2017-08-01

    Full Text Available The impact of anti-tumor necrosis factor (TNF therapies on inducible TNF-dependent activity in humans has never been evaluated in vivo. We aimed to test the hypothesis that patients responding to anti-TNF treatments exhibit attenuated TNF-dependent immune responses at the site of an immune challenge. We developed and validated four context-specific TNF-inducible transcriptional signatures to quantify TNF bioactivity in transcriptomic data. In anti-TNF treated rheumatoid arthritis (RA patients, we measured the expression of these biosignatures in blood, and in skin biopsies from the site of tuberculin skin tests (TSTs as a human experimental model of multivariate cell-mediated immune responses. In blood, anti-TNF therapies attenuated TNF bioactivity following ex vivo stimulation. However, at the site of the TST, TNF-inducible gene expression and genome-wide transcriptional changes associated with cell-mediated immune responses were comparable to that of RA patients receiving methotrexate only. These data demonstrate that anti-TNF agents in RA patients do not inhibit inducible TNF activity at the site of an acute inflammatory challenge in vivo, as modeled by the TST. We hypothesize instead that their therapeutic effects are limited to regulating TNF activity in chronic inflammation or by alternative non-canonical pathways.

  20. Tumor Necrosis Factor (TNF) Bioactivity at the Site of an Acute Cell-Mediated Immune Response Is Preserved in Rheumatoid Arthritis Patients Responding to Anti-TNF Therapy.

    Science.gov (United States)

    Byng-Maddick, Rachel; Turner, Carolin T; Pollara, Gabriele; Ellis, Matthew; Guppy, Naomi J; Bell, Lucy C K; Ehrenstein, Michael R; Noursadeghi, Mahdad

    2017-01-01

    The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated in vivo. We aimed to test the hypothesis that patients responding to anti-TNF treatments exhibit attenuated TNF-dependent immune responses at the site of an immune challenge. We developed and validated four context-specific TNF-inducible transcriptional signatures to quantify TNF bioactivity in transcriptomic data. In anti-TNF treated rheumatoid arthritis (RA) patients, we measured the expression of these biosignatures in blood, and in skin biopsies from the site of tuberculin skin tests (TSTs) as a human experimental model of multivariate cell-mediated immune responses. In blood, anti-TNF therapies attenuated TNF bioactivity following ex vivo stimulation. However, at the site of the TST, TNF-inducible gene expression and genome-wide transcriptional changes associated with cell-mediated immune responses were comparable to that of RA patients receiving methotrexate only. These data demonstrate that anti-TNF agents in RA patients do not inhibit inducible TNF activity at the site of an acute inflammatory challenge in vivo, as modeled by the TST. We hypothesize instead that their therapeutic effects are limited to regulating TNF activity in chronic inflammation or by alternative non-canonical pathways.

  1. Elevated frequencies of CD4(+) IL-21(+) T, CD4(+) IL-21R(+) T and IL-21(+) Th17 cells, and increased levels of IL-21 in bleomycin-induced mice may be associated with dermal and pulmonary inflammation and fibrosis.

    Science.gov (United States)

    Lei, Ling; He, Zhi-Yi; Zhao, Cheng; Sun, Xue-Jiao; Zhong, Xiao-Ning

    2016-04-01

    Systemic sclerosis (SSc) is characterized by immune abnormalities, progressive fibrosis of the skin and internal organs, and microvascular injury and damage. Interleukin-21 receptor (IL-21R) is expressed in the epidermis from patients with SSc. However, information describing the role of IL-21 in SSc is limited. We established a mouse model of bleomycin (BLM)-induced fibrosis. The frequency of CD4(+) IL-21(+) T, CD4(+) IL-21R(+) T and IL-21(+) Th17 cells in peripheral blood, skin and lungs of BLM-induced mice were detected by flow cytometry; IL-21 levels in the peripheral blood were evaluated by enzyme-linked immunosorbent assay (ELISA). CD4(+) T cells were isolated from the spleen of BLM-induced and control mice and cultured in vitro alone or in the presence of mrIL-21 or mrIL-21 plus transforming growth factor (TGF)-β1. The frequency of Th17 cells was detected by flow cytometry; levels of IL-17 were evaluated by ELISA, and the expression of IL-17A and retinoic-acid-receptor-related orphan receptors gamma t (RORγt) messenger RNA were analyzed by real-time polymerase chain reaction. Compared to control mice, the frequency of CD4(+) IL-21(+) T, CD4(+) 21R(+) T and IL-21(+) Th17 cells and the levels of IL-21 were significantly increased in BLM-induced mice. The frequency of CD4(+) IL-21(+) T, CD4(+) 21R(+) T and IL-21(+) Th17 cells and the levels of IL-21 were correlated with dermal and pulmonary inflammation and fibrosis. In vitro analyses indicate that IL-21 promoted the differentiation of Th17 cells from CD4(+) cells isolated from the spleen of BLM-induced mice. IL-21 may play an important role in the pathogenesis of SSc as a Th17 effector cytokine, and IL-21 may induce the differentiation of Th17 cells in the BLM-induced SSc mouse model. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  2. Dehydroeffusol effectively inhibits human gastric cancer cell-mediated vasculogenic mimicry with low toxicity

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    Liu, Wenming; Meng, Mei; Zhang, Bin; Du, Longsheng; Pan, Yanyan; Yang, Ping; Gu, Zhenlun; Zhou, Quansheng, E-mail: quanshengzhou@yahoo.com; Cao, Zhifei, E-mail: hunancao@163.com

    2015-09-01

    Accumulated data has shown that various vasculogenic tumor cells, including gastric cancer cells, are able to directly form tumor blood vessels via vasculogenic mimicry, supplying oxygen and nutrients to tumors, and facilitating progression and metastasis of malignant tumors. Therefore, tumor vasculogenic mimicry is a rational target for developing novel anticancer therapeutics. However, effective antitumor vasculogenic mimicry-targeting drugs are not clinically available. In this study, we purified 2,7-dihydroxyl-1-methyl-5-vinyl-phenanthrene, termed dehydroeffusol, from the traditional Chinese medicinal herb Juncus effusus L., and found that dehydroeffusol effectively inhibited gastric cancer cell-mediated vasculogenic mimicry in vitro and in vivo with very low toxicity. Dehydroeffusol significantly suppressed gastric cancer cell adhesion, migration, and invasion. Molecular mechanistic studies revealed that dehydroeffusol markedly inhibited the expression of a vasculogenic mimicry master gene VE-cadherin and reduced adherent protein exposure on the cell surface by inhibiting gene promoter activity. In addition, dehydroeffusol significantly decreased the expression of a key vasculogenic gene matrix metalloproteinase 2 (MMP2) in gastric cancer cells, and diminished MMP2 protease activity. Together, our results showed that dehydroeffusol effectively inhibited gastric cancer cell-mediated vasculogenic mimicry with very low toxicity, suggesting that dehydroeffusol is a potential drug candidate for anti-gastric cancer neovascularization and anti-gastric cancer therapy. - Highlights: • Dehydroeffusol markedly inhibits gastric cancer cell-mediated vasculogenic mimicry. • Dehydroeffusol suppresses the expression of vasculogenic mimicry key gene VE-cadherin. • Dehydroeffusol decreases the MMP2 expression and activity in gastric cancer cells. • Dehydroeffusol is a potential anti-cancer drug candidate with very low toxicity.

  3. Stem cell mediation of functional recovery after stroke in the rat.

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    Pedro Ramos-Cabrer

    Full Text Available BACKGROUND: Regenerative strategies of stem cell grafting have been demonstrated to be effective in animal models of stroke. In those studies, the effectiveness of stem cells promoting functional recovery was assessed by behavioral testing. These behavioral studies do, however, not provide access to the understanding of the mechanisms underlying the observed functional outcome improvement. METHODOLOGY/PRINCIPAL FINDINGS: In order to address the underlying mechanisms of stem cell mediated functional improvement, this functional improvement after stroke in the rat was investigated for six months after stroke by use of fMRI, somatosensory evoked potentials by electrophysiology, and sensorimotor behavior testing. Stem cells were grafted ipsilateral to the ischemic lesion. Rigorous exclusion of spontaneous recovery as confounding factor permitted to observe graft-related functional improvement beginning after 7 weeks and continuously increasing during the 6-month observation period. The major findings were i functional improvement causally related to the stem cells grafting; ii tissue replacement can be excluded as dominant factor for stem cell mediated functional improvement; iii functional improvement occurs by exclusive restitution of the function in the original representation field, without clear contributions from reorganization processes, and iv stem cells were not detectable any longer after six months. CONCLUSIONS/SIGNIFICANCE: A delayed functional improvement due to stem cell implantation has been documented by electrophysiology, fMRI and behavioral testing. This functional improvement occurred without cells acting as a tissue replacement for the necrotic tissue after the ischemic event. Combination of disappearance of grafted cells after six months on histological sections with persistent functional recovery was interpreted as paracrine effects by the grafted stem cells being the dominant mechanism of cell activity underlying the observed

  4. Successful Treatment of T Cell-Mediated Acute Rejection with Delayed CTLA4-Ig in Mice

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    James S. Young

    2017-09-01

    Full Text Available Clinical observations that kidney transplant recipients receiving belatacept who experienced T cell-mediated acute rejection can be successfully treated and subsequently maintained on belatacept-based immunosuppression suggest that belatacept is able to control memory T cells. We recently reported that treatment with CTLA4-Ig from day 6 posttransplantation successfully rescues allografts from acute rejection in a BALB/c to C57BL/6 heart transplant model, in part, by abolishing B cell germinal centers and reducing alloantibody titers. Here, we show that CTLA4-Ig is additionally able to inhibit established T cell responses independently of B cells. CTLA4-Ig inhibited the in vivo cytolytic activity of donor-specific CD8+ T cells, and the production of IFNγ by graft-infiltrating T cells. Delayed CTLA4-Ig treatment did not reduce the numbers of graft-infiltrating T cells nor prevented the accumulation of antigen-experienced donor-specific memory T cells in the spleen. Nevertheless, delayed CTLA4-Ig treatment successfully maintained long-term graft acceptance in the majority of recipients that had experienced a rejection crisis, and enabled the acceptance of secondary BALB/c heart grafts transplanted 30 days after the first transplantation. In summary, we conclude that delayed CTLA4-Ig treatment is able to partially halt ongoing T cell-mediated acute rejection. These findings extend the functional efficacy of CTLA4-Ig therapy to effector T cells and provide an explanation for why CTLA4-Ig-based immunosuppression in the clinic successfully maintains long-term graft survival after T cell-mediated rejection.

  5. A tale of two plaques: convergent mechanisms of T-cell-mediated inflammation in psoriasis and atherosclerosis.

    Science.gov (United States)

    Armstrong, April W; Voyles, Stephanie V; Armstrong, Ehrin J; Fuller, Erin N; Rutledge, John C

    2011-07-01

    Psoriasis and atherosclerosis are diseases in which effector T lymphocytes such as Helper T cells type 1 (Th1) and 17 (Th17) play integral roles in disease pathogenesis and progression. Regulatory T cells (Treg) also exert clinically important anti-inflammatory effects that are pathologically altered in psoriasis and atherosclerosis. We review the immunological pathways involving Th1, Th17 and Treg cells that are common to psoriasis and atherosclerosis. These shared pathways provide the basis for mechanisms that may explain the epidemiologic observation that patients with psoriasis have an increased risk of heart disease. Improved understanding of these pathways will guide future experiments and may lead to the development of therapeutics that prevent or treat cardiovascular complications in patients with psoriasis. © 2011 John Wiley & Sons A/S.

  6. Cell mediated immune response of Bufo arenarum and Leptodactylus ocellatus (Amphibia, Anura) to mycobacterial antigens.

    Science.gov (United States)

    Fliess, E L; Salibian, A

    1984-01-01

    The lymphocyte transformation test was applied to the study of cell mediated immune (CMI) response in vitro to mycobacterial antigens in Bufo arenarum and Leptodactylus ocellatus previously inoculated with a suspension of Mycobacterium tuberculosis. The stimulated samples of blood both in B. arenarum and L. ocellatus showed a significant increase in the percent of blastic dedifferentiation (almost 100% with respect to controls) suggesting the presence of a positive CMI response to PPD. The differences were observed on the fifth day of incubation and lasted until the seventh day.

  7. Role of T-cell-mediated inflammation in psoriasis: pathogenesis and targeted therapy

    Directory of Open Access Journals (Sweden)

    Flatz L

    2013-02-01

    Full Text Available Lukas Flatz, Curdin ConradDepartment of Dermatology, University Hospital of Lausanne (CHUV, Lausanne, SwitzerlandAbstract: Psoriasis is one of the most common chronic, inflammatory, T-cell-mediated autoimmune diseases. Over the past decade, increased knowledge of disease pathogenesis has fundamentally changed psoriasis treatment, with the introduction of biologics, and this has led to a multitude of improved selective targets providing potential therapeutic options. Indeed, numerous pathogenesis-based treatments are currently in development, as psoriasis has also become increasingly relevant for proof-of-concept studies. The purpose of this review was to summarize current knowledge of psoriasis immunopathogenesis, focusing on the T-cell-mediated immune response and its initiation. The authors describe recent advances in psoriasis treatment and discuss pathogenesis-based therapies that are currently in development or which could be envisioned for the future. Although current biologics are well tolerated, several issues such as long-term efficacy, long-term safety, and high costs keep driving the search for new and better therapies. With further advances in understanding disease pathogenesis, more genomic data from psoriasis patients becoming available, and potentially the identification of autoantigens in psoriasis, current research should lead to the development of a growing arsenal of improved targeted treatments and to further breakthrough immunotherapies.Keywords: autoimmunity, autoimmune disease, immune response, immunopathogenesis

  8. Systemic minor histocompatibility antigen expression in blood endothelial cells prevents T cell-mediated vascular immunopathology.

    Science.gov (United States)

    Caviezel-Firner, Sonja; Engeler, Daniel; Bolinger, Beatrice; Onder, Lucas; Scandella, Elke; Yu, Meimei; Kroczek, Richard A; Ludewig, Burkhard

    2013-12-01

    Attenuation of T cell-mediated damage of blood endothelial cells (BECs) in transplanted organs is important to prevent transplant vasculopathy (TV) and chronic rejection. Here, we assessed the importance of minor histocompatibility antigen (mHA) distribution and different coinhibitory molecules for T cell-BEC interaction. A transgenic mHA was directed specifically to BECs using the Tie2 promoter and cellular interactions were assessed in graft-versus-host disease-like and heterotopic heart transplantation settings. We found that cognate CD4(+) T-cell help was critical for the activation of BEC-specific CD8(+) T cells. However, systemic mHA expression on BECs efficiently attenuated adoptively transferred, BEC-specific CD4(+) and CD8(+) T cells and hence prevented tissue damage, whereas restriction of mHA expression to heart BECs precipitated the development of TV. Importantly, the lack of the coinhibitory molecules programmed death-1 (PD-1) and B and T lymphocyte attenuator fostered the initial activation of BEC-specific CD4(+) T cells, but did not affect development of TV. In contrast, TV was significantly augmented in the absence of PD-1 on BEC-specific CD8(+) T cells. Taken together, these results indicate that antigen distribution in the vascular bed determines the impact of coinhibition and, as a consequence, critically impinges on T cell-mediated vascular immunopathology. © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. T cell mediated cerebral hemorrhages and microhemorrhages during passive Aβ immunization in APPPS1 transgenic mice

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    de Calignon Alix

    2011-03-01

    Full Text Available Abstract Background Immunization against amyloid-β (Aβ, the peptide that accumulates in the form of senile plaques and in the cerebrovasculature in Alzheimer's disease (AD, causes a dramatic immune response that prevents plaque formation and clears accumulated Aβ in transgenic mice. In a clinical trial of Aβ immunization, some patients developed meningoencephalitis and hemorrhages. Neuropathological investigations of patients who died after the trial showed clearance of amyloid pathology, but also a powerful immune response involving activated T cells probably underlying the negative effects of the immunization. Results To define the impact of T cells on this inflammatory response we used passive immunization and adoptive transfer to separate the effect of IgG and T cell mediated effects on microhemorrhage in APPPS1 transgenic mice. Neither anti Aβ IgG nor adoptively transferred T cells, alone, led to increased cerebrovascular damage. However, the combination of adoptively transferred T cells and passive immunization led to massive cerebrovascular bleeding that ranged from multiple microhemorrhages in the parenchyma to large hematomas. Conclusions Our results indicate that vaccination can lead to Aβ and T cell induced cerebral micro-hemorrhages and acute hematomas, which are greatly exacerbated by T cell mediated activity.

  10. Tetherin promotes the innate and adaptive cell-mediated immune response against retrovirus infection in vivo.

    Science.gov (United States)

    Li, Sam X; Barrett, Bradley S; Heilman, Karl J; Messer, Ronald J; Liberatore, Rachel A; Bieniasz, Paul D; Kassiotis, George; Hasenkrug, Kim J; Santiago, Mario L

    2014-07-01

    Tetherin/BST-2 is a host restriction factor that could directly inhibit retroviral particle release by tethering nascent virions to the plasma membrane. However, the immunological impact of Tetherin during retrovirus infection remains unknown. We now show that Tetherin influences antiretroviral cell-mediated immune responses. In contrast to the direct antiviral effects of Tetherin, which are dependent on cell surface expression, the immunomodulatory effects are linked to the endocytosis of the molecule. Mice encoding endocytosis-competent C57BL/6 Tetherin exhibited lower viremia and pathology at 7 d postinfection with Friend retrovirus (FV) compared with mice encoding endocytosis-defective NZW/LacJ Tetherin. Notably, antiretroviral protection correlated with stronger NK cell responses. In addition, Friend retrovirus infection levels were significantly lower in wild-type C57BL/6 mice than in Tetherin knockout mice at 2 wk postinfection, and antiretroviral protection correlated with stronger NK cell and virus-specific CD8+ T cell responses. The results demonstrate that Tetherin acts as a modulator of the cell-mediated immune response against retrovirus infection in vivo.

  11. Cell-mediated immunity in Chagas' disease: Alterations induced by treatment with a trypanocidal drug (nifurtimox).

    Science.gov (United States)

    Lelchuk, R; Cardoni, R L; Fuks, A S

    1977-01-01

    Peripheral leucocyte migration inhibition (LMI) with Trypanosoma cruzi-specific antigens, measured as a migration index (MI), was studied in chronic Chagas' disease patients. The MI of untreated patients with polymerized antigens from culture forms (epimastigotes) of T. cruzi was significantly lower than that of controls. In contrast, when chronic Chagas' patients were treated with nifurtimox, 10 mg/kg/day for 2 months, the MI was not different from control values. Treated and untreated patients had normal T- and B-lymphocyte markers, measured by the ability to form rosettes either with sheep erythrocytes (E-RFC) or with sheep erythrocytes--antibody--complement (EAC-RFC). In addition, the number of lymphocytes bearing surface membrane Ig (SMIg) was the same as that of controls. Non-specific functional assays, such as PHA-induced blastogenesis and antibody-dependent cell-mediated cytotoxicity (ADCC) to sensitized chicken erythrocytes were also normal, both in treated and untreated patients. Thus, nifurtimox produced a particularly effect on cell-mediated immunity, specially detectable using LMI. PMID:414867

  12. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors.

    Science.gov (United States)

    Liu, Xiaojuan; Pu, Yang; Cron, Kyle; Deng, Liufu; Kline, Justin; Frazier, William A; Xu, Hairong; Peng, Hua; Fu, Yang-Xin; Xu, Meng Michelle

    2015-10-01

    Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Here, using syngeneic immunocompetent mouse tumor models, we reveal that the therapeutic effects of CD47 blockade depend on dendritic cell but not macrophage cross-priming of T cell responses. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the antitumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c+ cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of antitumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors.

  13. Characterization of CD4+T cell-mediated cytotoxicity in patients with multiple myeloma.

    Science.gov (United States)

    Zhang, Xiaole; Gao, Lei; Meng, Kai; Han, Chunting; Li, Qiang; Feng, Zhenjun; Chen, Lei

    2018-02-12

    Multiple myeloma (MM) is an incurable cancer characterized by the development of malignant plasma cells. The CD8 T cell-mediated cytotoxicity is considered a major player in antitumor immunity, but in MM patients, the CD8 T cells displayed senescence markers and were functionally impaired. To investigate whether cytotoxic CD4 T cells could act as a treatment alternative in MM, we examined the frequency and function of naturally occurring cytotoxic CD4 T cells in MM patients. The cytotoxic CD4 T cells were identified as granzyme-A, granzyme B-, and perforin-expressing CD4 T cells, and their frequencies were significantly upregulated in MM patients when compared with healthy controls. The frequencies of cytotoxic CD4 T cells in MM patients were not associated with the frequencies of cytotoxic CD8 T cells, but were negatively associated with disease severity. Interestingly, the expression levels of inhibitory molecules, including PD-1 and CTLA-4, were significantly lower in cytotoxic CD4 T cells than in cytotoxic CD8 T cells. When co-incubated with autologous CD38 + CD138 + plasma cells, CD4 T cells were capable of eliminating plasma cells with varying degrees of efficacy. In MM patients, the frequency of circulating plasma cells was negatively correlated with the frequency of cytotoxic CD4 T cells. Therefore, CD4 T cell-mediated cytotoxicity existed naturally in MM patients and could potentially act as an option in antitumor therapies. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. Chronological assessment of mast cell-mediated gut dysfunction and mucosal inflammation in a rat model of chronic psychosocial stress.

    Science.gov (United States)

    Vicario, María; Guilarte, Mar; Alonso, Carmen; Yang, Pinchang; Martínez, Cristina; Ramos, Laura; Lobo, Beatriz; González, Ana; Guilà, Meritxell; Pigrau, Marc; Saperas, Esteban; Azpiroz, Fernando; Santos, Javier

    2010-10-01

    Life stress and mucosal inflammation may influence symptom onset and severity in certain gastrointestinal disorders, particularly irritable bowel syndrome (IBS), in connection with dysregulated intestinal barrier. However, the mechanism responsible remains unknown. Crowding is a validated animal model reproducing naturalistic psychosocial stress, whose consequences on gut physiology remain unexplored. Our aims were to prove that crowding stress induces mucosal inflammation and intestinal dysfunction, to characterize dynamics in time, and to evaluate the implication of stress-induced mast cell activation on intestinal dysfunction. Wistar-Kyoto rats were submitted to 15 days of crowding stress (8 rats/cage) or sham-crowding (2 rats/cage). We measured spontaneous and corticotropin-releasing factor-mediated release of plasma corticosterone. Stress-induced intestinal chrono-pathobiology was determined by measuring intestinal inflammation, epithelial damage, mast cell activation and infiltration, and intestinal barrier function. Corticosterone release was higher in crowded rats throughout day 15. Stress-induced mild inflammation, manifested earlier in the ileum and the colon than in the jejunum. While mast cell counts remained mostly unchanged, piecemeal degranulation increased along time, as the mucosal content and luminal release of rat mast cell protease-II. Stress-induced mitochondrial injury and increased jejunal permeability, both events strongly correlated with mast cell activation at day 15. Taken together, we have provided evidences that long-term exposure to psychosocial stress promotes mucosal inflammation and mast cell-mediated barrier dysfunction in the rat bowel. The notable resemblance of these findings with those in some IBS patients, support the potential interest and translational validity of this experimental model for the research of stress-sensitive intestinal disorders, particularly IBS. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. The effect of arginine dietary supplementation in broiler breeder hens on offspring humoral and cell-mediated immune responses

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    AE Murakami

    2014-06-01

    Full Text Available The influence of supplementing the diet of broiler breeder hens with arginine (Arg on their offspring's humoral and cell-mediated immune response was evaluated in two experiments. In experiments I and II, breeder hens were fed diets containing graded levels of Arg (0.943, 1.093, 1.243, 1.393 and 1.543% digestible Arg. In experiment I, the offspring was randomly grouped according to the treatment received by the breeder hens, with five levels of Arg in the maternal diet and six replicates, giving a total 30 experimental units. In experiment II, the offspring were grouped in accordance with the treatment received by the breeder hens; however, Arg was added to the starter diet (1.300, 1.450, 1.600, 1.750 and 1.900% digestible Arg and also the growing diet (1.150, 1.300, 1.450, 1.600 and 1.750% digestible Arg. Supplementation of the broiler breeder hen diet did not influence (p > 0.05 the development of the lymphoid organs (cloacal bursa, thymus and spleen of the offspring, whether their diet were supplemented or not. Nevertheless, greater weight and dimensions cloacal bursa were found in the supplemented offspring in comparison with the nonsupplemented offspring. Macrophage phagocytic activity was found to be unaffected (p > 0.05, independently of the Arg supplementation. The offspring fed with supplemented diets showed a linear reduction in the antibody titer against Newcastle Disease (p 0.05 by the breeder hen diet. This study concluded that supplementing the breeder hen diet with arginine is insufficient to improve the humoral and cellular immune response, requiring supplementation of the offspring diet.

  16. T Helper 17/Regulatory T Cell Balance and Experimental Models of Peritoneal Dialysis-Induced Damage

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    Georgios Liappas

    2015-01-01

    Full Text Available Fibrosis is a general complication in many diseases. It is the main complication during peritoneal dialysis (PD treatment, a therapy for renal failure disease. Local inflammation and mesothelial to mesenchymal transition (MMT are well known key phenomena in peritoneal damage during PD. New data suggest that, in the peritoneal cavity, inflammatory changes may be regulated at least in part by a delicate balance between T helper 17 and regulatory T cells. This paper briefly reviews the implication of the Th17/Treg-axis in fibrotic diseases. Moreover, it compares current evidences described in PD animal experimental models, indicating a loss of Th17/Treg balance (Th17 predominance leading to peritoneal damage during PD. In addition, considering the new clinical and animal experimental data, new therapeutic strategies to reduce the Th17 response and increase the regulatory T response are proposed. Thus, future goals should be to develop new clinical biomarkers to reverse this immune misbalance and reduce peritoneal fibrosis in PD.

  17. T Helper 17/Regulatory T Cell Balance and Experimental Models of Peritoneal Dialysis-Induced Damage

    Science.gov (United States)

    Liappas, Georgios; Gónzalez-Mateo, Guadalupe Tirma; Majano, Pedro; Sánchez- Tomero, José Antonio; Ruiz-Ortega, Marta; Martín, Pilar; Sanchez-Díaz, Raquel; Selgas, Rafael; López-Cabrera, Manuel; Aguilera Peralta, Abelardo

    2015-01-01

    Fibrosis is a general complication in many diseases. It is the main complication during peritoneal dialysis (PD) treatment, a therapy for renal failure disease. Local inflammation and mesothelial to mesenchymal transition (MMT) are well known key phenomena in peritoneal damage during PD. New data suggest that, in the peritoneal cavity, inflammatory changes may be regulated at least in part by a delicate balance between T helper 17 and regulatory T cells. This paper briefly reviews the implication of the Th17/Treg-axis in fibrotic diseases. Moreover, it compares current evidences described in PD animal