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Sample records for autoimmune diabetic nod

  1. The dual role of scavenger receptor class A in development of diabetes in autoimmune NOD mice.

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    Mami Shimizu

    Full Text Available Human type 1 diabetes is an autoimmune disease that results from the autoreactive destruction of pancreatic β cells by T cells. Antigen presenting cells including dendritic cells and macrophages are required to activate and suppress antigen-specific T cells. It has been suggested that antigen uptake from live cells by dendritic cells via scavenger receptor class A (SR-A may be important. However, the role of SR-A in autoimmune disease is unknown. In this study, SR-A-/- nonobese diabetic (NOD mice showed significant attenuation of insulitis, lower levels of insulin autoantibodies, and suppression of diabetes development compared with NOD mice. We also found that diabetes progression in SR-A-/- NOD mice treated with low-dose polyinosinic-polycytidylic acid (poly(I:C was significantly accelerated compared with that in disease-resistant NOD mice treated with low-dose poly(I:C. In addition, injection of high-dose poly(I: C to mimic an acute RNA virus infection significantly accelerated diabetes development in young SR-A-/- NOD mice compared with untreated SR-A-/- NOD mice. Pathogenic cells including CD4+CD25+ activated T cells were increased more in SR-A-/- NOD mice treated with poly(I:C than in untreated SR-A-/- NOD mice. These results suggested that viral infection might accelerate diabetes development even in diabetes-resistant subjects. In conclusion, our studies demonstrated that diabetes progression was suppressed in SR-A-/- NOD mice and that acceleration of diabetes development could be induced in young mice by poly(I:C treatment even in SR-A-/- NOD mice. These results suggest that SR-A on antigen presenting cells such as dendritic cells may play an unfavorable role in the steady state and a protective role in a mild infection. Our findings imply that SR-A may be an important target for improving therapeutic strategies for type 1 diabetes.

  2. TAK1 inhibition prevents the development of autoimmune diabetes in NOD mice.

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    Cao, Hui; Lu, Jingli; Du, Jiao; Xia, Fei; Wei, Shouguo; Liu, Xiulan; Liu, Tingting; Liu, Yang; Xiang, Ming

    2015-01-01

    Transforming growth factor-β activated kinase-1 (TAK1, Map3k7), a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, is essential in innate and adaptive immune responses. We postulated that blockade of TAK1 would affect autoimmune diabetes in non-obese diabetic (NOD) mice. Administration of 5Z-7-oxozeaenol (OZ), a TAK1 inhibitor, decreased the incidence and delayed the onset of autoimmune diabetes in both spontaneous and accelerated (cyclophosphamide-induced) experimental NOD mice. OZ also reduced insulitis, preserved islet function, increased the expression of α1- antitrypsin (AAT), and severely inhibited NF-κB and JNK/AP-1 signaling pathways in immune organs and pancreatic tissues. Importantly, TAK1 inhibition by OZ elicited a Th1 to Th2 cytokine shift, and increased TGF-β1 production in cultured T lymphocytes supernatants. Systemic TAK1 inhibition induced immature DCs with lower expressions of MHC-II and CD86, attenuated DC-mediated T cell proliferation in allogeneic MLR, and production of cytokine IL-12p70 in DCs suspensions. The results indicate that TAK1 inhibition with OZ was associated with a lower frequency of autoimmune diabetes in NOD mice. The net effect of TAK1 inhibition in NOD mice therefore appears to be protective rather than disease-enhancing. Strategies targeting TAK1 specifically in NOD mice might prove useful for the treatment of autoimmune diabetes in general. PMID:26459028

  3. Deficiency of Nuclear Factor-κB c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice.

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    Ramakrishnan, Parameswaran; Yui, Mary A; Tomalka, Jeffrey A; Majumdar, Devdoot; Parameswaran, Reshmi; Baltimore, David

    2016-08-01

    The nuclear factor-κB protein c-Rel plays a critical role in controlling autoimmunity. c-Rel-deficient mice are resistant to streptozotocin-induced diabetes, a drug-induced model of autoimmune diabetes. We generated c-Rel-deficient NOD mice to examine the role of c-Rel in the development of spontaneous autoimmune diabetes. We found that both CD4(+) and CD8(+) T cells from c-Rel-deficient NOD mice showed significantly decreased T-cell receptor-induced IL-2, IFN-γ, and GM-CSF expression. Despite compromised T-cell function, c-Rel deficiency dramatically accelerated insulitis and hyperglycemia in NOD mice along with a substantial reduction in T-regulatory (Treg) cell numbers. Supplementation of isogenic c-Rel-competent Treg cells from prediabetic NOD mice reversed the accelerated diabetes development in c-Rel-deficient NOD mice. The results suggest that c-Rel-dependent Treg cell function is critical in suppressing early-onset autoimmune diabetogenesis in NOD mice. This study provides a novel natural system to study autoimmune diabetes pathogenesis and reveals a previously unknown c-Rel-dependent mechanistic difference between chemically induced and spontaneous diabetogenesis. The study also reveals a unique protective role of c-Rel in autoimmune diabetes, which is distinct from other T-cell-dependent autoimmune diseases such as arthritis and experimental autoimmune encephalomyelitis, where c-Rel promotes autoimmunity. PMID:27217485

  4. Sodium meta-arsenite prevents the development of autoimmune diabetes in NOD mice

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    Sodium meta-arsenite (SA) is an orally available arsenic compound. We investigated the effects of SA on the development of autoimmune type 1 diabetes. Female non-obese diabetic (NOD) mice were orally intubated with SA (5 mg/kg/day) from 8 weeks of age for 8 weeks. The cumulative incidence of diabetes was monitored until 30 weeks of age, islet histology was examined, and lymphocytes including T cells, B cells, CD4+ IFN-γ+ cells, CD8+ IFN-γ+ cells, CD4+ IL-4+ cells, and regulatory T cells were analyzed. We also investigated the diabetogenic ability of splenocytes using an adoptive transfer model and the effect of SA on the proliferation, activation, and expression of glucose transporter 1 (Glut1) in splenocytes treated with SA in vitro and splenocytes isolated from SA-treated mice. SA treatment decreased the incidence of diabetes and delayed disease onset. SA treatment reduced the infiltration of immunocytes in islets, and splenocytes from SA-treated mice showed a reduced ability to transfer diabetes. The number of total splenocytes and T cells and both the number and the proportion of CD4+ IFN-γ+ and CD8+ IFN-γ+ T cells in the spleen were significantly reduced in SA-treated NOD mice compared with controls. The number, but not the proportion, of regulatory T cells was decreased in SA-treated NOD mice. Treatment with SA either in vitro or in vivo inhibited proliferation of splenocytes. In addition, the expression of Glut1 and phosphorylated ERK1/2 was decreased by SA treatment. These results suggest that SA reduces proliferation and activation of T cells, thus preventing autoimmune diabetes in NOD mice. - Highlights: • SA prevents the development of diabetes and delays the age of onset in NOD mice. • SA decreases the number but not the proportion of T lymphocytes in NOD mice. • SA reduces IFN-γ-producing T lymphocytes in NOD mice. • SA reduces proliferation and activation of T lymphocytes in vitro and in vivo. • SA reduces the expression of glucose

  5. Sodium meta-arsenite prevents the development of autoimmune diabetes in NOD mice

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    Lee, Y.S.; Kim, D.; Lee, E.K. [Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon 406-840 (Korea, Republic of); Kim, S. [Komipharm International Co. Ltd., 3188, Seongnam-dong, Jungwon-gu, Seongnam-si, Gyeonggi-do 462-827 (Korea, Republic of); Choi, C.S. [Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon 406-840 (Korea, Republic of); Endocrinology, Internal Medicine, Gachon University Gil Medical Center, 1198 Guwol-Dong, Namdong-Gu, Incheon 405-760 (Korea, Republic of); Gachon Medical Research Institute, Gil Hospital, 1198 Guwol-Dong, Namdong-Gu, Incheon 405-760 (Korea, Republic of); Jun, H.S., E-mail: hsjun@gachon.ac.kr [Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon 406-840 (Korea, Republic of); College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon 406-840 (Korea, Republic of); Gachon Medical Research Institute, Gil Hospital, 1198 Guwol-Dong, Namdong-Gu, Incheon 405-760 (Korea, Republic of)

    2015-04-15

    Sodium meta-arsenite (SA) is an orally available arsenic compound. We investigated the effects of SA on the development of autoimmune type 1 diabetes. Female non-obese diabetic (NOD) mice were orally intubated with SA (5 mg/kg/day) from 8 weeks of age for 8 weeks. The cumulative incidence of diabetes was monitored until 30 weeks of age, islet histology was examined, and lymphocytes including T cells, B cells, CD4+ IFN-γ+ cells, CD8+ IFN-γ+ cells, CD4+ IL-4+ cells, and regulatory T cells were analyzed. We also investigated the diabetogenic ability of splenocytes using an adoptive transfer model and the effect of SA on the proliferation, activation, and expression of glucose transporter 1 (Glut1) in splenocytes treated with SA in vitro and splenocytes isolated from SA-treated mice. SA treatment decreased the incidence of diabetes and delayed disease onset. SA treatment reduced the infiltration of immunocytes in islets, and splenocytes from SA-treated mice showed a reduced ability to transfer diabetes. The number of total splenocytes and T cells and both the number and the proportion of CD4+ IFN-γ+ and CD8+ IFN-γ+ T cells in the spleen were significantly reduced in SA-treated NOD mice compared with controls. The number, but not the proportion, of regulatory T cells was decreased in SA-treated NOD mice. Treatment with SA either in vitro or in vivo inhibited proliferation of splenocytes. In addition, the expression of Glut1 and phosphorylated ERK1/2 was decreased by SA treatment. These results suggest that SA reduces proliferation and activation of T cells, thus preventing autoimmune diabetes in NOD mice. - Highlights: • SA prevents the development of diabetes and delays the age of onset in NOD mice. • SA decreases the number but not the proportion of T lymphocytes in NOD mice. • SA reduces IFN-γ-producing T lymphocytes in NOD mice. • SA reduces proliferation and activation of T lymphocytes in vitro and in vivo. • SA reduces the expression of glucose

  6. Different immunological responses to early-life antibiotic exposure affecting autoimmune diabetes development in NOD mice.

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    Hu, Youjia; Jin, Ping; Peng, Jian; Zhang, Xiaojun; Wong, F Susan; Wen, Li

    2016-08-01

    Environmental factors clearly influence the pathogenesis of Type 1 diabetes, an autoimmune disease. We have studied gut microbiota as important environmental agents that could affect the initiation or progression of type 1 diabetes especially in the prenatal period. We used neomycin, targeting mainly Gram negative or vancomycin, targeting mainly Gram positive bacteria, to treat pregnant NOD mothers and to study autoimmune diabetes development in their offspring. Neomycin-treated offspring were protected from diabetes, while vancomycin-treated offspring had accelerated diabetes development, and both antibiotics caused distinctly different shifts in gut microbiota composition compared with the offspring from untreated control mice. Our study demonstrated that neomycin treatment of pregnant mothers leads to generation of immune-tolerogenic antigen-presenting cells (APCs) in the offspring and these APCs had reduced specific autoantigen-presenting function both in vitro and in vivo. Moreover, the protection from diabetes mediated by tolerogenic APCs was vertically transmissible to the second generation. In contrast, more diabetogenic inflammatory T cells were found in the lymphoid organs of the offspring from the vancomycin-treated pregnant mothers. This change however was not transmitted to the second generation. Our results suggested that prenatal exposure to antibiotic influenced gut bacterial composition at the earliest time point in life and is critical for consequent education of the immune system. As different bacteria can induce different immune responses, understanding these differences and how to generate self-tolerogenic APCs could be important for developing new therapy for type 1 diabetes. PMID:27178773

  7. Helminth protection against autoimmune diabetes in NOD mice is independent of a type 2 immune shift and requires TGFβ

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    Hübner, Marc P.; Shi, Yinghui; Torrero, Marina N.; Mueller, Ellen; Larson, David; Soloviova, Kateryna; Gondorf, Fabian; Hoerauf, Achim (Prof. Dr.); Killoran, Kristin E.; Stocker, J. Thomas; Davies, Stephen J; Tarbell, Kristin V; Mitre, Edward

    2011-01-01

    Leading hypotheses to explain helminth-mediated protection against autoimmunity postulate that type 2 or regulatory immune responses induced by helminth infections in the host limit pathogenic Th1-driven autoimmune responses. We tested these hypotheses by investigating whether infection with the filarial nematode Litomosoides sigmodontis prevents diabetes onset in IL-4-deficient nonobese diabetic (NOD) mice and whether depletion or absence of regulatory T cells, IL-10, or TGFβ alters helminth...

  8. Systemic Toll-like receptor stimulation suppresses experimental allergic asthma and autoimmune diabetes in NOD mice.

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    Aude Aumeunier

    Full Text Available BACKGROUND: Infections may be associated with exacerbation of allergic and autoimmune diseases. Paradoxically, epidemiological and experimental data have shown that some microorganisms can also prevent these pathologies. This observation is at the origin of the hygiene hypothesis according to which the decline of infections in western countries is at the origin of the increased incidence of both Th1-mediated autoimmune diseases and Th2-mediated allergic diseases over the last decades. We have tested whether Toll-like receptor (TLR stimulation can recapitulate the protective effect of infectious agents on allergy and autoimmunity. METHODS AND FINDINGS: Here, we performed a systematic study of the disease-modifying effects of a set of natural or synthetic TLR agonists using two experimental models, ovalbumin (OVA-induced asthma and spontaneous autoimmune diabetes, presenting the same genetic background of the non obese diabetic mouse (NOD that is highly susceptible to both pathologies. In the same models, we also investigated the effect of probiotics. Additionally, we examined the effect of the genetic invalidation of MyD88 on the development of allergic asthma and spontaneous diabetes. We demonstrate that multiple TLR agonists prevent from both allergy and autoimmunity when administered parenterally. Probiotics which stimulate TLRs also protect from these two diseases. The physiological relevance of these findings is further suggested by the major acceleration of OVA-induced asthma in MyD88 invalidated mice. Our results strongly indicate that the TLR-mediated effects involve immunoregulatory cytokines such as interleukin (IL-10 and transforming growth factor (TGF-beta and different subsets of regulatory T cells, notably CD4+CD25+FoxP3+ T cells for TLR4 agonists and NKT cells for TLR3 agonists. CONCLUSIONS/SIGNIFICANCE: These observations demonstrate that systemic administration of TLR ligands can suppress both allergic and autoimmune responses

  9. mt-Nd2a Modifies Resistance Against Autoimmune Type 1 Diabetes in NOD Mice at the Level of the Pancreatic β-Cell

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    Chen, Jing; Gusdon, Aaron M.; Piganelli, Jon; Leiter, Edward H.; Mathews, Clayton E

    2010-01-01

    OBJECTIVE To investigate whether a single nucleotide polymorphism (SNP) in the mitochondrial gene for NADH dehydrogenase 2 (mt-Nd2) can modulate susceptibility to type 1 diabetes in NOD mice. RESEARCH DESIGN AND METHODS NOD/ShiLtJ mice conplastic for the alloxan resistant (ALR)/Lt-derived mt-Nd2a allele (NOD.mtALR) were created and compared with standard NOD (carrying the mt-Nd2c allele) for susceptibility to spontaneous autoimmune diabetes, or to diabetes elicited by reciprocal adoptive sple...

  10. Effect of gluten-free diet on incidence of spontaneously developing autoimmune diabetes in NOD mice

    Czech Academy of Sciences Publication Activity Database

    Funda, David; Řeháková, Zuzana; Kozáková, Hana; Kaas, A.; Bock, T.; Buschard, K.; Štěpánková, Renata; Hrnčíř, Tomáš; Tučková, Ludmila

    Paříž, 2002. s. 53. [International Symposium On Coeliac Disease /10./. 02.06.2002-05.06.2002, Paříž] Institutional research plan: CEZ:AV0Z5020903 Keywords : gluten -free * diabetes * nod mice Subject RIV: EE - Microbiology, Virology

  11. Overexpression of thioredoxin in islets transduced by a lentiviral vector prolongs graft survival in autoimmune diabetic NOD mice

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    Sytwu Huey-Kang

    2009-08-01

    Full Text Available Abstract Pancreatic islet transplantation is considered an appropriate treatment to achieve insulin independence in type I diabetic patients. However, islet isolation and transplantation-induced oxidative stress and autoimmune-mediated destruction are still the major obstacles to the long-term survival of graft islets in this potential therapy. To protect islet grafts from inflammatory damage and prolong their survival, we transduced islets with an antioxidative gene thioredoxin (TRX using a lentiviral vector before transplantation. We hypothesized that the overexpression of TRX in islets would prolong islet graft survival when transplanted into diabetic non-obese diabetic (NOD mice. Methods Islets were isolated from NOD mice and transduced with lentivirus carrying TRX (Lt-TRX or enhanced green fluorescence protein (Lt-eGFP, respectively. Transduced islets were transplanted under the left kidney capsule of female diabetic NOD mice, and blood glucose concentration was monitored daily after transplantation. The histology of the islet graft was assessed at the end of the study. The protective effect of TRX on islets was investigated. Results The lentiviral vector effectively transduced islets without altering the glucose-stimulating insulin-secretory function of islets. Overexpression of TRX in islets reduced hydrogen peroxide-induced cytotoxicity in vitro. After transplantation into diabetic NOD mice, euglycemia was maintained for significantly longer in Lt-TRX-transduced islets than in Lt-eGFP-transduced islets; the mean graft survival was 18 vs. 6.5 days (n = 9 and 10, respectively, p Conclusion We successfully transduced the TRX gene into islets and demonstrated that these genetically modified grafts are resistant to inflammatory insult and survived longer in diabetic recipients. Our results further support the concept that the reactive oxygen species (ROS scavenger and antiapoptotic functions of TRX are critical to islet survival after

  12. Japanese herbal medicine TJ-48 prevents autoimmune diabetes in NOD mice.

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    Ikemoto, Tetsuya; Sugimoto, Koji; Takita, Morihito; Shimoda, Masayuki; Noguchi, Hirofumi; Naziruddin, Bashoo; Levy, Marlon F; Shimada, Mitsuo; Matsumoto, Shinichi

    2011-01-01

    Type 1 diabetes mellitus (T1DM) is mainly caused by CD8(+) cytotoxic T cell infiltration into islets. Recently, the role of regulatory T cells (Tregs) in the prevention of the onset of T1DM was reported. We reported that TJ-48, a common Japanese herbal medicine, decreased Treg population in cancer patients, thus we investigated whether TJ-48 had an influence on T1DM onset using NOD mice. In the TJ-48 group, TJ-48 (2.0g/kg/day) was administered in the drinking water for NOD mice from three weeks of age to 20 weeks of age. Their body weight and fast blood glucose (FBG) were measured every week. Histology (Hematoxylin-Eosin staining) was investigated every month. Lymphocyte profiles were investigated every month with FACS. The results were compared to the age-matched NOD mice control group. FBG of the control group mice showed diabetic status of 66.7% at 18 weeks of age. On the other hand, the TJ-48 group mice showed diabetic status of 16.7% at 18 weeks of age (p = 1.905E-06). There were no significant differences in general conditions or body weight between the two groups. Lymphocyte infiltrations into islets were dramatically suppressed in the TJ-48 group. The effect of TJ-48 on decreasing Tregs was less apparent in the NOD mice model. TJ-48 inhibited lymphocyte infiltrations into islets, which led to preventing the onset of T1DM in NOD mice. PMID:21721154

  13. Prevention of spontaneous autoimmune diabetes in NOD mice by transferring in vitro antigen-pulsed syngeneic dendritic cells

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    Papaccio, G; Nicoletti, F; Pisanti, F A; Bendtzen, K; Galdieri, M

    2000-01-01

    To evaluate the effect of antigen-pulsed dendritic cell (DC) transfer on the development of diabetes, 5-week-old female NOD mice received a single iv injection of splenic syngeneic DC from euglycemic NOD mice pulsed in vitro with human y globulin (HGG). Eleven of 12 mice were protected from the d...

  14. Linkage on chromosome 3 of autoimmune diabetes and defective Fc receptor for lgG in NOD mice

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    Prins, J.B.; Todd, J.A.; Rodrigues, N.R.; Ghosh, S. (Univ. of Oxford (United Kingdom)); Hogarth, P.M. (Austin Research Institute, Heidelberg (Australia)); Wicker, L.S.; Podolin, P.L.; Gaffney, E.; Peterson, L.B.; Fischer, P.A.; Sirotina, A. (Merck Research Laboratories, Rahway, NJ (United States))

    1993-04-30

    A congenic, non-obese diabetic (NOD) mouse strain that contains a segment of chromosome 3 from the diabetes-resistant mouse strain B6.PL-Thy-1[sup a] was less susceptible to diabetes than NOD mice. A fully penetrant immunological defect also mapped to this segment, which encodes the high-affinity Fc receptor for immunoglobulin G (lgG), Fc[gamma]Rl. The NOD Fcgr1 allele, which results in a deletion of the cytoplasmic tail, caused a 73 percent reduction in the turnover of cell surface receptor-antibody complexes. The development of congenic strains and the characterization of Mendelian traits that are specific to the disease phenotype demonstrate the feasibility of dissecting the pathophysiology of complex, non-Mendelian diseases.

  15. Imaging dynamics of CD11c+ cells and Foxp3+ cells in progressive autoimmune insulitis in the NOD mouse model of type 1 diabetes

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    Schmidt-Christensen, Anja; Hansen, Lisbeth; Ilegems, Erwin;

    2013-01-01

    Aims/hypothesis The aim of this study was to visualise the dynamics and interactions of the cells involved in autoimmune-driven inflammation in type 1 diabetes. Methods We adopted the anterior chamber of the eye (ACE) transplantation model to perform non-invasive imaging of leucocytes infiltrating...... that, in spite of the immune privileged status of the eye, the ACE-transplanted islets develop infiltration and beta cell destruction, recapitulating the autoimmune insulitis of the pancreas, and exemplify this by analysing reporter cell populations expressing green fluorescent protein under the Cd11c...... the endocrine pancreas during initiation and progression of insulitis in the NOD mouse. Individual, ACE-transplanted islets of Langerhans were longitudinally and repetitively imaged by stereomicroscopy and two-photon microscopy to follow fluorescently labelled leucocyte subsets. Results We demonstrate...

  16. CRISPR-Cas9-Mediated Modification of the NOD Mouse Genome With Ptpn22R619W Mutation Increases Autoimmune Diabetes.

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    Lin, Xiaotian; Pelletier, Stephane; Gingras, Sebastien; Rigaud, Stephanie; Maine, Christian J; Marquardt, Kristi; Dai, Yang D; Sauer, Karsten; Rodriguez, Alberto R; Martin, Greg; Kupriyanov, Sergey; Jiang, Ling; Yu, Liping; Green, Douglas R; Sherman, Linda A

    2016-08-01

    An allelic variant of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), PTPN22(R620W), is strongly associated with type 1 diabetes (T1D) in humans and increases the risk of T1D by two- to fourfold. The NOD mouse is a spontaneous T1D model that shares with humans many genetic pathways contributing to T1D. We hypothesized that the introduction of the murine orthologous Ptpn22(R619W) mutation to the NOD genome would enhance the spontaneous development of T1D. We microinjected CRISPR-Cas9 and a homology-directed repair template into NOD single-cell zygotes to introduce the Ptpn22(R619W) mutation to its endogenous locus. The resulting Ptpn22(R619W) mice showed increased insulin autoantibodies and earlier onset and higher penetrance of T1D. This is the first report demonstrating enhanced T1D in a mouse modeling human PTPN22(R620W) and the utility of CRISPR-Cas9 for direct genetic alternation of NOD mice. PMID:27207523

  17. Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade

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    Ablamunits, Vitaly; Henegariu, Octavian; Hansen, Jakob Bondo;

    2012-01-01

    Inflammatory cytokines are involved in autoimmune diabetes: among the most prominent is interleukin (IL)-1ß. We postulated that blockade of IL-1ß would modulate the effects of anti-CD3 monoclonal antibody (mAb) in treating diabetes in NOD mice. To test this, we treated hyperglycemic NOD mice with...

  18. Expression of genetically determined diabetes and insulitis in the nonobese diabetic (NOD) mouse at the level of bone marrow-derived cells. Transfer of diabetes and insulitis to nondiabetic (NOD X B10) F1 mice with bone marrow cells from NOD mice

    International Nuclear Information System (INIS)

    The development of autoimmune diabetes in the nonobese diabetic (NOD) mouse is controlled by at least three recessive loci, including one linked to the MHC. To determine whether any of these genetic loci exert their effects via the immune system, radiation bone marrow chimeras were constructed in which (NOD X B10)F1-irradiated recipients were reconstituted with NOD bone marrow cells. Unmanipulated (NOD X B10)F1 mice, or irradiated F1 mice reconstituted with F1 or B10 bone marrow, did not display insulitis or diabetes. In contrast, insulitis was observed in a majority of the NOD----F1 chimeras and diabetes developed in 21% of the mice. These data demonstrate that expression of the diabetic phenotype in the NOD mouse is dependent on NOD-derived hematopoietic stem cells. Diabetogenic genes in the NOD mouse do not appear to function at the level of the insulin-producing beta cells since NOD----F1 chimeras not only developed insulitis and diabetes but also rejected beta cells within pancreas transplants from newborn B10 mice. These data suggest that the beta cells of the NOD mouse do not express a unique antigenic determinant that is the target of the autoimmune response

  19. Bioluminescence Imaging Reveals Dynamics of Beta Cell Loss in the Non-Obese Diabetic (NOD) Mouse Model

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    John Virostko; Armandla Radhika; Greg Poffenberger; Dula, Adrienne N.; Moore, Daniel J.; Alvin C Powers

    2013-01-01

    We generated a mouse model (MIP-Luc-VU-NOD) that enables non-invasive bioluminescence imaging (BLI) of beta cell loss during the progression of autoimmune diabetes and determined the relationship between BLI and disease progression. MIP-Luc-VU-NOD mice displayed insulitis and a decline in bioluminescence with age which correlated with beta cell mass, plasma insulin, and pancreatic insulin content. Bioluminescence declined gradually in female MIP-Luc-VU-NOD mice, reaching less than 50% of the ...

  20. Gangliosides and autoimmune diabetes.

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    Misasi, R; Dionisi, S; Farilla, L; Carabba, B; Lenti, L; Di Mario, U; Dotta, F

    1997-09-01

    -dependent (type 1) diabetes mellitus. This last disease is caused by the autoimmune destruction of insulin-producing pancreatic islet cells in genetically predisposed individuals. Autoantibodies and T lymphocytes directed towards multiple islet autoantigens have been detected in the circulation, well before the clinical onset of the disease, in a prodromal phase during which pancreatic islet beta-cells are presumably destroyed. Among the target autoantigens, some are of protein nature but others are acidic glycolipids such as sulphatides158 and the gangliosides GT3, GD3 and especially GM2-1. This last component is specifically expressed in pancreatic islets and has been shown to represent a target of IgG autoantibodies highly associated with diabetes development in first-degree relatives of type 1 diabetic individuals. In addition, the GM2-1 ganglioside appears to be one of the antigens recognized by cytoplasmic ICA, a heterogeneous group of antibodies which specifically react with islets on pancreatic frozen sections. In conclusion, studies performed in the last decade have clearly indicated that gangliosides represent a heterogeneous class of molecules that are involved in several cellular processes that are of crucial importance in physiological as well as in pathological conditions. Interestingly, these molecules, despite their small size, have been shown to represent not only important antigens in tumour immunology but are also able to elicit a specific autoimmune response, thus representing important autoantigens in some autoimmune disorders. It is of interest that, in addition to neurological autoimmune disorders where autoimmunity to gangliosides is frequent and usually of considerable magnitude, an autoimmune response to this class of molecules has been observed in autoimmune diabetes. (ABSTRACT TRUNCATED) PMID:9307889

  1. Gestational Diabetes and Thyroid Autoimmunity

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    Fabrizio Monaco; Giorgio Napolitano; Cesidio Giuliani; Ester Vitacolonna; Ines Bucci; Barbara Di Nenno; Annalisa Passante; Annunziata Lapolla; Dominique Cerrone; Fabio Capani

    2012-01-01

    Background. About 10% of pregnancies are complicated by previously unknown impairment of glucose metabolism, which is defined as gestational diabetes. There are little data available on prevalence of thyroid disorders in patients affected by gestational diabetes, and about their postgestational thyroid function and autoimmunity. We therefore investigated pancreatic and thyroid autoimmunity in gestational diabetic patients and in women who had had a previous gestational diabetic pregnancy. Met...

  2. The nonconventional MHC class II molecule DM governs diabetes susceptibility in NOD mice.

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    Marc A J Morgan

    Full Text Available The spontaneous destruction of insulin producing pancreatic beta cells in non-obese diabetic (NOD mice provides a valuable model of type 1 diabetes. As in humans, disease susceptibility is controlled by the classical MHC class II genes that guide CD4(+ T cell responses to self and foreign antigens. It has long been suspected that the dedicated class II chaperone designated HLA-DM in humans or H-2M in mice also makes an important contribution, but due to tight linkage within the MHC, a possible role played by DM peptide editing has not been previously tested by conventional genetic approaches. Here we exploited newly established germ-line competent NOD ES cells to engineer a loss of function allele. DM deficient NOD mice display defective class II peptide occupancy and surface expression, and are completely protected against type 1 diabetes. Interestingly the mutation results in increased proportional representation of CD4(+Foxp3(+ regulatory T cells and the absence of pathogenic CD4(+ T effectors. Overall, this striking phenotype establishes that DM-mediated peptide selection plays an essential role in the development of autoimmune diabetes in NOD mice.

  3. Type 1 diabetes associated autoimmunity.

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    Kahaly, George J; Hansen, Martin P

    2016-07-01

    Diabetes mellitus is increasing in prevalence worldwide. The economic costs are considerable given the cardiovascular complications and co-morbidities that it may entail. Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the loss of insulin-producing pancreatic β-cells. The pathogenesis of T1D is complex and multifactorial and involves a genetic susceptibility that predisposes to abnormal immune responses in the presence of ill-defined environmental insults to the pancreatic islets. Genetic background may affect the risk for autoimmune disease and patients with T1D exhibit an increased risk of other autoimmune disorders such as autoimmune thyroid disease, Addison's disease, autoimmune gastritis, coeliac disease and vitiligo. Approximately 20%-25% of patients with T1D have thyroid antibodies, and up to 50% of such patients progress to clinical autoimmune thyroid disease. Approximately 0.5% of diabetic patients have concomitant Addison's disease and 4% have coeliac disease. The prevalence of autoimmune gastritis and pernicious anemia is 5% to 10% and 2.6% to 4%, respectively. Early detection of antibodies and latent organ-specific dysfunction is advocated to alert physicians to take appropriate action in order to prevent full-blown disease. Patients and family members should be educated to be able to recognize signs and symptoms of underlying disease. PMID:26903475

  4. Gene therapy with neurogenin3, betacellulin and SOCS1 reverses diabetes in NOD mice.

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    Li, R; Buras, E; Lee, J; Liu, R; Liu, V; Espiritu, C; Ozer, K; Thompson, B; Nally, L; Yuan, G; Oka, K; Chang, B; Samson, S; Yechoor, V; Chan, L

    2015-11-01

    Islet transplantation for type 1 diabetes is limited by a shortage of donor islets and requirement for immunosuppression. We approached this problem by inducing in vivo islet neogenesis in non-obese diabetic (NOD) diabetic mice, a model of autoimmune diabetes. We demonstrate that gene therapy with helper-dependent adenovirus carrying neurogenin3 (Ngn3), an islet lineage-defining transcription factor, and betacellulin (Btc), an islet growth factor, leads to the induction of periportal insulin-positive cell clusters in the liver, which are rapidly destroyed. To specifically accord protection to these 'neo-islets' from cytokine-mediated destruction, we overexpressed suppressor of cytokine signaling 1 (SOCS1) gene, using a rat insulin promoter in combination with Ngn3 and Btc. With this approach, about half of diabetic mice attained euglycemia sustained for over 4 months, regain glucose tolerance and appropriate glucose-stimulated insulin secretion. Histological analysis revealed periportal islet hormone-expressing 'neo-islets' in treated mouse livers. Despite evidence of persistent 'insulitis' with activated T cells, these 'neo-islets' persist to maintain euglycemia. This therapy does not affect diabetogenicity of splenocytes, as they retain the ability to transfer diabetes. This study thus provides a proof-of-concept for engineering in vivo islet neogenesis with targeted resistance to cytokine-mediated destruction to provide a long-term reversal of diabetes in NOD mice. PMID:26172077

  5. Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes

    International Nuclear Information System (INIS)

    Type 1 diabetes mellitus (T1DM) is an autoimmune disease leading to near complete pancreatic β-cell destruction. New evidence suggests that β-cell regeneration is possible, but ongoing autoimmune damage prevents restoration of β-cell mass. We tested the hypothesis that simultaneously blocking autoimmune cytokine damage and supplying a growth-promoting stimulus for β-cells would provide a novel approach to reverse T1DM. Therefore, in this study we combined lisofylline to suppress autoimmunity and exendin-4 to enhance β-cell proliferation for treating autoimmune-mediated diabetes in the non-obese diabetic (NOD) mouse model. We found that this combined therapy effectively reversed new-onset diabetes within a week of therapy, and even maintained euglycemia up to 145 days after treatment withdrawal. The therapeutic effect of this regimen was associated with improved β-cell metabolism and insulin secretion, while reducing β-cell apoptosis. It is possible that such combined therapy could become a new strategy to defeat T1DM in humans

  6. Gene therapy with Neurogenin3, Betacellulin and SOCS-1 Reverses Diabetes in NOD Mice

    Science.gov (United States)

    Li, Rongying; Buras, Eric; Lee, Jeongkyung; Liu, Ruya; Liu, Victoria; Espiritu, Christie; Ozer, Kerem; Thompson, Bonnie; Nally, Laura; Yuan, Guoyue; Oka, Kazuhiro; Chang, Benny; Samson, Susan; Yechoor, Vijay; Chan, Lawrence

    2015-01-01

    Islet transplantation for Type 1 diabetes is limited by a shortage of donor islets and requirement for immunosuppression. We approached this problem by inducing in vivo islet neogenesis in NOD diabetic mice, a model of autoimmune diabetes. We demonstrate that gene therapy with helper-dependent adenovirus (HDAd) carrying neurogenin3, an islet lineage-defining transcription factor and betacellulin, an islet growth factor, leads to the induction of periportal insulin-positive cell clusters in the liver, which are rapidly destroyed. To specifically accord protection to these ‘neo-islets’ from cytokine-mediated destruction, we overexpressed suppressor of cytokine signaling 1 (SOCS1) gene, using a rat insulin promoter in combination with neurogenin3 and betacellulin. With this approach, about half of diabetic mice attained euglycemia sustained for over 4 months, regain glucose tolerance and appropriate glucose-stimulated insulin secretion. Histological analysis revealed periportal islet hormone-expressing ‘neo-islets’ in treated mouse livers. Despite evidence of persistent ‘insulitis’ with activated T-cells, these ‘neo-islets’ persist to maintain euglycemia. This therapy does not affect diabetogenicity of splenocytes, as they retain the ability to transfer diabetes. This study thus provides a proof-of-concept for engineering in vivo islet neogenesis with targeted resistance to cytokine-mediated destruction to provide a long-term reversal of diabetes in NOD mice. PMID:26172077

  7. Genetic architecture of early pre-inflammatory stage transcription signatures of autoimmune diabetes in the pancreatic lymph nodes of the NOD mouse reveals significant gene enrichment on chromosomes 6 and 7

    Directory of Open Access Journals (Sweden)

    Beatrice Regnault

    2015-12-01

    Full Text Available Autoimmune diseases are characterized by the stimulation of an excessive immune response to self-tissues by inner and/or outer organism factors. Common characteristics in their etiology include a complex genetic predisposition and environmental triggers as well as the implication of the major histocompatibility (MHC locus on human chromosome 6p21. A restraint number of non-MHC susceptibility genes, part of the genetic component of type 1 diabetes have been identified in human and in animal models, while the complete spectrum of genes involved remains unknown. We elaborate herein patterns of chromosomal organization of 162 genes differentially expressed in the pancreatic lymph nodes of Non-Obese Diabetic mice, carefully selected by early sub-phenotypic evaluation (presence or absence of insulin autoantibodies. Chromosomal assignment of these genes revealed a non-random distribution on five chromosomes (47%. Significant gene enrichment was observed in particular for two chromosomes, 6 and 7. While a subset of these genes coding for secreted proteins showed significant enrichment on both chromosomes, the overall pool of genes was significantly enriched on chromosome 7. The significance of this unexpected gene distribution on the mouse genome is discussed in the light of novel findings indicating that genes affecting common diseases map to recombination “hotspot” regions of mammalian genomes. The genetic architecture of transcripts differentially expressed in specific stages of autoimmune diabetes offers novel venues towards our understanding of patterns of inheritance potentially affecting the pathological disease mechanisms.

  8. Pancreatic β-Cells Limit Autoimmune Diabetes via an Immunoregulatory Antimicrobial Peptide Expressed under the Influence of the Gut Microbiota.

    Science.gov (United States)

    Sun, Jia; Furio, Laetitia; Mecheri, Ramine; van der Does, Anne M; Lundeberg, Erik; Saveanu, Loredana; Chen, Yongquan; van Endert, Peter; Agerberth, Birgitta; Diana, Julien

    2015-08-18

    Antimicrobial peptides (AMPs) expressed by epithelial and immune cells are largely described for the defense against invading microorganisms. Recently, their immunomodulatory functions have been highlighted in various contexts. However how AMPs expressed by non-immune cells might influence autoimmune responses in peripheral tissues, such as the pancreas, is unknown. Here, we found that insulin-secreting β-cells produced the cathelicidin related antimicrobial peptide (CRAMP) and that this production was defective in non-obese diabetic (NOD) mice. CRAMP administrated to prediabetic NOD mice induced regulatory immune cells in the pancreatic islets, dampening the incidence of autoimmune diabetes. Additional investigation revealed that the production of CRAMP by β-cells was controlled by short-chain fatty acids produced by the gut microbiota. Accordingly, gut microbiota manipulations in NOD mice modulated CRAMP production and inflammation in the pancreatic islets, revealing that the gut microbiota directly shape the pancreatic immune environment and autoimmune diabetes development. PMID:26253786

  9. Autoimmune Diabetes: An Overview of Experimental Models and Novel Therapeutics.

    Science.gov (United States)

    You, Sylvaine; Chatenoud, Lucienne

    2016-01-01

    Type 1 diabetes (T1D) results from a chronic and selective destruction of insulin-secreting β-cells within the islets of Langerhans of the pancreas by autoreactive CD4(+) and CD8(+) T lymphocytes. The use of animal models of T1D was instrumental for deciphering the steps of the autoimmune process leading to T1D. The non-obese diabetic (NOD) mouse and the bio-breeding (BB) rat spontaneously develop the disease similar to the human pathology in terms of the immune responses triggering autoimmune diabetes and of the genetic and environmental factors influencing disease susceptibility. The generation of genetically modified models allowed refining our understanding of the etiology and the pathogenesis of the disease. In the present review, we provide an overview of the experimental models generated and used to gain knowledge on the molecular and cellular mechanisms underlying the breakdown of self-tolerance in T1D and the progression of the autoimmune response. Immunotherapeutic interventions designed in these animal models and translated into the clinical arena in T1D patients will also be discussed. PMID:26530798

  10. [Autoimmune diseases in type 1 diabetes].

    Science.gov (United States)

    Lechleitner, Monika; Hoppichler, Friedrich; Kaser, Susanne

    2016-04-01

    According to literature about 30 % of the patients with type 1 diabetes develop further autoimmune diseases. Thyroid dysfunction represents with 15‒30 % the most common disorder, followed by gastritis with 5‒10 %, celiac disease with 4‒9 % and vitiligo with 2‒10 %. Addison's disease seems to be less prevalent. Diagnostic procedures in the course of the comprehensive care for diabetic patients should therefore include screening for further autoimmune diseases. PMID:27052247

  11. Combination of worm antigen and proinsulin prevents type 1 diabetes in NOD mice after the onset of insulitis.

    Science.gov (United States)

    Ajendra, Jesuthas; Berbudi, Afiat; Hoerauf, Achim; Hübner, Marc P

    2016-03-01

    Animal studies demonstrated that administration of helminth products can protect from autoimmune diseases. However, the success of such administrations is limited in the case of type 1 diabetes, as protection is only provided if the administration is started before the development of insulitis. In this study we investigated whether inclusion of helminth antigen administrations to an antigen-specific treatment with proinsulin improves the protective effect by triggering non-specific regulatory immune responses. Using a combination therapy of intraperitoneal Litomosoides sigmodontis antigen and intranasal pro-insulin, onset of diabetes was prevented in NOD mice after insulitis started, while either administration alone failed to protect. This protection was associated with an increased frequency of regulatory T cells within the pancreatic lymph nodes and a reduced inflammation of the pancreatic islets. This suggests that inclusion of helminth antigens improve the protective effect provided by antigen-specific therapies and represent a new potential therapeutic approach against autoimmune diseases. PMID:26898311

  12. The Effects of Alpha Interferon on the Development of Autoimmune Thyroiditis in the NOD H2h4 Mouse

    Directory of Open Access Journals (Sweden)

    Yael Oppenheim

    2003-01-01

    Full Text Available Alpha interferon (αIFN therapy is known to induce thyroid autoimmunity in up to 40% of patients. The mechanism is unknown, but Th1 switching has been hypothesized. The aim of our study was to examine whether αIFN accelerated the development of thyroiditis in genetically susceptible mice. We took advantage of NOD-H2h4, a genetically susceptible animal model, which develops thyroiditis when fed a high iodine diet. Six to eight week old male NOD H2h4 mice were injected with mouse αIFN (200 units or with saline three times a week for 8 weeks. All mice drank iodinated water (0.15%. Mice were sacrificed after 8 weeks of injection. Their thyroids were examined for histology and blood was tested for antithyroglobulin antibody levels. T4 and glucose levels were also assessed. In the IFN-injected group, 6/13 (46.2% developed thyroiditis and/or thyroid antibodies while in the saline-injected group, only 4/13 (30.8% developed thyroiditis and/or thyroid antibodies (p=0.4. The grade of thyroiditis was not different amongst the two groups. None of the mice developed clinical thyroiditis or diabetes mellitus. Our results showed that αIFN treatment did not accelerate thyroiditis in this mouse model. This may imply that αIFN induces thyroiditis in a non-genetically dependent manner, and this would not be detected in a genetically susceptible mouse model if the effect were small. Alternatively, it is possible that αIFN did not induce thyroiditis in mice because, unlike in humans, in mice αIFN does not induce Th1 switching.

  13. Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice.

    Science.gov (United States)

    Brown, Kirsty; Godovannyi, Artem; Ma, Caixia; Zhang, YiQun; Ahmadi-Vand, Zahra; Dai, Chaunbin; Gorzelak, Monika A; Chan, YeeKwan; Chan, Justin M; Lochner, Arion; Dutz, Jan P; Vallance, Bruce A; Gibson, Deanna L

    2016-02-01

    Accumulating evidence supports that the intestinal microbiome is involved in Type 1 diabetes (T1D) pathogenesis through the gut-pancreas nexus. Our aim was to determine whether the intestinal microbiota in the non-obese diabetic (NOD) mouse model played a role in T1D through the gut. To examine the effect of the intestinal microbiota on T1D onset, we manipulated gut microbes by: (1) the fecal transplantation between non-obese diabetic (NOD) and resistant (NOR) mice and (2) the oral antibiotic and probiotic treatment of NOD mice. We monitored diabetes onset, quantified CD4+T cells in the Peyer's patches, profiled the microbiome and measured fecal short-chain fatty acids (SCFA). The gut microbiota from NOD mice harbored more pathobionts and fewer beneficial microbes in comparison with NOR mice. Fecal transplantation of NOD microbes induced insulitis in NOR hosts suggesting that the NOD microbiome is diabetogenic. Moreover, antibiotic exposure accelerated diabetes onset in NOD mice accompanied by increased T-helper type 1 (Th1) and reduced Th17 cells in the intestinal lymphoid tissues. The diabetogenic microbiome was characterized by a metagenome altered in several metabolic gene clusters. Furthermore, diabetes susceptibility correlated with reduced fecal SCFAs. In an attempt to correct the diabetogenic microbiome, we administered VLS#3 probiotics to NOD mice but found that VSL#3 colonized the intestine poorly and did not delay diabetes. We conclude that NOD mice harbor gut microbes that induce diabetes and that their diabetogenic microbiome can be amplified early in life through antibiotic exposure. Protective microbes like VSL#3 are insufficient to overcome the effects of a diabetogenic microbiome. PMID:26274050

  14. Daintain/AIF-1 (Allograft Inflammatory Factor-1) accelerates type 1 diabetes in NOD mice

    International Nuclear Information System (INIS)

    Highlights: ► Daintain/AIF-1 is over-expressed in the blood of NOD mice suffering from insulitis. ► Daintain/AIF-1 stimulates white blood cell proliferation in NOD mice. ► Daintain/AIF-1 increases blood glucose levels and triggers type 1 diabetes. ► Daintain/AIF-1 accelerates insulitis, while its antibody prevents insulitis. ► Daintain/AIF-1 enhances the levels of nitric oxide in the pancreases of NOD mice. -- Abstract: A large body of experimental evidence suggests that cytokines trigger pancreatic β-cell death in type 1 diabetes mellitus. Daintain/AIF-1 (Allograft Inflammatory Factor-1), a specific marker for activated macrophages, is accumulated in the pancreatic islets of pre-diabetic BB rats. In the present study, we demonstrate that daintain/AIF-1 is released into blood and the levels of daintain/AIF-1 in the blood of type 1 diabetes-prone non-obese diabetic (NOD) mice suffering from insulitis are significantly higher than that in healthy NOD mice. When injected intravenously into NOD mice, daintain/AIF-1 stimulates white blood cell proliferation, increases the concentrations of blood glucose, impairs insulin expression, up-regulates nitric oxide (NO) production in pancreases and accelerates diabetes in NOD mice, while the antibody against daintain/AIF-1 delays or prevents insulitis in NOD mice. These results imply daintain/AIF-1 triggers type 1 diabetes probably via arousing immune cells activation and induction of NO production in pancreas of NOD mice.

  15. Daintain/AIF-1 (Allograft Inflammatory Factor-1) accelerates type 1 diabetes in NOD mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yan-Ying, E-mail: biozyy@163.com [College of Life Science and Technology, Southwest University for Nationalities, Chengdu 610041 (China); Huang, Xin-Yuan [College of Life Science and Technology, Hubei Engineering University, Xiaogan 432000 (China); Chen, Zheng-Wang [Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074 (China)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer Daintain/AIF-1 is over-expressed in the blood of NOD mice suffering from insulitis. Black-Right-Pointing-Pointer Daintain/AIF-1 stimulates white blood cell proliferation in NOD mice. Black-Right-Pointing-Pointer Daintain/AIF-1 increases blood glucose levels and triggers type 1 diabetes. Black-Right-Pointing-Pointer Daintain/AIF-1 accelerates insulitis, while its antibody prevents insulitis. Black-Right-Pointing-Pointer Daintain/AIF-1 enhances the levels of nitric oxide in the pancreases of NOD mice. -- Abstract: A large body of experimental evidence suggests that cytokines trigger pancreatic {beta}-cell death in type 1 diabetes mellitus. Daintain/AIF-1 (Allograft Inflammatory Factor-1), a specific marker for activated macrophages, is accumulated in the pancreatic islets of pre-diabetic BB rats. In the present study, we demonstrate that daintain/AIF-1 is released into blood and the levels of daintain/AIF-1 in the blood of type 1 diabetes-prone non-obese diabetic (NOD) mice suffering from insulitis are significantly higher than that in healthy NOD mice. When injected intravenously into NOD mice, daintain/AIF-1 stimulates white blood cell proliferation, increases the concentrations of blood glucose, impairs insulin expression, up-regulates nitric oxide (NO) production in pancreases and accelerates diabetes in NOD mice, while the antibody against daintain/AIF-1 delays or prevents insulitis in NOD mice. These results imply daintain/AIF-1 triggers type 1 diabetes probably via arousing immune cells activation and induction of NO production in pancreas of NOD mice.

  16. Latent autoimmune diabetes of the adult: current knowledge and uncertainty

    OpenAIRE

    Laugesen, E; Østergaard, J A; Leslie, R D G

    2015-01-01

    Patients with adult-onset autoimmune diabetes have less Human Leucocyte Antigen (HLA)-associated genetic risk and fewer diabetes-associated autoantibodies compared with patients with childhood-onset Type 1 diabetes. Metabolic changes at diagnosis reflect a broad clinical phenotype ranging from diabetic ketoacidosis to mild non-insulin-requiring diabetes, also known as latent autoimmune diabetes of the adult (LADA). This latter phenotype is the most prevalent form of adult-onset autoimmune dia...

  17. Identification of Candidate Tolerogenic CD8+ T Cell Epitopes for Therapy of Type 1 Diabetes in the NOD Mouse Model

    Directory of Open Access Journals (Sweden)

    Cailin Yu

    2016-01-01

    Full Text Available Type 1 diabetes is an autoimmune disease in which insulin-producing pancreatic islet β cells are the target of self-reactive B and T cells. T cells reactive with epitopes derived from insulin and/or IGRP are critical for the initiation and maintenance of disease, but T cells reactive with other islet antigens likely have an essential role in disease progression. We sought to identify candidate CD8+ T cell epitopes that are pathogenic in type 1 diabetes. Proteins that elicit autoantibodies in human type 1 diabetes were analyzed by predictive algorithms for candidate epitopes. Using several different tolerizing regimes using synthetic peptides, two new predicted tolerogenic CD8+ T cell epitopes were identified in the murine homolog of the major human islet autoantigen zinc transporter ZnT8 (aa 158–166 and 282–290 and one in a non-β cell protein, dopamine β-hydroxylase (aa 233–241. Tolerizing vaccination of NOD mice with a cDNA plasmid expressing full-length proinsulin prevented diabetes, whereas plasmids encoding ZnT8 and DβH did not. However, tolerizing vaccination of NOD mice with the proinsulin plasmid in combination with plasmids expressing ZnT8 and DβH decreased insulitis and enhanced prevention of disease compared to vaccination with the plasmid encoding proinsulin alone.

  18. Identification of Candidate Tolerogenic CD8+ T Cell Epitopes for Therapy of Type 1 Diabetes in the NOD Mouse Model

    Science.gov (United States)

    Yu, Cailin; Burns, Jeremy C.; Robinson, William H.; Utz, Paul J.; Ho, Peggy P.; Steinman, Lawrence; Frey, Alan B.

    2016-01-01

    Type 1 diabetes is an autoimmune disease in which insulin-producing pancreatic islet β cells are the target of self-reactive B and T cells. T cells reactive with epitopes derived from insulin and/or IGRP are critical for the initiation and maintenance of disease, but T cells reactive with other islet antigens likely have an essential role in disease progression. We sought to identify candidate CD8+ T cell epitopes that are pathogenic in type 1 diabetes. Proteins that elicit autoantibodies in human type 1 diabetes were analyzed by predictive algorithms for candidate epitopes. Using several different tolerizing regimes using synthetic peptides, two new predicted tolerogenic CD8+ T cell epitopes were identified in the murine homolog of the major human islet autoantigen zinc transporter ZnT8 (aa 158–166 and 282–290) and one in a non-β cell protein, dopamine β-hydroxylase (aa 233–241). Tolerizing vaccination of NOD mice with a cDNA plasmid expressing full-length proinsulin prevented diabetes, whereas plasmids encoding ZnT8 and DβH did not. However, tolerizing vaccination of NOD mice with the proinsulin plasmid in combination with plasmids expressing ZnT8 and DβH decreased insulitis and enhanced prevention of disease compared to vaccination with the plasmid encoding proinsulin alone. PMID:27069933

  19. Use of autoantigen-loaded phosphatidylserine-liposomes to arrest autoimmunity in type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Irma Pujol-Autonell

    Full Text Available The development of new therapies to induce self-tolerance has been an important medical health challenge in type 1 diabetes. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow β-cell regeneration. Based on the immunomodulatory effects of apoptosis, we hypothesized that apoptotic mimicry can help to restore tolerance lost in autoimmune diabetes.To generate a synthetic antigen-specific immunotherapy based on apoptosis features to specifically reestablish tolerance to β-cells in type 1 diabetes.A central event on the surface of apoptotic cells is the exposure of phosphatidylserine, which provides the main signal for efferocytosis. Therefore, phosphatidylserine-liposomes loaded with insulin peptides were generated to simulate apoptotic cells recognition by antigen presenting cells. The effect of antigen-specific phosphatidylserine-liposomes in the reestablishment of peripheral tolerance was assessed in NOD mice, the spontaneous model of autoimmune diabetes. MHC class II-peptide tetramers were used to analyze the T cell specific response after treatment with phosphatidylserine-liposomes loaded with peptides.We have shown that phosphatidylserine-liposomes loaded with insulin peptides induce tolerogenic dendritic cells and impair autoreactive T cell proliferation. When administered to NOD mice, liposome signal was detected in the pancreas and draining lymph nodes. This immunotherapy arrests the autoimmune aggression, reduces the severity of insulitis and prevents type 1 diabetes by apoptotic mimicry. MHC class II tetramer analysis showed that peptide-loaded phosphatidylserine-liposomes expand antigen-specific CD4+ T cells in vivo. The administration of phosphatidylserine-free liposomes emphasizes the importance of phosphatidylserine in the modulation of antigen-specific CD4+ T cell expansion.We conclude that this innovative immunotherapy based on the use of liposomes constitutes a promising strategy for

  20. 1,25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes

    Science.gov (United States)

    Casteels, K; Waer, M; Bouillon, R; Depovere, J; Valckx, D; Laureys, J; Mathieu, C

    1998-01-01

    The activated form of vitamin D, 1,25(OH)2D3, and its analogues can prevent type I diabetes in NOD mice. Protection is achieved without signs of systemic immunosuppression and is associated with a restoration of the defective immune regulator system of the NOD mice. The aim of the present study was to investigate whether this restoration of regulator cell function is the only mechanism in the prevention of diabetes by 1,25(OH)2D3. We tested therefore if 1,25(OH)2D3 could prevent cyclophosphamide-induced diabetes, since diabetes occurring after cyclophosphamide injection is believed to be due to an elimination of suppresser cells. NOD mice treated with 1,25(OH)2D3 (5 μg/kg every 2 days) from the time of weaning were clearly protected against diabetes induced by cyclophosphamide (200 mg/kg body wt at 70 days old) (2/12 (17%) versus 36/53 (68%) in control mice, P < 0.005). By co-transfer experiments it was demonstrated that cyclophosphamide had indeed eliminated the suppresser cells present in 1,25(OH)2D3-treated mice. Since cyclophosphamide injection did not break the protection offered by 1,25(OH)2D3, it was clear that diabetogenic effector cells were affected by 1,25(OH)2D3 treatment as well. This was confirmed by the finding that splenocytes from 1,25(OH)2D3-treated mice were less capable of transferring diabetes in young, irradiated NOD mice, and by the demonstration of lower Th1 cytokine levels in the pancreases of 1,25(OH)2D3-treated, cyclophosphamide-injected mice. This better elimination of effector cells in 1,25(OH)2D3-treated mice could be explained by a restoration of the sensitivity to cyclophosphamide-induced apoptosis in both thymocytes and splenocytes, in normally apoptosis-resistant NOD mice. Altogether, these data indicate that the protection against diabetes offered by 1,25(OH)2D3 may be independent of the presence of suppresser cells, and may involve increased apoptosis of Th1 autoimmune effector cells. PMID:9649179

  1. HLA-A2–Matched Peripheral Blood Mononuclear Cells From Type 1 Diabetic Patients, but Not Nondiabetic Donors, Transfer Insulitis to NOD-scid/γcnull/HLA-A2 Transgenic Mice Concurrent With the Expansion of Islet-Specific CD8+ T cells

    OpenAIRE

    Whitfield-Larry, Fatima; Young, Ellen F.; Talmage, Garrick; Fudge, Elizabeth; Azam, Anita; Patel, Shipra; Largay, Joseph; Byrd, Warren; Buse, John; Calikoglu, Ali S.; Shultz, Leonard D.; Frelinger, Jeffrey A.

    2011-01-01

    OBJECTIVE Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing β-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human ef...

  2. Prevention of early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice

    Czech Academy of Sciences Publication Activity Database

    Funda, David; Fundová, Petra; Hansen, A. K.; Buschard, K.

    2014-01-01

    Roč. 9, č. 4 (2014). E-ISSN 1932-6203 R&D Projects: GA ČR GA310/09/1640; GA MZd(CZ) NS10340 Institutional support: RVO:61388971 Keywords : gliadin * diabetes * diabetes 1 type * NOD mice Subject RIV: EC - Immunology Impact factor: 3.234, year: 2014

  3. Early over expression of messenger RNA for multiple genes, including insulin, in the Pancreatic Lymph Nodes of NOD mice is associated with Islet Autoimmunity

    Directory of Open Access Journals (Sweden)

    Eisenbarth George

    2009-10-01

    Full Text Available Abstract Background Autoimmune diabetes (T1D onset is preceded by a long inflammatory process directed against the insulin-secreting β cells of the pancreas. Deciphering the early autoimmune mechanisms represents a challenge due to the absence of clinical signs at early disease stages. The aim of this study was to identify genes implicated in the early steps of the autoimmune process, prior to inflammation, in T1D. We have previously established that insulin autoantibodies (E-IAA predict early diabetes onset delineating an early phenotypic check point (window 1 in disease pathogenesis. We used this sub-phenotype and applied differential gene expression analysis in the pancreatic lymph nodes (PLN of 5 weeks old Non Obese Diabetic (NOD mice differing solely upon the presence or absence of E-IAA. Analysis of gene expression profiles has the potential to provide a global understanding of the disease and to generate novel hypothesis concerning the initiation of the autoimmune process. Methods Animals have been screened weekly for the presence of E-IAA between 3 and 5 weeks of age. E-IAA positive or negative NOD mice at least twice were selected and RNAs isolated from the PLN were used for microarray analysis. Comparison of transcriptional profiles between positive and negative animals and functional annotations of the resulting differentially expressed genes, using software together with manual literature data mining, have been performed. Results The expression of 165 genes was modulated between E-IAA positive and negative PLN. In particular, genes coding for insulin and for proteins known to be implicated in tissue remodelling and Th1 immunity have been found to be highly differentially expressed. Forty one genes showed over 5 fold differences between the two sets of samples and 30 code for extracellular proteins. This class of proteins represents potential diagnostic markers and drug targets for T1D. Conclusion Our data strongly suggest that the

  4. Acceleration of type 1 diabetes mellitus in proinsulin 2–deficient NOD mice

    OpenAIRE

    Thébault-Baumont, Karine; Dubois-Laforgue, Danielle; Krief, Patricia; Briand, Jean-Paul; Halbout, Philippe; Vallon-Geoffroy, Karine; Morin, Joëlle; Laloux, Véronique; Lehuen, Agnès; Carel, Jean-Claude; Jami, Jacques; Muller, Sylviane; Boitard, Christian

    2003-01-01

    Accumulating evidence favors a role for proinsulin as a key autoantigen in diabetes. In the mouse, two proinsulin isoforms coexist. Most studies point to proinsulin 2 as the major isoform recognized by T cells in the NOD mouse. We studied mice in which a null proinsulin 2 mutation was transferred from proinsulin 2–deficient 129 mice onto the NOD background along with 16 genetic markers (including I-Ag7 MHC molecule) associated with diabetes. Intercross mice from the fourth backcross generatio...

  5. Antigen-Experienced CD4lo T Cells Are Linked to Deficient Contraction of the Immune Response in Autoimmune Diabetes

    Directory of Open Access Journals (Sweden)

    Sean Linkes

    2010-01-01

    Full Text Available Following proper activation, naïve “CD4lo” T cells differentiate into effector T cells with enhanced expression of CD4 -“CD4hi” effectors. Autoimmune diabetes-prone NOD mice display a unique set of antigen-experienced “CD4lo” T cells that persist after primary stimulation. Here, we report that a population of such cells remained after secondary and tertiary TCR stimulation and produced cytokines upon antigenic challenge. However, when NOD blasts were induced in the presence of rIL-15, the number of antigen-experienced “CD4lo” T cells was significantly reduced. Clonal contraction, mediated in part by CD95-dependent activation-induced cell death (AICD, normally regulates the accumulation of “CD4hi” effectors. Interestingly, CD95 expression was dramatically reduced on the AICD-resistant NOD “CD4lo” T cells. Thus, while autoimmune disease has often been attributed to the engagement of robust autoimmunity, we suggest that the inability to effectively contract the immune response distinguishes benign autoimmunity from progressive autoimmune diseases that are characterized by chronic T cell-mediated inflammation.

  6. Cooperation of invariant NKT cells and CD46+CD256+ T regulatory cells in prevention of autoimmune diabetes in non-obese diabetic mice treated with α-galactosylceramide

    Institute of Scientific and Technical Information of China (English)

    Weipeng Li; Fang Ji; Yong Zhang; Ying Wang; Neng yang; Hailiang Ge; Fuqing Wang

    2008-01-01

    CD1d-restricted natural killer T (NKT) cells and CD4+CD25+regulatory T (Treg) cells are two thymus-derived subsets of regulatory T cells that play an important role in the maintenance of self-tolerance. Yet the functional changes of the two subsets of regulatory T cells in the development of diabetes in non-obese diabetic (NOD) mice remain unclear, and how NKT cells and CD4+CD25+ Treg cells cooperate functionally in the regulation of autoimmune diabetes is also uncertain.We provide evidence that in NOD mice, an animal model of human type 1 diabetes, the functions of both NKT cells and CD4+CD25+ Treg cells decrease in an age-dependent manner.We show that treatment with α-galactosylceramide increases the size of the CD4+CD25+ Treg cell compartment in NOD mice, and augments the expression of forkhead/winged helix transcription factor and the potency of CD4+CD25+ Treg cells to inhibit proliferation of CD4+CD25- T cells. Our data indicate that NKT cells and CD4+CD25+ Treg cells might cooperate in the prevention of autoimmune diabetes in NOD mice treated with α-galactosylceramide. Induced cooperation of NKT cells and CD4+CD25+ Treg cells could serve as a strategy to treat human autoimmune disease, such as type 1 diabetes.

  7. B cell–deficient NOD.H-2h4 mice have CD4+CD25+ T regulatory cells that inhibit the development of spontaneous autoimmune thyroiditis

    OpenAIRE

    Yu, Shiguang; Maiti, Prasanta K; Dyson, Melissa; Jain, Renu; Braley-Mullen, Helen

    2006-01-01

    Wild-type (WT) NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (SAT) when given 0.05% NaI in their drinking water, whereas B cell–deficient NOD.H-2h4 mice are SAT resistant. To test the hypothesis that resistance of B cell–deficient mice to SAT was due to the activity of regulatory CD4+CD25+ T (T reg) cells activated if autoantigen was initially presented on non–B cells, CD25+ T reg cells were transiently depleted in vivo using anti-CD25. B cell–deficient NOD.H-2h4 mice given three ...

  8. Autoreactive effector/memory CD4+ and CD8+ T cells infiltrating grafted and endogenous islets in diabetic NOD mice exhibit similar T cell receptor usage.

    Directory of Open Access Journals (Sweden)

    Ramiro Diz

    Full Text Available Islet transplantation provides a "cure" for type 1 diabetes but is limited in part by recurrent autoimmunity mediated by β cell-specific CD4(+ and CD8(+ T cells. Insight into the T cell receptor (TCR repertoire of effector T cells driving recurrent autoimmunity would aid the development of immunotherapies to prevent islet graft rejection. Accordingly, we used a multi-parameter flow cytometry strategy to assess the TCR variable β (Vβ chain repertoires of T cell subsets involved in autoimmune-mediated rejection of islet grafts in diabetic NOD mouse recipients. Naïve CD4(+ and CD8(+ T cells exhibited a diverse TCR repertoire, which was similar in all tissues examined in NOD recipients including the pancreas and islet grafts. On the other hand, the effector/memory CD8(+ T cell repertoire in the islet graft was dominated by one to four TCR Vβ chains, and specific TCR Vβ chain usage varied from recipient to recipient. Similarly, islet graft- infiltrating effector/memory CD4(+ T cells expressed a limited number of prevalent TCR Vβ chains, although generally TCR repertoire diversity was increased compared to effector/memory CD8(+ T cells. Strikingly, the majority of NOD recipients showed an increase in TCR Vβ12-bearing effector/memory CD4(+ T cells in the islet graft, most of which were proliferating, indicating clonal expansion. Importantly, TCR Vβ usage by effector/memory CD4(+ and CD8(+ T cells infiltrating the islet graft exhibited greater similarity to the repertoire found in the pancreas as opposed to the draining renal lymph node, pancreatic lymph node, or spleen. Together these results demonstrate that effector/memory CD4(+ and CD8(+ T cells mediating autoimmune rejection of islet grafts are characterized by restricted TCR Vβ chain usage, and are similar to T cells that drive destruction of the endogenous islets.

  9. Genetic Heterogeneity in Latent Autoimmune Diabetes Is Linked to Various Degrees of Autoimmune Activity

    OpenAIRE

    Pettersen, Elin; Skorpen, Frank; Kvaløy, Kirsti; Midthjell, Kristian; Grill, Valdemar

    2009-01-01

    OBJECTIVE Previous studies have indicated that the latent autoimmune diabetes in adults (LADA) phenotype is heterogeneous and that LADA patients share features of type 1 and type 2 diabetes in various proportions. We tested for association of known type 1 and type 2 diabetes susceptibility genes in LADA subjects and analyzed relationships to a marker of autoimmune activity (titers of anti-GAD) and a phenotypic risk factor of type 2 diabetes (BMI). RESEARCH DESIGN AND METHODS Data were assembl...

  10. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice

    OpenAIRE

    Nakayama, Maki; Abiru, Norio; Moriyama, Hiroaki; Babaya, Naru; Liu, Edwin; Miao, Dongmei; Yu, Liping; Wegmann, Dale R.; Hutton, John C.; Elliott, John F.; Eisenbarth, George S.

    2005-01-01

    A fundamental question about the pathogenesis of spontaneous autoimmune diabetes is whether there are primary autoantigens. For type 1 diabetes it is clear that multiple islet molecules are the target of autoimmunity in man and animal models1,2. It is not clear whether any of the target molecules are essential for the destruction of islet beta cells. Here we show that the proinsulin/insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the non-...

  11. Latent autoimmune diabetes of the adult: current knowledge and uncertainty

    Science.gov (United States)

    Laugesen, E; Østergaard, J A; Leslie, R D G

    2015-01-01

    Patients with adult-onset autoimmune diabetes have less Human Leucocyte Antigen (HLA)-associated genetic risk and fewer diabetes-associated autoantibodies compared with patients with childhood-onset Type 1 diabetes. Metabolic changes at diagnosis reflect a broad clinical phenotype ranging from diabetic ketoacidosis to mild non-insulin-requiring diabetes, also known as latent autoimmune diabetes of the adult (LADA). This latter phenotype is the most prevalent form of adult-onset autoimmune diabetes and probably the most prevalent form of autoimmune diabetes in general. Although LADA is associated with the same genetic and immunological features as childhood-onset Type 1 diabetes, it also shares some genetic features with Type 2 diabetes, which raises the question of genetic heterogeneity predisposing to this form of the disease. The potential value of screening patients with adult-onset diabetes for diabetes-associated autoantibodies to identify those with LADA is emphasized by their lack of clinically distinct features, their different natural history compared with Type 2 diabetes and their potential need for a dedicated management strategy. The fact that, in some studies, patients with LADA show worse glucose control than patients with Type 2 diabetes, highlights the need for further therapeutic studies. Challenges regarding classification, epidemiology, genetics, metabolism, immunology, clinical presentation and treatment of LADA were discussed at a 2014 workshop arranged by the Danish Diabetes Academy. The presentations and discussions are summarized in this review, which sets out the current ideas and controversies surrounding this form of diabetes. What’s new? Latent autoimmune diabetes of the adult (LADA) is an autoimmune diabetes defined by adult-onset, presence of diabetes associated autoantibodies, and no insulin treatment requirement for a period after diagnosis. Immunologically, glutamic acid decarboxylase 65 autoantibodies are by far the most

  12. Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia.

    Science.gov (United States)

    Fahrmann, Johannes; Grapov, Dmitry; Yang, Jun; Hammock, Bruce; Fiehn, Oliver; Bell, Graeme I; Hara, Manami

    2015-06-01

    Nonobese diabetic (NOD) mice are a commonly used model of type 1 diabetes (T1D). However, not all animals will develop overt diabetes despite undergoing similar autoimmune insult. In this study, a comprehensive metabolomic approach, consisting of gas chromatography time-of-flight (GC-TOF) mass spectrometry (MS), ultra-high-performance liquid chromatography-accurate mass quadruple time-of-flight (UHPLC-qTOF) MS and targeted UHPLC-tandem mass spectrometry-based methodologies, was used to capture metabolic alterations in the metabolome and lipidome of plasma from NOD mice progressing or not progressing to T1D. Using this multi-platform approach, we identified >1,000 circulating lipids and metabolites in male and female progressor and nonprogressor animals (n = 71). Statistical and multivariate analyses were used to identify age- and sex-independent metabolic markers, which best differentiated metabolic profiles of progressors and nonprogressors. Key T1D-associated perturbations were related with 1) increases in oxidation products glucono-δ-lactone and galactonic acid and reductions in cysteine, methionine and threonic acid, suggesting increased oxidative stress; 2) reductions in circulating polyunsaturated fatty acids and lipid signaling mediators, most notably arachidonic acid (AA) and AA-derived eicosanoids, implying impaired states of systemic inflammation; 3) elevations in circulating triacylglyercides reflective of hypertriglyceridemia; and 4) reductions in major structural lipids, most notably lysophosphatidylcholines and phosphatidylcholines. Taken together, our results highlight the systemic perturbations that accompany a loss of glycemic control and development of overt T1D. PMID:25852003

  13. A bispecific protein capable of engaging CTLA-4 and MHCII protects non-obese diabetic mice from autoimmune diabetes.

    Directory of Open Access Journals (Sweden)

    Hongmei Zhao

    Full Text Available Crosslinking ligand-engaged cytotoxic T lymphocyte antigen-4 (CTLA-4 to the T cell receptor (TCR with a bispecific fusion protein (BsB comprised of a mutant mouse CD80 and lymphocyte activation antigen-3 (LAG-3 has been shown to attenuate TCR signaling and to direct T-cell differentiation toward Foxp3(+ regulatory T cells (Tregs in an allogenic mixed lymphocyte reaction (MLR. Here, we show that antigen-specific Tregs can also be induced in an antigen-specific setting in vitro. Treatment of non-obese diabetic (NOD female mice between 9-12 weeks of age with a short course of BsB elicited a transient increase of Tregs in the blood and moderately delayed the onset of autoimmune type 1 diabetes (T1D. However, a longer course of treatment (10 weeks of 4-13 weeks-old female NOD animals with BsB significantly delayed the onset of disease or protected animals from developing diabetes, with only 13% of treated animals developing diabetes by 35 weeks of age compared to 80% of the animals in the control group. Histopathological analysis of the pancreata of the BsB-treated mice that remained non-diabetic revealed the preservation of insulin-producing β-cells despite the presence of different degrees of insulitis. Thus, a bifunctional protein capable of engaging CTLA-4 and MHCII and indirectly co-ligating CTLA-4 to the TCR protected NOD mice from developing T1D.

  14. Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetes

    DEFF Research Database (Denmark)

    Funda, D.P.; Kaas, A.; Tlaskalova-Hogenova, H.;

    2008-01-01

    BACKGROUND: Environmental factors such as nutrition or exposure to infections play a substantial role in the pathogenesis of type 1 diabetes (T1D). We have previously shown that gluten-free, non-purified diet largely prevented diabetes in non-obese diabetic (NOD) mice. In this study we tested...... hypothesis that early introduction of gluten-enriched (gluten+) diet may increase diabetes incidence in NOD mice. METHODS: Standard, gluten-free, gluten+ modified Altromin diets and hydrolysed-casein-based Pregestimil diet were fed to NOD females and diabetes incidence was followed for 310 days. Insulitis...... score and numbers of gut mucosal lymphocytes were determined in non-diabetic animals. RESULTS: A significantly lower diabetes incidence (p < 0.0001) was observed in NOD mice fed gluten-free diet (5.9%, n = 34) and Pregestimil diet (10%, n = 30) compared to mice on the standard Altromin diet (60.6%, n...

  15. Thymic epithelium determines a spontaneous chronic neuritis in Icam1(tm1Jcgr)NOD mice.

    Science.gov (United States)

    Meyer zu Horste, Gerd; Mausberg, Anne K; Cordes, Steffen; El-Haddad, Houda; Partke, Hans-Joachim; Leussink, Verena I; Roden, Michael; Martin, Stephan; Steinman, Lawrence; Hartung, Hans-Peter; Kieseier, Bernd C

    2014-09-15

    The NOD mouse strain spontaneously develops autoimmune diabetes. A deficiency in costimulatory molecules, such as B7-2, on the NOD genetic background prevents diabetes but instead triggers an inflammatory peripheral neuropathy. This constitutes a shift in the target of autoimmunity, but the underlying mechanism remains unknown. In this study, we demonstrate that NOD mice deficient for isoforms of ICAM-1, which comediate costimulatory functions, spontaneously develop a chronic autoimmune peripheral neuritis instead of diabetes. The disease is transferred by CD4(+) T cells, which infiltrate peripheral nerves together with macrophages and B cells and are autoreactive against peripheral myelin protein zero. These Icam1(tm1Jcgr)NOD mice exhibit unaltered numbers of regulatory T cells, but increased IL-17-producing T cells, which determine the severity, but not the target specificity, of autoimmunity. Ab-mediated ICAM-1 blockade triggers neuritis only in young NOD mice. Thymic epithelium from Icam1(tm1Jcgr)NOD mice features an altered expression of costimulatory molecules and induces neuritis and myelin autoreactivity after transplantation into nude mice in vivo. Icam1(tm1Jcgr)NOD mice exhibit a specifically altered TCR repertoire. Our findings introduce a novel animal model of chronic inflammatory neuropathies and indicate that altered expression of ICAM-1 on thymic epithelium shifts autoimmunity specifically toward peripheral nerves. This improves our understanding of autoimmunity in the peripheral nervous system with potential relevance for human diseases. PMID:25108020

  16. NOD mouse model for Sjogren's syndrome: lack of longitudinal stability

    NARCIS (Netherlands)

    B.M. Lodde; F. Mineshiba; M.R. Kok; J. Wang; C. Zheng; M. Schmidt; A.P. Cotrim; M. Kriete; P.P. Tak; B.J. Baum

    2006-01-01

    OBJECTIVES: The non-obese diabetic (NOD) mouse is not only a widely used model for diabetes mellitus type I, but also for the chronic autoimmune disease Sjogren's syndrome (SS), mainly affecting salivary and lacrimal glands. We studied the efficacy of local recombinant serotype 2 adeno-associated vi

  17. Hematopoietic stem cell transplantation prevents diabetes in NOD mice but does not contribute to significant islet cell regeneration once disease is established.

    Science.gov (United States)

    Kang, Elizabeth M; Zickler, Philipp P; Burns, Sean; Langemeijer, Saskia M; Brenner, Sebastian; Phang, Oswald A; Patterson, Noelle; Harlan, David; Tisdale, John F

    2005-06-01

    The treatment of type I diabetes by islet cell transplantation, while promising, remains restricted due to the incomplete efficacy and toxicity associated with current immunosuppression, and by limited organ availability. Given reports suggesting bone marrow derived stem cell plasticity, we sought to determine whether such cells could give rise to pancreatic islet cells in vivo. In the context of autoimmune diabetes, we transplanted unfractionated bone marrow from beta-gal trangenic donor mice into NOD mice prior to, at, and two weeks beyond the onset of disease. Successful bone marrow engraftment before diabetes onset prevented disease in all mice and for 1 year after transplant. However, despite obtaining full hematopoietic engraftment in over 50 transplanted mice, only one mouse became insulin independent, and no beta-Gal positive islets were detected in any of the mice. To test whether tolerance to islets was achieved, we injected islets obtained from the same allogeneic donor strain as the hematopoietic cells into 4 transplant recipients, and 2 had a reversion of their diabetes. Thus allogeneic bone marrow transplantation prevents autoimmune diabetes and tolerizes the recipient to donor islet grants, even in diabetic animals, yet the capacity of bone marrow derived cells to differentiate into functional islet cells, at least without additional manipulation, is limited in our model. PMID:15911094

  18. Materno-Fetal Transfer of Preproinsulin Through the Neonatal Fc Receptor Prevents Autoimmune Diabetes.

    Science.gov (United States)

    Culina, Slobodan; Gupta, Nimesh; Boisgard, Raphael; Afonso, Georgia; Gagnerault, Marie-Claude; Dimitrov, Jordan; Østerbye, Thomas; Justesen, Sune; Luce, Sandrine; Attias, Mikhaël; Kyewski, Bruno; Buus, Søren; Wong, F Susan; Lacroix-Desmazes, Sebastien; Mallone, Roberto

    2015-10-01

    The first signs of autoimmune activation leading to β-cell destruction in type 1 diabetes (T1D) appear during the first months of life. Thus, the perinatal period offers a suitable time window for disease prevention. Moreover, thymic selection of autoreactive T cells is most active during this period, providing a therapeutic opportunity not exploited to date. We therefore devised a strategy by which the T1D-triggering antigen preproinsulin fused with the immunoglobulin (Ig)G Fc fragment (PPI-Fc) is delivered to fetuses through the neonatal Fc receptor (FcRn) pathway, which physiologically transfers maternal IgGs through the placenta. PPI-Fc administered to pregnant PPIB15-23 T-cell receptor-transgenic mice efficiently accumulated in fetuses through the placental FcRn and protected them from subsequent diabetes development. Protection relied on ferrying of PPI-Fc to the thymus by migratory dendritic cells and resulted in a rise in thymic-derived CD4(+) regulatory T cells expressing transforming growth factor-β and in increased effector CD8(+) T cells displaying impaired cytotoxicity. Moreover, polyclonal splenocytes from nonobese diabetic (NOD) mice transplacentally treated with PPI-Fc were less diabetogenic upon transfer into NOD.scid recipients. Transplacental antigen vaccination provides a novel strategy for early T1D prevention and, further, is applicable to other immune-mediated conditions. PMID:25918233

  19. Autoimmune mechanisms in type 1 diabetes.

    Science.gov (United States)

    Knip, Mikael; Siljander, Heli

    2008-07-01

    Type 1 diabetes (T1D) is perceived as a chronic immune-mediated disease with a subclinical prodromal period characterized by selective loss of insulin-producing beta-cells in the pancreatic islets in genetically susceptible subjects. Autoreactive T cells, both CD4 and CD8 cells, have been implicated as active players in beta-cell destruction. A series of autoantigens have been identified in T1D including insulin, glutamic acid decarboxylase (GAD), the protein tyrosine phosphatase-related islet antigen 2 (IA-2), and most recently the zinc transporter Slc30A8 residing in the insulin secretory granule of the beta-cell. The issue whether there is any primary autoantigen in T1D has remained controversial. Given that there are two major HLA haplotypes conferring disease susceptibility, i.e. the DR3-DQ2 haplotype and the DR4-DQ8 haplotype, one may assume that there will be at least two primary antigens in T1D. The first signs of beta-cell autoimmunity might appear already during the first year of life. Autoantibodies may be considered as markers of an ongoing disease process in the pancreatic islets, and they can be used for prediction of T1D in non-diabetic individuals. Autoantigen-specific T-cell responses have been detected from peripheral blood in both patients with T1D and in unaffected subjects, but a clear discrimination between diabetic and non-diabetic subjects have rarely been seen until recently. PMID:18625444

  20. Prevention or early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice

    DEFF Research Database (Denmark)

    Funda, David; Fundova, Petra; Hansen, Axel Kornerup;

    2014-01-01

    gluten-free diets prevent T1D in animal models. Herewith we investigated whether intranasal (i.n.) administration of gliadin or gluten may arrest the diabetogenic process. I.n. administration of gliadin to 4-week-old NOD mice significantly reduced the diabetes incidence. Similarly, the insulitis was.......n. vaccination with gliadin, an environmental antigen with possible etiological influence in T1D, may represent a novel, safer strategy for prevention or even early cure of T1D....

  1. Short-term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice.

    Science.gov (United States)

    Brezar, Vedran; Culina, Slobodan; Gagnerault, Marie-Claude; Mallone, Roberto

    2012-06-01

    Despite encouraging results in the NOD mouse, type 1 diabetes prevention trials using subcutaneous insulin have been unsuccessful. To explain these discrepancies, 3-week-old NOD mice were treated for 7 weeks with subcutaneous insulin at two different doses: a high dose (0.5 U/mouse) used in previous mouse studies; and a low dose (0.005 U/mouse) equivalent to that used in human trials. Effects on insulitis and diabetes were monitored along with immune and metabolic modifications. Low-dose insulin did not have any effect on disease incidence. High-dose treatment delayed but did not prevent diabetes, with reduced insulitis reappearing once insulin discontinued. This effect was not associated with significant immune changes in islet infiltrates, either in terms of cell composition or frequency and IFN-γ secretion of islet-reactive CD8(+) T cells recognizing the immunodominant epitopes insulin B(15-23) and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)(206-214). Delayed diabetes and insulitis were associated with lower blood glucose and endogenous C-peptide levels, which rapidly returned to normal upon treatment discontinuation. In conclusion, high- but not low-dose prophylactic insulin treatment delays diabetes onset and is associated with metabolic changes suggestive of β-cell "rest" which do not persist beyond treatment. These findings have important implications for designing insulin-based prevention trials. PMID:22678909

  2. CXCR4 antagonist AMD3100 ameliorates thyroid damage in autoimmune thyroiditis in NOD.H‑2h4 mice.

    Science.gov (United States)

    Liu, Xin; Mao, Jinyuan; Han, Cheng; Peng, Shiqiao; Li, Chenyan; Jin, Ting; Fan, Chenling; Shan, Zhongyan; Teng, Weiping

    2016-04-01

    CXC chemokine ligand 12 (CXCL12) and its receptor, CXC chemokine receptor 4 (CXCR4), are upregulated in mice with autoimmune thyroid diseases. However, whether this interaction is involved in the pathophysiology of autoimmune thyroiditis (AIT) remains to be elucidated. In the present study, the effects of the CXCR4 antagonist, AMD3100, in an iodine‑induced autoimmune thyroiditis model were investigated. NOD.H‑2h4 mice were randomly separated into a control, AIT and AIT+AMD3100 groups. The mice were fed with 0.05% sodium iodide water for 8 weeks to induce AIT. The AMD3100‑treated mice were administered with the CXCR4 antagonist at a dose of 10 mg/kg intraperitoneally three times a week during the experimental period. The percentages of CD19+interleukin (IL)10+ B cells and CD4+IL10+ T cells, and the mRNA expression levels of IL10 in the splenocytes were reduced in the AIT group, compared with the control group, however, they increased following AMD3100 treatment, compared with the untreated AIT group. The percentages of CD4+ T cells, CD8+ T cells, CD19+ B cells and CD8+ interferon (IFN)γ+ T cells, and the mRNA expression levels of IFNγ increased in the AIT group, compared with the control group, however, these were reduced in the AMD3100 group, compared with the AIT group. The AMD3100‑treated mice also had lower serum thyroglobulin antibody titers and reduced lymphocytic infiltration in the thyroid, compared with the untreated AIT mice. These results suggested that inhibition of this chemokine axis may offer potential as a therapeutic target for the treatment of AIT. PMID:26935473

  3. Altered Expression of Somatostatin Receptors in Pancreatic Islets from NOD Mice Cultured at Different Glucose Concentrations In Vitro and in Islets Transplanted to Diabetic NOD Mice In Vivo

    Directory of Open Access Journals (Sweden)

    Eva Ludvigsen

    2011-01-01

    Full Text Available Somatostatin acts via five receptors (sst1-5. We investigated if the changes in pancreatic islet sst expression in diabetic NOD mice compared to normoglycemic mice are a consequence of hyperglycemia or the ongoing immune reaction in the pancreas. Pancreatic islets were isolated from NOD mice precultured for 5 days and further cultured for 3 days at high or low glucose before examined. Islets were also isolated from NOD mice and transplanted to normal or diabetic mice in a number not sufficient to cure hyperglycemia. After three days, the transplants were removed and stained for sst1-5 and islet hormones. Overall, changes in sst islet cell expression were more common in islets cultured in high glucose concentration in vitro as compared to the islet transplantation in vivo to diabetic mice. The beta and PP cells exhibited more frequent changes in sst expression, while the alpha and delta cells were relatively unaffected by the high glucose condition. Our findings suggest that the glucose level may alter sst expressed in islets cells; however, immune mechanisms may counteract such changes in islet sst expression.

  4. Celiac Disease Autoimmunity in Patients with Autoimmune Diabetes and Thyroid Disease among Chinese Population

    Science.gov (United States)

    Zhao, Zhiyuan; Zou, Jing; Zhao, Lingling; Cheng, Yan; Cai, Hanqing; Li, Mo; Liu, Edwin; Yu, Liping; Liu, Yu

    2016-01-01

    The prevalence of celiac disease autoimmunity or tissue transglutaminase autoantibodies (TGA) amongst patients with type 1 diabetes (T1D) and autoimmune thyroid disease (AITD) in the Chinese population remains unknown. This study examined the rate of celiac disease autoimmunity amongst patients with T1D and AITD in the Chinese population. The study included 178 patients with type 1 diabetes and 119 with AITD where 36 had both T1D and AITD, classified as autoimmune polyglandular syndrome type 3 variant (APS3v). The study also included 145 patients with type 2 diabetes (T2D), 97 patients with non-autoimmune thyroid disease (NAITD), and 102 healthy controls. Serum islet autoantibodies, thyroid autoantibodies and TGA were measured by radioimmunoassay. TGA positivity was found in 22% of patients with either type 1 diabetes or AITD, much higher than that in patients with T2D (3.4%; pdiseases were present. Routine TGA screening in patients with T1D or AITD will be important to early identify celiac disease autoimmunity for better clinical care of patients. PMID:27427767

  5. Dimethyl sulfoxide inhibits spontaneous diabetes and autoimmune recurrence in non-obese diabetic mice by inducing differentiation of regulatory T cells

    International Nuclear Information System (INIS)

    Type 1 diabetes mellitus (T1D) is caused by the destruction of insulin-producing β cells in pancreatic islets by autoimmune T cells. Islet transplantation has been established as an effective therapeutic strategy for T1D. However, the survival of islet grafts can be disrupted by recurrent autoimmunity. Dimethyl sulfoxide (DMSO) is a solvent for organic and inorganic substances and an organ-conserving agent used in solid organ transplantations. DMSO also exerts anti-inflammatory, reactive oxygen species scavenger and immunomodulatory effects and therefore exhibits therapeutic potential for the treatment of several human inflammatory diseases. In this study, we investigated the therapeutic potential of DMSO in the inhibition of autoimmunity. We treated an animal model of islet transplantation (NOD mice) with DMSO. The survival of the syngeneic islet grafts was significantly prolonged. The population numbers of CD8, DC and Th1 cells were decreased, and regulatory T (Treg) cell numbers were increased in recipients. The expression levels of IFN-γ and proliferation of T cells were also reduced following DMSO treatment. Furthermore, the differentiation of Treg cells from naive CD4 T cells was significantly increased in the in vitro study. Our results demonstrate for the first time that in vivo DMSO treatment suppresses spontaneous diabetes and autoimmune recurrence in NOD mice by inhibiting the Th1 immune response and inducing the differentiation of Treg cells. - Highlights: • We report a therapeutic potential of DMSO in autoimmune diabetes. • DMSO exhibits an immune modulatory effect. • DMSO treatment increases regulatory T cell differentiation. • The increase in STAT5 signaling pathway explains the effect of DMSO in Tregs

  6. Dimethyl sulfoxide inhibits spontaneous diabetes and autoimmune recurrence in non-obese diabetic mice by inducing differentiation of regulatory T cells

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Gu-Jiun [Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, ROC (China); Sytwu, Huey-Kang [Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, ROC (China); Yu, Jyh-Cherng [Department of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC (China); Chen, Yuan-Wu [School of Dentistry, National Defense Medical Center, Taipei, Taiwan, ROC (China); Department of Oral and Maxillofacial Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC (China); Kuo, Yu-Liang [Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC (China); School of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan, ROC (China); Yu, Chiao-Chi [Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, ROC (China); Department of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC (China); Chang, Hao-Ming; Chan, De-Chuan [Department of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC (China); Huang, Shing-Hwa, E-mail: h610129@gmail.com [Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, ROC (China); Department of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC (China)

    2015-01-15

    Type 1 diabetes mellitus (T1D) is caused by the destruction of insulin-producing β cells in pancreatic islets by autoimmune T cells. Islet transplantation has been established as an effective therapeutic strategy for T1D. However, the survival of islet grafts can be disrupted by recurrent autoimmunity. Dimethyl sulfoxide (DMSO) is a solvent for organic and inorganic substances and an organ-conserving agent used in solid organ transplantations. DMSO also exerts anti-inflammatory, reactive oxygen species scavenger and immunomodulatory effects and therefore exhibits therapeutic potential for the treatment of several human inflammatory diseases. In this study, we investigated the therapeutic potential of DMSO in the inhibition of autoimmunity. We treated an animal model of islet transplantation (NOD mice) with DMSO. The survival of the syngeneic islet grafts was significantly prolonged. The population numbers of CD8, DC and Th1 cells were decreased, and regulatory T (Treg) cell numbers were increased in recipients. The expression levels of IFN-γ and proliferation of T cells were also reduced following DMSO treatment. Furthermore, the differentiation of Treg cells from naive CD4 T cells was significantly increased in the in vitro study. Our results demonstrate for the first time that in vivo DMSO treatment suppresses spontaneous diabetes and autoimmune recurrence in NOD mice by inhibiting the Th1 immune response and inducing the differentiation of Treg cells. - Highlights: • We report a therapeutic potential of DMSO in autoimmune diabetes. • DMSO exhibits an immune modulatory effect. • DMSO treatment increases regulatory T cell differentiation. • The increase in STAT5 signaling pathway explains the effect of DMSO in Tregs.

  7. Contrasting Roles of Islet Resident Immunoregulatory Macrophages and Dendritic Cells in Experimental Autoimmune Type 1 Diabetes.

    Directory of Open Access Journals (Sweden)

    Thomas B Thornley

    Full Text Available The innate immune system critically shapes diabetogenic adaptive immunity during type 1 diabetes (T1D pathogenesis. While the role of tissue-infiltrating monocyte-derived macrophages in T1D is well established, the role of their tissue-resident counterparts remains undefined. We now demonstrate that islet resident macrophages (IRMs from non-autoimmune mice have an immunoregulatory phenotype and powerfully induce FoxP3+ Tregs in vitro. The immunoregulatory phenotype and function of IRMs is compromised by TLR4 activation in vitro. Moreover, as T1D approaches in NOD mice, the immunoregulatory phenotype of IRMs is diminished as is their relative abundance compared to immunostimulatory DCs. Our findings suggest that maintenance of IRM abundance and their immunoregulatory phenotype may constitute a novel therapeutic strategy to prevent and/or cure T1D.

  8. Naturally Occurring Anthraquinones: Chemistry and Therapeutic Potential in Autoimmune Diabetes

    Directory of Open Access Journals (Sweden)

    Shih-Chang Chien

    2015-01-01

    Full Text Available Anthraquinones are a class of aromatic compounds with a 9,10-dioxoanthracene core. So far, 79 naturally occurring anthraquinones have been identified which include emodin, physcion, cascarin, catenarin, and rhein. A large body of literature has demonstrated that the naturally occurring anthraquinones possess a broad spectrum of bioactivities, such as cathartic, anticancer, anti-inflammatory, antimicrobial, diuretic, vasorelaxing, and phytoestrogen activities, suggesting their possible clinical application in many diseases. Despite the advances that have been made in understanding the chemistry and biology of the anthraquinones in recent years, research into their mechanisms of action and therapeutic potential in autoimmune disorders is still at an early stage. In this paper, we briefly introduce the etiology of autoimmune diabetes, an autoimmune disorder that affects as many as 10 million worldwide, and the role of chemotaxis in autoimmune diabetes. We then outline the chemical structure and biological properties of the naturally occurring anthraquinones and their derivatives with an emphasis on recent findings about their immune regulation. We discuss the structure and activity relationship, mode of action, and therapeutic potential of the anthraquinones in autoimmune diabetes, including a new strategy for the use of the anthraquinones in autoimmune diabetes.

  9. Early life treatment with vancomycin reduces diabetes incidence in NOD mice

    DEFF Research Database (Denmark)

    Hansen, Camilla Hartmann Friis

    immune response and a fine-tuned balance between these immunological components is crucial for characteristics of the disease, such as severity, onset time and recovery. The balance between the regulatory and the adaptive immune response is heavily influenced by early life bacterial stimulation. An......Type 1 diabetes (T1D) results from an uncontrolled T cell mediated destruction of the insulin-producing beta-cells in the pancreas. Causal factors include a combination of genetics, early life incidents and the food we eat. The involved adaptive immune response can be down regulated by a regulatory...... interplay that is likely to represent a critical environmental component to diabetes induction. In a period after birth alterations of the early microbial colonization of the gut therefore can be expected to have an immense impact on diabetes progression later in life. In this study neonate NOD mice were...

  10. Apoptosis of purified CD4+ T cell subsets is dominated by cytokine deprivation and absence of other cells in new onset diabetic NOD mice.

    Directory of Open Access Journals (Sweden)

    Ayelet Kaminitz

    Full Text Available BACKGROUND: Regulatory T cells (Treg play a significant role in immune homeostasis and self-tolerance. Excessive sensitivity of isolated Treg to apoptosis has been demonstrated in NOD mice and humans suffering of type 1 diabetes, suggesting a possible role in the immune dysfunction that underlies autoimmune insulitis. In this study the sensitivity to apoptosis was measured in T cells from new onset diabetic NOD females, comparing purified subsets to mixed cultures. PRINCIPAL FINDINGS: Apoptotic cells are short lived in vivo and death occurs primarily during isolation, manipulation and culture. Excessive susceptibility of CD25(+ T cells to spontaneous apoptosis is characteristic of isolated subsets, however disappears when death is measured in mixed splenocyte cultures. In variance, CD25(- T cells display balanced sensitivity to apoptosis under both conditions. The isolation procedure removes soluble factors, IL-2 playing a significant role in sustaining Treg viability. In addition, pro- and anti-apoptotic signals are transduced by cell-to-cell interactions: CD3 and CD28 protect CD25(+ T cells from apoptosis, and in parallel sensitize naïve effector cells to apoptosis. Treg viability is modulated both by other T cells and other subsets within mixed splenocyte cultures. Variations in sensitivity to apoptosis are often hindered by fast proliferation of viable cells, therefore cycling rates are mandatory to adequate interpretation of cell death assays. CONCLUSIONS: The sensitivity of purified Treg to apoptosis is dominated by cytokine deprivation and absence of cell-to-cell interactions, and deviate significantly from measurements in mixed populations. Balanced sensitivity of naïve/effector and regulatory T cells to apoptosis in NOD mice argues against the concept that differential susceptibility affects disease evolution and progression.

  11. IL-2 immunotherapy reveals potential for innate beta cell regeneration in the non-obese diabetic mouse model of autoimmune diabetes.

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    Yaiza Diaz-de-Durana

    Full Text Available Type-1 diabetes (T1D is an autoimmune disease targeting insulin-producing beta cells, resulting in dependence on exogenous insulin. To date, significant efforts have been invested to develop immune-modulatory therapies for T1D treatment. Previously, IL-2 immunotherapy was demonstrated to prevent and reverse T1D at onset in the non-obese diabetic (NOD mouse model, revealing potential as a therapy in early disease stage in humans. In the NOD model, IL-2 deficiency contributes to a loss of regulatory T cell function. This deficiency can be augmented with IL-2 or antibody bound to IL-2 (Ab/IL-2 therapy, resulting in regulatory T cell expansion and potentiation. However, an understanding of the mechanism by which reconstituted regulatory T cell function allows for reversal of diabetes after onset is not clearly understood. Here, we describe that Ab/IL-2 immunotherapy treatment, given at the time of diabetes onset in NOD mice, not only correlated with reversal of diabetes and expansion of Treg cells, but also demonstrated the ability to significantly increase beta cell proliferation. Proliferation appeared specific to Ab/IL-2 immunotherapy, as anti-CD3 therapy did not have a similar effect. Furthermore, to assess the effect of Ab/IL-2 immunotherapy well after the development of diabetes, we tested the effect of delaying treatment for 4 weeks after diabetes onset, when beta cells were virtually absent. At this late stage after diabetes onset, Ab/IL-2 treatment was not sufficient to reverse hyperglycemia. However, it did promote survival in the absence of exogenous insulin. Proliferation of beta cells could not account for this improvement as few beta cells remained. Rather, abnormal insulin and glucagon dual-expressing cells were the only insulin-expressing cells observed in islets from mice with established disease. Thus, these data suggest that in diabetic NOD mice, beta cells have an innate capacity for regeneration both early and late in disease

  12. Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin-dependent diabetes.

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    Sophie Candon

    Full Text Available Insulin-dependent or type 1 diabetes is a prototypic autoimmune disease whose incidence steadily increased over the past decades in industrialized countries. Recent evidence suggests the importance of the gut microbiota to explain this trend. Here, non-obese diabetic (NOD mice that spontaneously develop autoimmune type 1 diabetes were treated with different antibiotics to explore the influence of a targeted intestinal dysbiosis in the progression of the disease. A mixture of wide spectrum antibiotics (i.e. streptomycin, colistin and ampicillin or vancomycin alone were administered orally from the moment of conception, treating breeding pairs, and during the postnatal and adult life until the end of follow-up at 40 weeks. Diabetes incidence significantly and similarly increased in male mice following treatment with these two antibiotic regimens. In NOD females a slight yet not significant trend towards an increase in disease incidence was observed. Changes in gut microbiota composition were assessed by sequencing the V3 region of bacterial 16S rRNA genes. Administration of the antibiotic mixture resulted in near complete ablation of the gut microbiota. Vancomycin treatment led to increased Escherichia, Lactobacillus and Sutterella genera and decreased members of the Clostridiales order and Lachnospiraceae, Prevotellaceae and Rikenellaceae families, as compared to control mice. Massive elimination of IL-17-producing cells, both CD4+TCRαβ+ and TCRγδ+ T cells was observed in the lamina propria of the ileum and the colon of vancomycin-treated mice. These results show that a directed even partial ablation of the gut microbiota, as induced by vancomycin, significantly increases type 1 diabetes incidence in male NOD mice thus prompting for caution in the use of antibiotics in pregnant women and newborns.

  13. Type 1 diabetes and polyglandular autoimmune syndrome:A review

    Institute of Scientific and Technical Information of China (English)

    Martin P Hansen; Nina Matheis; George J Kahaly

    2015-01-01

    Type 1 diabetes (T1D) is an autoimmune disorder causedby inflammatory destruction of the pancreatic tissue. Theetiopathogenesis and characteristics of the pathologicprocess of pancreatic destruction are well described. Inaddition, the putative susceptibility genes for T1D as amonoglandular disease and the relation to polyglandularautoimmune syndrome (PAS) have also been wellexplored. The incidence of T1D has steadily increasedin most parts of the world, especially in industrializednations. T1D is frequently associated with autoimmuneendocrine and non-endocrine diseases and patients withT1D are at a higher risk for developing several glandularautoimmune diseases. Familial clustering is observed,which suggests that there is a genetic predisposition.Various hypotheses pertaining to viral- and bacterialinducedpancreatic autoimmunity have been proposed,however a definitive delineation of the autoimmunepathomechanism is still lacking. In patients with PAS,pancreatic and endocrine autoantigens either colocalizeon one antigen-presenting cell or are expressed on two/various target cells sharing a common amino acid, whichfacilitates binding to and activation of T cells. The mostprevalent PAS phenotype is the adult type 3 variant orPAS type Ⅲ, which encompasses T1D and autoimmunethyroid disease. This review discusses the findings ofrecent studies showing noticeable differences in thegenetic background and clinical phenotype of T1D eitheras an isolated autoimmune endocrinopathy or within thescope of polyglandular autoimmune syndrome.

  14. The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes.

    Science.gov (United States)

    Tai, Ningwen; Wong, F Susan; Wen, Li

    2016-07-01

    Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by T cell-mediated destruction of the insulin-producing pancreatic β cells. A combination of genetic and environmental factors eventually leads to the loss of functional β cell mass and hyperglycemia. Both innate and adaptive immunity are involved in the development of T1D. In this review, we have highlighted the most recent findings on the role of innate immunity, especially the pattern recognition receptors (PRRs), in disease development. In murine models and human studies, different PRRs, such as toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat-containing (or Nod-like) receptors (NLRs), have different roles in the pathogenesis of T1D. These PRRs play a critical role in defending against infection by sensing specific ligands derived from exogenous microorganisms to induce innate immune responses and shape adaptive immunity. Animal studies have shown that TLR7, TLR9, MyD88 and NLPR3 play a disease-predisposing role in T1D, while controversial results have been found with other PRRs, such as TLR2, TLR3, TLR4, TLR5 and others. Human studies also shown that TLR2, TLR3 and TLR4 are expressed in either islet β cells or infiltrated immune cells, indicating the innate immunity plays a role in β cell autoimmunity. Furthermore, some human genetic studies showed a possible association of TLR3, TLR7, TLR8 or NLRP3 genes, at single nucleotide polymorphism (SNP) level, with human T1D. Increasing evidence suggest that the innate immunity modulates β cell autoimmunity. Thus, targeting pathways of innate immunity may provide novel therapeutic strategies to fight this disease. PMID:27021275

  15. Comprehensive Survey of miRNA-mRNA Interactions Reveals That Ccr7 and Cd247 (CD3 zeta) are Posttranscriptionally Controlled in Pancreas Infiltrating T Lymphocytes of Non-Obese Diabetic (NOD) Mice

    Science.gov (United States)

    Macedo, Claudia; Sakamoto-Hojo, Elza T.; Donadi, Eduardo A.; Passos, Geraldo A.

    2015-01-01

    In autoimmune type 1 diabetes mellitus (T1D), auto-reactive clones of CD4+ and CD8+ T lymphocytes in the periphery evolve into pancreas-infiltrating T lymphocytes (PILs), which destroy insulin-producing beta-cells through inflammatory insulitis. Previously, we demonstrated that, during the development of T1D in non-obese diabetic (NOD) mice, a set of immune/inflammatory reactivity genes were differentially expressed in T lymphocytes. However, the posttranscriptional control involving miRNA interactions that occur during the evolution of thymocytes into PILs remains unknown. In this study, we postulated that miRNAs are differentially expressed during this period and that these miRNAs can interact with mRNAs involved in auto-reactivity during the progression of insulitis. To test this hypothesis, we used NOD mice to perform, for the first time, a comprehensive survey of miRNA and mRNA expression as thymocytes mature into peripheral CD3+ T lymphocytes and, subsequently, into PILs. Reconstruction of miRNA-mRNA interaction networks for target prediction revealed the participation of a large set of miRNAs that regulate mRNA targets related to apoptosis, cell adhesion, cellular regulation, cellular component organization, cellular processes, development and the immune system, among others. The interactions between miR-202-3p and the Ccr7 chemokine receptor mRNA or Cd247 (Cd3 zeta chain) mRNA found in PILs are highlighted because these interactions can contribute to a better understanding of how the lack of immune homeostasis and the emergence of autoimmunity (e.g., T1D) can be associated with the decreased activity of Ccr7 or Cd247, as previously observed in NOD mice. We demonstrate that these mRNAs are controlled at the posttranscriptional level in PILs. PMID:26606254

  16. Tight Junctions, Intestinal Permeability, and Autoimmunity Celiac Disease and Type 1 Diabetes Paradigms

    NARCIS (Netherlands)

    Visser, Jeroen; Rozing, Jan; Sapone, Anna; Lammers, Karen; Fasano, Alessio; Fromm, M; Schulzke, JD

    2009-01-01

    Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on celiac disease (CD), an autoimmune enteropathy, and type I diabetes (TID), a hyperglycosaemia caused by a destructive autoimmune p

  17. Thioreductase containing epitopes inhibit the development of type 1 diabetes in the NOD mouse model

    Directory of Open Access Journals (Sweden)

    Elin eMalek Abrahimians

    2016-03-01

    Full Text Available Autoreactive CD4+ T cells recognizing islet-derived antigens play a primary role in type 1 diabetes. Specific suppression of such cells therefore represents a strategic target for the cure of the disease. We have developed a methodology by which CD4+ T cells acquire apoptosis-inducing properties on antigen-presenting cells after cognate recognition of natural sequence epitopes. We describe here that inclusion of a thiol-disulfide oxidoreductase (thioreductase motif within the flanking residues of a single MHC class II-restricted GAD65 epitope induces GAD65-specific cytolytic CD4+ T cells (cCD4+ T. The latter, obtained either in vitro or by active immunization, acquire an effector memory phenotype and lyse APCs by a Fas-FasL interaction. Further, cCD4+ T cells eliminate by apoptosis activated bystander CD4+ T cells recognizing alternative epitopes processed by the same APC. Active immunization with a GAD65 class II-restricted thioreductase-containing T cell epitope protects mice from diabetes and abrogates insulitis. Passive transfer of in vitro-elicited cCD4+ T cells establishes that such cells are efficient in suppressing autoimmunity. These findings provide strong evidence for a new vaccination strategy to prevent type 1 diabetes.

  18. Alcohol facilitates CD1d loading, subsequent activation of NKT cells, and reduces the incidence of diabetes in NOD mice.

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    Karsten Buschard

    Full Text Available BACKGROUND: Ethanol ('alcohol' is a partly hydrophobic detergent that may affect the accessibility of glycolipids thereby influencing immunological effects of these molecules. METHODS: The study included cellular in vitro tests using α-galactosylceramide (αGalCer, and in vivo NOD mice experiments detecting diabetes incidence and performing behavioural and bacterial analyses. RESULTS: Alcohol in concentrations from 0.6% to 2.5% increased IL-2 production from NKT cells stimulated with αGalCer by 60% (p<0.05. CD1d expressed on HeLa cells contained significantly increasing amounts of αGalCer with increasing concentrations of alcohol, suggesting that alcohol facilitated the passive loading of αGalCer to CD1d. NOD mice were found to tolerate 5% ethanol in their drinking water without signs of impairment in liver function. Giving this treatment, the diabetes incidence declined significantly. Higher numbers of CD3+CD49b+ NKT cells were found in spleen and liver of the alcohol treated compared to the control mice (p<0.05, whereas the amount of CD4+Foxp3+ regulator T cells did not differ. Increased concentrations of IFN-γ were detected in 24-hour blood samples of alcohol treated mice. Behavioural studies showed no change in attitude of the ethanol-consuming mice, and bacterial composition of caecum samples was not affected by alcohol, disqualifying these as protective mechanisms. CONCLUSION: Alcohol facilitates the uptake of glycolipids and the stimulation of NKT cells, which are known to counteract Type 1 diabetes development. We propose that this is the acting mechanism by which treatment with alcohol reduces the incidence of diabetes in NOD mice. This is corroborated by epidemiology showing beneficial effect of alcohol to reduce the severity of atherosclerosis and related diseases.

  19. The urgent need to prevent type 1 autoimmune childhood diabetes.

    Science.gov (United States)

    Laron, Zvi; Hampe, Christiane S; Shulman, Lester M

    2015-03-01

    Clinical onset of autoimmune Type 1 diabetes mellitus (T1DM) develops after an asymptomatic, complex interaction between host genetic and environmental factors lasting several years. The world-wide increase in T1DM incidence with no cure in sight necessitates the identification of the causative environmental factors in order to develop methods for preventing them from participating in the autoimmune process leading to T1DM. Human trials to prevent insulitis or development of T1DM (secondary prevention trials) have not as yet produced satisfactory outcomes despite promising results from T1DM animal models, possibly because the autoimmune response had already progressed too far and could not be stopped or reversed. Primary prevention trials conducted with individuals with increased genetic risk, but without signs of autoimmune response or metabolic abnormalities have also not yet produced any clear benefit. A correlation between month of birth and T1DM implicated seasonal infectious pathogens in the etiology of T1DM. This has prompted a search for those seasonal pathogens including viruses that might lead to onset of T1DM. Many studies investigated immediate viral triggers, e.g., viral infections at the time of clinical onset of T1DM. Fewer studies have investigated virus infections as the initial or early trigger in a cascade of events leading to development of TIDM. Seasonal virus infections of pregnant women may be transmitted in utero and induce the first damage to the developing fetus's beta-cells. The identification of specific pathogenic viruses may enable development for pregestational vaccines to diminish the incidence of childhood T1DM. PMID:25962204

  20. Intranasal vaccination with proinsulin DNA induces regulatory CD4+ T cells that prevent experimental autoimmune diabetes.

    Science.gov (United States)

    Every, Alison L; Kramer, David R; Mannering, Stuart I; Lew, Andrew M; Harrison, Leonard C

    2006-04-15

    Insulin, an autoantigen in type 1 diabetes, when administered mucosally to diabetes-prone NOD mice induces regulatory T cells (T(reg)) that protect against diabetes. Compared with protein, Ag encoded as DNA has potential advantages as a therapeutic agent. We found that intranasal vaccination of NOD mice with plasmid DNA encoding mouse proinsulin II-induced CD4+ T(reg) that suppressed diabetes development, both after adoptive cotransfer with "diabetogenic" spleen cells and after transfer into NOD mice given cyclophosphamide to accelerate diabetes onset. In contrast to prototypic CD4+ CD25+ T(reg), CD4+ T(reg) induced by proinsulin DNA were both CD25+ and CD25- and not defined by markers such as glucocorticoid-induced TNFR-related protein (GITR), CD103, or Foxp3. Intriguingly, despite induction of T(reg) and reduced islet inflammation, diabetes incidence in proinsulin DNA-treated mice was unchanged. However, diabetes was prevented when DNA vaccination was performed under the cover of CD40 ligand blockade, known to prevent priming of CTL by mucosal Ag. Thus, intranasal vaccination with proinsulin DNA has therapeutic potential to prevent diabetes, as demonstrated by induction of protective T(reg), but further modifications are required to improve its efficacy, which could be compromised by concomitant induction of pathogenic immunity. PMID:16585551

  1. Bridging Mice to Men: Using HLA Transgenic Mice to Enhance the Future Prediction and Prevention of Autoimmune Type 1 Diabetes in Humans.

    Science.gov (United States)

    Serreze, David V; Niens, Marijke; Kulik, John; DiLorenzo, Teresa P

    2016-01-01

    Similar to the vast majority of cases in humans, the development of type 1 diabetes (T1D) in the NOD mouse model is due to T-cell mediated autoimmune destruction of insulin producing pancreatic β cells. Particular major histocompatibility complex (MHC) haplotypes (designated HLA in humans; and H2 in mice) provide the primary genetic risk factor for T1D development. It has long been appreciated that within the MHC, particular unusual class II genes contribute to the development of T1D in both humans and NOD mice by allowing for the development and functional activation of β cell autoreactive CD4 T cells. However, studies in NOD mice have revealed that through interactions with other background susceptibility genes, the quite common class I variants (K(d), D(b)) characterizing this strain's H2 (g7) MHC haplotype aberrantly acquire an ability to support the development of β cell autoreactive CD8 T cell responses also essential to T1D development. Similarly, recent studies indicate that in the proper genetic context some quite common HLA class I variants also aberrantly contribute to T1D development in humans. This review focuses on how "humanized" HLA transgenic NOD mice can be created and used to identify class I dependent β cell autoreactive CD8 T cell populations of clinical relevance to T1D development. There is also discussion on how HLA transgenic NOD mice can be used to develop protocols that may ultimately be useful for the prevention of T1D in humans by attenuating autoreactive CD8 T cell responses against pancreatic β cells. PMID:27150089

  2. Type 1 Diabetes Prone NOD Mice Have Diminished Cxcr1 mRNA Expression in Polymorphonuclear Neutrophils and CD4+ T Lymphocytes.

    Directory of Open Access Journals (Sweden)

    Karine Haurogné

    Full Text Available In humans, CXCR1 and CXCR2 are two homologous proteins that bind ELR+ chemokines. Both receptors play fundamental roles in neutrophil functions such as migration and reactive oxygen species production. Mouse Cxcr1 and Cxcr2 genes are located in an insulin-dependent diabetes genetic susceptibility locus. The non obese diabetic (NOD mouse is a spontaneous well-described animal model for insulin-dependent type 1 diabetes. In this disease, insulin deficiency results from the destruction of insulin-producing beta cells by autoreactive T lymphocytes. This slow-progressing disease is dependent on both environmental and genetic factors. Here, we report descriptive data about the Cxcr1 gene in NOD mice. We demonstrate decreased expression of mRNA for Cxcr1 in neutrophils and CD4+ lymphocytes isolated from NOD mice compared to other strains, related to reduced NOD Cxcr1 gene promoter activity. Looking for Cxcr1 protein, we next analyze the membrane proteome of murine neutrophils by mass spectrometry. Although Cxcr2 protein is clearly found in murine neutrophils, we did not find evidence of Cxcr1 peptides using this method. Nevertheless, in view of recently-published experimental data obtained in NOD mice, we argue for possible Cxcr1 involvement in type 1 diabetes pathogenesis.

  3. Sleeping Beauty Transposon Mutagenesis as a Tool for Gene Discovery in the NOD Mouse Model of Type 1 Diabetes.

    Science.gov (United States)

    Elso, Colleen M; Chu, Edward P F; Alsayb, May A; Mackin, Leanne; Ivory, Sean T; Ashton, Michelle P; Bröer, Stefan; Silveira, Pablo A; Brodnicki, Thomas C

    2015-12-01

    A number of different strategies have been used to identify genes for which genetic variation contributes to type 1 diabetes (T1D) pathogenesis. Genetic studies in humans have identified >40 loci that affect the risk for developing T1D, but the underlying causative alleles are often difficult to pinpoint or have subtle biological effects. A complementary strategy to identifying "natural" alleles in the human population is to engineer "artificial" alleles within inbred mouse strains and determine their effect on T1D incidence. We describe the use of the Sleeping Beauty (SB) transposon mutagenesis system in the nonobese diabetic (NOD) mouse strain, which harbors a genetic background predisposed to developing T1D. Mutagenesis in this system is random, but a green fluorescent protein (GFP)-polyA gene trap within the SB transposon enables early detection of mice harboring transposon-disrupted genes. The SB transposon also acts as a molecular tag to, without additional breeding, efficiently identify mutated genes and prioritize mutant mice for further characterization. We show here that the SB transposon is functional in NOD mice and can produce a null allele in a novel candidate gene that increases diabetes incidence. We propose that SB transposon mutagenesis could be used as a complementary strategy to traditional methods to help identify genes that, when disrupted, affect T1D pathogenesis. PMID:26438296

  4. High-throughput sequencing reveals restricted TCR Vβ usage and public TCRβ clonotypes among pancreatic lymph node memory CD4(+) T cells and their involvement in autoimmune diabetes.

    Science.gov (United States)

    Marrero, Idania; Aguilera, Carlos; Hamm, David E; Quinn, Anthony; Kumar, Vipin

    2016-06-01

    Islet-reactive memory CD4(+) T cells are an essential feature of type 1 diabetes (T1D) as they are involved in both spontaneous disease and in its recurrence after islet transplantation. Expansion and enrichment of memory T cells have also been shown in the peripheral blood of diabetic patients. Here, using high-throughput sequencing, we investigated the clonal diversity of the TCRβ repertoire of memory CD4(+) T cells in the pancreatic lymph nodes (PaLN) of non-obese diabetic (NOD) mice and examined their clonal overlap with islet-infiltrating memory CD4T cells. Both prediabetic and diabetic NOD mice exhibited a restricted TCRβ repertoire dominated by clones expressing TRBV13-2, TRBV13-1 or TRBV5 gene segments. There is a limited degree of TCRβ overlap between the memory CD4 repertoire of PaLN and pancreas as well as between the prediabetic and diabetic group. However, public TCRβ clonotypes were identified across several individual animals, some of them with sequences similar to the TCRs from the islet-reactive T cells suggesting their antigen-driven expansion. Moreover, the majority of the public clonotypes expressed TRBV13-2 (Vβ8.2) gene segment. Nasal vaccination with an immunodominat peptide derived from the TCR Vβ8.2 chain led to protection from diabetes, suggesting a critical role for Vβ8.2(+) CD4(+) memory T cells in T1D. These results suggest that memory CD4(+) T cells bearing limited dominant TRBV genes contribute to the autoimmune diabetes and can be potentially targeted for intervention in diabetes. Furthermore, our results have important implications for the identification of public T cell clonotypes as potential novel targets for immune manipulation in human T1D. PMID:27161799

  5. Dietary supplementation with high doses of regular vitamin D3 safely reduces diabetes incidence in NOD mice when given early and long term.

    Science.gov (United States)

    Takiishi, Tatiana; Ding, Lei; Baeke, Femke; Spagnuolo, Isabella; Sebastiani, Guido; Laureys, Jos; Verstuyf, Annemieke; Carmeliet, Geert; Dotta, Francesco; Van Belle, Tom L; Gysemans, Conny A; Mathieu, Chantal

    2014-06-01

    High doses of the active form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], prevent diabetes in the NOD mouse but also elicit unwanted calcemic side effects. Because immune cells themselves can convert vitamin D3 into 1,25(OH)2D3 locally, we hypothesized that dietary vitamin D3 can also prevent disease. Thus, we evaluated whether dietary administration of high doses of regular vitamin D3 (800 IU/day) during different periods of life (pregnancy and lactation, early life [3-14 weeks of age], or lifelong [3-35 weeks of age]) safely prevents diabetes in NOD mice. We found that only lifelong treatment raised serum 25-hydroxyvitamin D3 from 173 nmol/L in controls to 290 nmol/L, without inducing signs of calcemic or bone toxicity, and significantly reduced diabetes development in both male and female NOD mice. This diabetes protection by vitamin D3 correlated with preserved pancreatic insulin content and improved insulitis scores. Moreover, vitamin D3 treatment decreased interferon-γ-positive CD8(+) T cells and increased CD4(+)(CD25(+))FoxP3(+) T cells in pancreatic draining lymph nodes. In conclusion, this study shows for the first time that high doses of regular dietary vitamin D3 can safely prevent diabetes in NOD mice when administered lifelong, although caution is warranted with regards to administering equivalently high doses in humans. PMID:24550187

  6. Easily obtainable clinical features increase the diagnostic accuracy for later autoimmune diabetes in adults. An evidence based report

    NARCIS (Netherlands)

    Lutgens, M.W.M.D.; Meijer, M.; Peeters, B.; Poulsen, M.N.F.; Rutten, M.J.; Bots, M.L.; Heijden, van der G.J.M.G.; Soedamah-Muthu, S.S.

    2008-01-01

    Background Latent autoimmune diabetes in adults (LADA) represents a subgroup of diabetes mellitus. LADA is characterised by adult-onset diabetes and circulating autoimmune antibodies. LADA patients may need a different therapeutic approach than the usual type 2 diabetes mellitus. When LADA is inadeq

  7. Over-expression of Stat5b confers protection against diabetes in the non-obese diabetic (NOD) mice via up-regulation of CD4+CD25+ regulatory T cells

    International Nuclear Information System (INIS)

    Highlights: ► This is the first study to provide direct evidence of the role of Stat5b in NOD mice. ► Over-expression of wild type Stat5b transgene protects NOD mice against diabetes. ► This protection may be mediated by the up-regulation of CD4+CD25+ Tregs. -- Abstract: The signal transducers and activators of transcription (STAT) family of proteins play a critical role in cytokine signaling required for fine tuning of immune regulation. Previous reports showed that a mutation (L327M) in the Stat5b protein leads to aberrant cytokine signaling in the NOD mice. To further elaborate the role of Stat5b in diabetes, we established a NOD transgenic mouse that over-expresses the wild type Stat5b gene. The incidences of spontaneous diabetes as well as cyclophosphamide-induced diabetes were significantly reduced and delayed in the Stat5b transgenic NOD mice compared to their littermate controls. The total cell numbers of CD4+ T cells and especially CD8+ T cells in the spleen and pancreatic lymph node were increased in the Stat5b transgenic NOD mice. Consistent with these findings, CD4+ and CD8+ T cells from the Stat5b transgenic NOD mice showed a higher proliferation capacity and up-regulation of multiple cytokines including IL-2, IFN-γ, TNF-α and IL-10 as well as anti-apoptotic gene Bcl-xl. Furthermore, the number and proportion of CD4+CD25+ regulatory T cells were significantly increased in transgenic mice although in vitro suppression ability of the regulatory T-cells was not affected by the transgene. Our results suggest that Stat5b confers protection against diabetes in the NOD mice by regulating the numbers and function of multiple immune cell types, especially by up-regulating CD4+CD25+ regulatory T cells.

  8. Prevention of spontaneous and cyclophosphamide-induced diabetes in non-obese diabetic (NOD) mice with oral 2-acetyl-4-tetrahydroxybutylimidazole (THI), a component of caramel colouring III.

    Science.gov (United States)

    Mandel, T E; Koulmanda, M; Mackay, I R

    1992-01-01

    The effect of oral administration of THI, a compound present in ammonia caramel food colouring, was studied in spontaneous and induced murine diabetes mellitus. Continuous administration of THI at 400 ppm in drinking water reduced the prevalence of spontaneous diabetes in female NOD/Lt mice from 63% in untreated controls to 8% in treated animals. Since cyclophosphamide (CP) accelerates and intensifies diabetes in NOD mice, we also studied the effect of THI in this model. Diabetes incidence was reduced from 100% in mice given only CP to 13-14% in mice given THI either concurrently or from 14 days previously. Histologically, THI greatly reduced the severity of insulitis. As measured by flow cytometry, all THI-treated mice had a 60-80% reduction in splenic CD4+ and CD8+ T cells. THI-treated mice showed no untoward effects and specifically no weight loss, or pathological changes in their livers, kidneys or lungs. However, there was moderate atrophy of the thymus cortex. THI is a small imidazole-containing compound with structural similarity to histamine and urocanic acid, both known to have immunosuppressive properties. It is a widely used food additive with no known long-term toxic effects at low dosage. Thus, THI could be a useful immunosuppressive agent. PMID:1606724

  9. Role of Peritoneal Macrophages in Cytomegalovirus-induced Acceleration of Autoimmune Diabetes in BB-rats

    Directory of Open Access Journals (Sweden)

    Jan-Luuk Hillebrands

    2003-01-01

    Full Text Available Background: As one of the natural perturbants, infection with cytomegalovirus (CMV is believed to play a role in the development of Type I diabetes. Using the DP-BB rat model for autoimmune diabetes, we here report about possible mechanisms responsible for R(atCMV-induced accelerated onset of diabetes.

  10. LADA (latent autoimmune diabetes in adults in Norway – occurrence, risk factors, treatment and complications

    Directory of Open Access Journals (Sweden)

    Sofia Carlsson

    2013-06-01

    Full Text Available LADA (latent autoimmune diabetes in adults may be the most common form of autoimmune diabetes and thus encompasses a significant proportion of the diabetic population. Still, knowledge about this common form of diabetes is limited. In this paper we give an overview of some aspects of LADA, primarily using data from the Nord-Trøndelag Health Study (HUNT. In HUNT, LADA accounts for 7% of all incident cases of diabetes in adults. Data from HUNT indicate that risk factors for LADA include overweight, physical inactivity, family history of diabetes and low psychosocial well-being. Risk factors thus seem to be largely similar to those of type 2 diabetes which suggests a partially shared pathogenesis, in spite of the autoimmune nature of LADA. With regard to genetic factors LADA may be a genetic mix of type 1 and type 2 diabetes, as LADA patients seem to have an increased prevalence of HLA haplotypes linked to type 1 diabetes, and possibly also genes associated with type 2 diabetes. Patients with LADA are at increased mortality risk, primarily from cardiovascular disease. The excess risk seems to be linked to poor glycemic control rather than metabolic risk factors. These results emphasise the importance of optimal treatment modalities to improve survival in LADA. Documentation of optimal treatment for LADA is still lacking and there is an urgent need for studies in this field.

  11. Combined treatment with sitagliptin and vitamin D in a patient with latent autoimmune diabetes in adults

    Science.gov (United States)

    Rapti, E; Karras, S; Grammatiki, M; Mousiolis, A; Tsekmekidou, X; Potolidis, E; Zebekakis, P; Daniilidis, M

    2016-01-01

    Summary Latent autoimmune diabetes in adults (LADA) is a relatively new type of diabetes with a clinical phenotype of type 2 diabetes (T2D) and an immunological milieu characterized by high titers of islet autoantibodies, resembling the immunological profile of type 1 diabetes (T1D). Herein, we report a case of a young male, diagnosed with LADA based on both clinical presentation and positive anti-glutamic acid decarboxylase antibodies (GAD-abs), which were normalized after combined treatment with a dipeptidyl peptidase-4 inhibitor (DPP-4) (sitagliptin) and cholecalciferol. Learning points Anti-glutamic acid decarboxylase antibodies (GAD-abs) titers in young patients being previously diagnosed as type 2 diabetes (T2D) may help establish the diagnosis of latent autoimmune diabetes in adults (LADA). Sitagliptin administration in patients with LADA might prolong the insulin-free period. Vitamin D administration in patients with LADA might have a protective effect on the progression of the disease.

  12. Protective role of adenovirus vector-mediated interleukin-10 gene therapy on endogenous islet β-cells in recent-onset type 1 diabetes in NOD mice

    Science.gov (United States)

    LI, CHENG; ZHANG, LIJUAN; CHEN, YANYAN; LIN, XIAOJIE; LI, TANG

    2016-01-01

    The aim of the present study was to provide an animal experimental basis for the protective effect of the adenoviral vector-mediated interleukin-10 (Ad-mIL-10) gene on islet β-cells during the early stages of type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. A total of 24 female NOD mice at the onset of diabetes were allocated at random into three groups (n=8 per group): Group 1, intraperitoneally injected with 0.1 ml Ad-mIL-10; group 2, intraperitoneally injected with 0.1 ml adenovirus vector; and group 3, was a diabetic control. In addition to groups 1, 2 and 3, 8 age- and gender-matched NOD mice were intraperitoneally injected with 0.1 ml PBS and assigned to group 4 as a normal control. All mice were examined weekly for body weight, urine glucose and blood glucose values prior to onset of diabetes, and at 1, 2 and 3 weeks after that, and all mice were sacrificed 3 weeks after injection. Serum levels of interleukin (IL)-10, interferon (IFN)-γ, IL-4, insulin and C-peptide were evaluated, and in addition the degree of insulitis and the local expression of IL-10 gene in the pancreas were detected. The apoptosis rate of pancreatic β-cells was determined using a TUNEL assay. Compared with groups 2 and 3, IL-10 levels in the serum and pancreas were elevated in group 1. Serum IFN-γ levels were decreased while serum IL-4 levels and IFN-γ/IL-4 ratio were significantly increased in group 1 (P0.05). The administration of the Ad-mIL-10 gene induced limited immune regulatory and protective effects on islet β-cell function in NOD mice with early T1D, while no significant reduction in insulitis, islet β-cell apoptosis rate and blood glucose was observed.

  13. Anterior Hypopituitarism is Rare and Autoimmune Disease is Common in Adults with Idiopathic Central Diabetes Insipidus.

    LENUS (Irish Health Repository)

    2012-02-01

    Objective: Central diabetes insipidus is a rare clinical condition with a heterogenous aetiology. Up to 40% of cases are classified as idiopathic, though many of these are thought to have an autoimmune basis. Published data has suggested that anterior hypopituitarism is common in childhood onset idiopathic diabetes insipidus. We aimed to assess the incidence of anterior hypopituitarism in a cohort of adult patients with idiopathic diabetes insipidus. Design and Patients: We performed a retrospective review of the databases of two pituitary investigation units. This identified 39 patients with idiopathic diabetes insipidus. All had undergone MRI scanning and dynamic pituitary testing (either insulin tolerance testing or GHRH\\/arginine and short synacthen testing) to assess anterior pituitary function. Results: One patient had partial growth hormone deficiency; no other anterior pituitary hormonal deficits were found. 33% had at least one autoimmune disease in addition to central diabetes insipidus. Conclusions: Our data suggest that anterior hypopituitarism is rare in adult idiopathic diabetes insipidus. Routine screening of these patients for anterior hypopituitarism may not therefore be indicated. The significant prevalence of autoimmune disease in this cohort supports the hypothesis that idiopathic diabetes insipidus may have an autoimmune aetiology.

  14. The gene expression profile of CD11c+ CD8α- dendritic cells in the pre-diabetic pancreas of the NOD mouse.

    Directory of Open Access Journals (Sweden)

    Wouter Beumer

    Full Text Available Two major dendritic cell (DC subsets have been described in the pancreas of mice: The CD11c+ CD8α- DCs (strong CD4+ T cell proliferation inducers and the CD8α+ CD103+ DCs (T cell apoptosis inducers. Here we analyzed the larger subset of CD11c+ CD8α- DCs isolated from the pancreas of pre-diabetic NOD mice for genome-wide gene expression (validated by Q-PCR to elucidate abnormalities in underlying gene expression networks. CD11c+ CD8α- DCs were isolated from 5 week old NOD and control C57BL/6 pancreas. The steady state pancreatic NOD CD11c+ CD8α- DCs showed a reduced expression of several gene networks important for the prime functions of these cells, i.e. for cell renewal, immune tolerance induction, migration and for the provision of growth factors including those for beta cell regeneration. A functional in vivo BrdU incorporation test showed the reduced proliferation of steady state pancreatic DC. The reduced expression of tolerance induction genes (CD200R, CCR5 and CD24 was supported on the protein level by flow cytometry. Also previously published functional tests on maturation, immune stimulation and migration confirm the molecular deficits of NOD steady state DC. Despite these deficiencies NOD pancreas CD11c+ CD8α- DCs showed a hyperreactivity to LPS, which resulted in an enhanced pro-inflammatory state characterized by a gene profile of an enhanced expression of a number of classical inflammatory cytokines. The enhanced up-regulation of inflammatory genes was supported by the in vitro cytokine production profile of the DCs. In conclusion, our data show that NOD pancreatic CD11c+ CD8α- DCs show various deficiencies in steady state, while hyperreactive when encountering a danger signal such as LPS.

  15. Transgenic expression of TGF-β on thyrocytes inhibits development of spontaneous autoimmune thyroiditis and increases regulatory T cells in thyroids of NOD.H-2h4 mice

    OpenAIRE

    Yu, Shiguang; Fang, Yujiang; Sharp, Gordon C.; Braley-Mullen, Helen

    2010-01-01

    Transgenic NOD.H-2h4 mice expressing TGF-β under control of the thyroglobulin promoter were generated to address the role of TGF-β in development of thyrocyte hyperplasia. In contrast to non-transgenic (Tg−) littermates which develop lymphocytic spontaneous autoimmune thyroiditis (L-SAT), all TGF-β transgenic (Tg+) mice given NaI water for 2–7 mo develop thyroid lesions characterized by severe thyroid epithelial cell hyperplasia and proliferation (TEC H/P) with fibrosis and less lymphocyte in...

  16. Spectratyping analysis of the islet-reactive T cell repertoire in diabetic NOD Igμnull mice after polyclonal B cell reconstitution

    Directory of Open Access Journals (Sweden)

    Sercarz Eli E

    2011-07-01

    Full Text Available Abstract Background Non Obese Diabetic mice lacking B cells (NOD.Igμnull mice do not develop diabetes despite their susceptible background. Upon reconstitution of B cells using a chimera approach, animals start developing diabetes at 20 weeks of age. Methods We have used the spectratyping technique to follow the T cell receptor (TCR V beta repertoire of NOD.Igμnull mice following B cell reconstitution. This technique provides an unbiased approach to understand the kinetics of TCR expansion. We have also analyzed the TCR repertoire of reconstituted animals receiving cyclophosphamide treatment and following tissue transplants to identify common aggressive clonotypes. Results We found that B cell reconstitution of NOD.Igμnull mice induces a polyclonal TCR repertoire in the pancreas 10 weeks later, gradually diversifying to encompass most BV families. Interestingly, these clonotypic BV expansions are mainly confined to the pancreas and are absent from pancreatic lymph nodes or spleens. Cyclophosphamide-induced diabetes at 10 weeks post-B cell reconstitution reorganized the predominant TCR repertoires by removing potential regulatory clonotypes (BV1, BV8 and BV11 and increasing the frequency of others (BV4, BV5S2, BV9, BV16-20. These same clonotypes are more frequently present in neonatal pancreatic transplants under the kidney capsule of B-cell reconstituted diabetic NOD.Igμnull mice, suggesting their higher invasiveness. Phenotypic analysis of the pancreas-infiltrating lymphocytes during diabetes onset in B cell reconstituted animals show a predominance of CD19+ B cells with a B:T lymphocyte ratio of 4:1. In contrast, in other lymphoid organs (pancreatic lymph nodes and spleens analyzed by FACS, the B:T ratio was 1:1. Lymphocytes infiltrating the pancreas secrete large amounts of IL-6 and are of Th1 phenotype after CD3-CD28 stimulation in vitro. Conclusions Diabetes in NOD.Igμnull mice appears to be caused by a polyclonal repertoire of T cell

  17. IMMUNOLOGICAL AND METABOLIC FACTORS INTERACTION IN THE DEVELOPMENT AND PROGRESSION OF MICROVASCULAR COMPLICATIONS IN LATENT AUTOIMMUNE DIABETES OF ADULTS (LADA)

    OpenAIRE

    T. V. Saprina; T S Prokhorenko; F. E. Lazarenko; I. N. Vorozhtsova; N V Ryazantseva

    2014-01-01

    Some researchers found that the development of microvascular complications (nephropathy, retinopathy) with latent autoimmune diabetes adults (LADA) occurs much earlier than in type 1 diabetes mellitus. The research devoted to the study of the spectrum and the time of development of microangiopathy in patients with latent autoimmune diabetes of adults, compared to patients with type 1 and 2 diabetes mellitus. Also studied immunological factors (cytokine secretion of mononuclear leukocytes) as ...

  18. Lessons from type 1 diabetes for understanding natural history and prevention of autoimmune disease

    OpenAIRE

    Simmons, Kimber; Michels, Aaron W

    2014-01-01

    Type 1 diabetes (T1D) is a chronic autoimmune disorder resulting from immune mediated destruction of insulin producing beta cells within the pancreatic islets. The natural history of T1D is well defined with distinct stages in disease development. Genetics and environmental factors contribute to disease susceptibility, followed by autoimmune targeting of proteins within beta cells. Preclinical T1D is marked by the presence of islet autoantibodies and normal blood glucose levels. Prediction of...

  19. Over-expression of Stat5b confers protection against diabetes in the non-obese diabetic (NOD) mice via up-regulation of CD4{sup +}CD25{sup +} regulatory T cells

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Yulan; Purohit, Sharad [Center for Biotechnology and Genomic Medicine, Georgia Health Sciences University, GA (United States); Department of Pathology, Medical College of Georgia, Georgia Health Sciences University, GA (United States); Chen, Xueqin; Yi, Bing [Center for Biotechnology and Genomic Medicine, Georgia Health Sciences University, GA (United States); She, Jin-Xiong, E-mail: jshe@georgiahealth.edu [Center for Biotechnology and Genomic Medicine, Georgia Health Sciences University, GA (United States); Department of Pathology, Medical College of Georgia, Georgia Health Sciences University, GA (United States)

    2012-08-10

    Highlights: Black-Right-Pointing-Pointer This is the first study to provide direct evidence of the role of Stat5b in NOD mice. Black-Right-Pointing-Pointer Over-expression of wild type Stat5b transgene protects NOD mice against diabetes. Black-Right-Pointing-Pointer This protection may be mediated by the up-regulation of CD4{sup +}CD25{sup +} Tregs. -- Abstract: The signal transducers and activators of transcription (STAT) family of proteins play a critical role in cytokine signaling required for fine tuning of immune regulation. Previous reports showed that a mutation (L327M) in the Stat5b protein leads to aberrant cytokine signaling in the NOD mice. To further elaborate the role of Stat5b in diabetes, we established a NOD transgenic mouse that over-expresses the wild type Stat5b gene. The incidences of spontaneous diabetes as well as cyclophosphamide-induced diabetes were significantly reduced and delayed in the Stat5b transgenic NOD mice compared to their littermate controls. The total cell numbers of CD4{sup +} T cells and especially CD8{sup +} T cells in the spleen and pancreatic lymph node were increased in the Stat5b transgenic NOD mice. Consistent with these findings, CD4{sup +} and CD8{sup +} T cells from the Stat5b transgenic NOD mice showed a higher proliferation capacity and up-regulation of multiple cytokines including IL-2, IFN-{gamma}, TNF-{alpha} and IL-10 as well as anti-apoptotic gene Bcl-xl. Furthermore, the number and proportion of CD4{sup +}CD25{sup +} regulatory T cells were significantly increased in transgenic mice although in vitro suppression ability of the regulatory T-cells was not affected by the transgene. Our results suggest that Stat5b confers protection against diabetes in the NOD mice by regulating the numbers and function of multiple immune cell types, especially by up-regulating CD4{sup +}CD25{sup +} regulatory T cells.

  20. The Effect of Diabetes-Associated Autoantigens on Cell Processes in Human PBMCs and Their Relevance to Autoimmune Diabetes Development

    Czech Academy of Sciences Publication Activity Database

    Včeláková, J.; Blatný, R.; Halbhuber, Z.; Kolář, Michal; Neuwirth, Aleš; Petruželková, L.; Ulmannová, T.; Koloušková, S.; Sumnik, Z.; Pithová, P.; Krivjanská, M.; Filipp, Dominik; Štechová, K.

    2013-01-01

    Roč. 2013, May (2013), s. 589451. ISSN 2314-6745 Grant ostatní: GA MŠk(CZ) 2B06019 Institutional support: RVO:68378050 Keywords : type 1 diabetes * autoimmune disease * Th17 * TGF-beta Subject RIV: EB - Genetics ; Molecular Biology

  1. High Levels of Education Are Associated With an Increased Risk of Latent Autoimmune Diabetes in Adults

    OpenAIRE

    Olsson, Lisa; Ahlbom, Anders; Grill, Valdemar; Midthjell, Kristian; Carlsson, Sofia

    2010-01-01

    OBJECTIVE To investigate whether the risk for autoimmune diabetes in adults differs between socioeconomic groups and to compare such risk with that for type 2 diabetes. RESEARCH DESIGN AND METHODS The inhabitants of the Norwegian county of Nord-Trøndelag were investigated by questionnaires and clinical examinations on three occasions during 1984–2008. We used information from a subset consisting of 56,296 subjects (participating in at least two surveys), including 122 incident cases of autoim...

  2. Longitudinal three-dimensional visualisation of autoimmune diabetes by functional optical coherence imaging

    DEFF Research Database (Denmark)

    Berclaz, Corinne; Schmidt-Christensen, Anja; Szlag, Daniel;

    2016-01-01

    destruction and associated alterations of islet vascularisation. METHODS: NOD mouse and human islets transplanted into the anterior chamber of the eye (ACE) were imaged with FOCI, in which the optical contrast of FOCI is based on intrinsic variations of the index of refraction resulting in a faster...... functional and structural diabetes-induced alterations of the islets. The label-free detection of beta cell volume and infiltration together with vascularisation offers a unique extension to study ACE-transplanted human islets. These results are contributing to a deeper understanding of human islet...... transplant rejection and label-free in vivo monitoring of drug efficacy....

  3. Novel Mode of Defective Neural Tube Closure in the Non-Obese Diabetic (NOD) Mouse Strain.

    Science.gov (United States)

    Salbaum, J Michael; Kruger, Claudia; MacGowan, Jacalyn; Herion, Nils J; Burk, David; Kappen, Claudia

    2015-01-01

    Failure to close the neural tube results in birth defects, with severity ranging from spina bifida to lethal anencephaly. Few genetic risk factors for neural tube defects are known in humans, highlighting the critical role of environmental risk factors, such as maternal diabetes. Yet, it is not well understood how altered maternal metabolism interferes with embryonic development, and with neurulation in particular. We present evidence from two independent mouse models of diabetic pregnancy that identifies impaired migration of nascent mesodermal cells in the primitive streak as the morphogenetic basis underlying the pathogenesis of neural tube defects. We conclude that perturbed gastrulation not only explains the neurulation defects, but also provides a unifying etiology for the broad spectrum of congenital malformations in diabetic pregnancies. PMID:26593875

  4. Biopsy of the pancreas: the predictive value and therapeutic impact on autoimmune diabetes

    Directory of Open Access Journals (Sweden)

    Wael Nassar

    2015-01-01

    Full Text Available Diabetes mellitus is by definition an end-stage organ failure. Type 1 diabetes mellitus is an autoimmune disease. Autoinflammatory infiltrate appears to characterize the insulitis associated with type 1 diabetes mellitus. In recent times, a comprehensive composition of peri-islet capsules and their basement membrane (BM has been described. Lymphocytic infiltration around the islets without invasion of the BM is the first step in disease induction (nondestructive insulitis phase. Invasion of the BM by leukocytic infiltration (destructive insulitis phase occurs over a period of several years, offering good window for therapeutic intervention. Clinical symptoms appear only when 70-90% of β-cell mass are destroyed. These data emphasize on the importance of identification and classification of such pathologic features by performing a biopsy of the pancreas, along with histoimmunochemistry analysis at the prehyperglycemic stage in a high-risk, genetically predisposed, autoimmune-suspected patient, which may at least in part help in achieving new therapeutic approaches and halting the progression to end-stage pancreatic disease known as diabetes mellitus. In this review, we emphasize the predictive role biopsy of the pancreas can have, by building up a solid gold standard tool in the diagnosis, staging, and therapeutic follow-up of autoimmune diabetes mellitus.

  5. Dysregulation of T lymphocyte proliferative responses in autoimmunity.

    Directory of Open Access Journals (Sweden)

    Sydney K Elizer

    Full Text Available T cells are critically dependent on cellular proliferation in order to carry out their effector functions. Autoimmune strains are commonly thought to have uncontrolled T cell proliferation; however, in the murine model of autoimmune diabetes, hypo-proliferation of T cells leading to defective AICD was previously uncovered. We now determine whether lupus prone murine strains are similarly hyporesponsive. Upon extensive characterization of T lymphocyte activation, we have observed a common feature of CD4 T cell activation shared among three autoimmune strains-NOD, MRL, and NZBxNZW F1s. When stimulated with a polyclonal mitogen, CD4 T cells demonstrate arrested cell division and diminished dose responsiveness as compared to the non-autoimmune strain C57BL/6, a phenotype we further traced to a reliance on B cell mediated costimulation, which underscores the success of B cell directed immune therapies in preventing T cell mediated tissue injury. In turn, the diminished proliferative capacity of these CD4 T cells lead to a decreased, but activation appropriate, susceptibility to activation induced cell death. A similar decrement in stimulation response was observed in the CD8 compartment of NOD mice; NOD CD8 T cells were distinguished from lupus prone strains by a diminished dose-responsiveness to anti-CD3 mediated stimulation. This distinction may explain the differential pathogenetic pathways activated in diabetes and lupus prone murine strains.

  6. Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a Broad Clinical Phenotype

    DEFF Research Database (Denmark)

    Hawa, Mohammed I; Kolb, Hubert; Schloot, Nanette;

    2013-01-01

    autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 WHO IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P <0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than......OBJECTIVESSpecific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non-insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes.RESEARCH DESIGN AND METHODSWe...... consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30-70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A).RESULTSOf 6,156 patients, 541...

  7. STUDY ON THE RELATIONSHIP BETWEEN MITOCHONDRIAL GENE MUTATION AND LATENT AUTOIMMUNE DIABETES MELLITUS IN ADULTS

    Institute of Scientific and Technical Information of China (English)

    崔璨; 李强; 张一娜; 张巾超

    2002-01-01

    Objective.To identify the A3243G mutation of mitochondrial(mt) DNA in patients with latent autoimmune diabetes mellitus in adults (LADA) of Han nationality in the northeast area of China. Methods.Seventy nine diabetics of Han nationality,whose families have resided in the northeast area of China for more than 3 generations,were divided into 3 groups: Group 1 (22 cases of type 2 diabetes with maternal inheritance history),Group 2 (34 cases of LADA),Group 3 (23 cases of type 1 diabetes in adolescents).The A3243G of mt DNA was detected in these 79 subjects with the method of PCR RFLP. Results.None of the 79 diabetics studied was positively identified for the A3243G mutation of mt DNA. Conclusion.The A3243G mutation of mt DNA might not be related to the onset of LADA in diabetic population of Han nationality in northeast area of China and there might not be close relationship between A3243G mutation of mt DNA and autoimmunity.

  8. Nodding Syndrome

    Centers for Disease Control (CDC) Podcasts

    2013-12-19

    Dr. Scott Dowell, a CDC director, discusses the rare illness, nodding syndrome, in children in Africa.  Created: 12/19/2013 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 1/27/2014.

  9. Pancreatic insulin-producing cells differentiated from human embryonic stem cells correct hyperglycemia in SCID/NOD mice, an animal model of diabetes.

    Directory of Open Access Journals (Sweden)

    Xiu-feng Hua

    Full Text Available Human pancreatic islet transplantation is a prospective curative treatment for diabetes. However, the lack of donor pancreases greatly limits this approach. One approach to overcome the limited supply of donor pancreases is to generate functional islets from human embryonic stem cells (hESCs, a cell line with unlimited proliferative capacity, through rapid directed differentiation. This study investigated whether pancreatic insulin-producing cells (IPCs differentiated from hESCs could correct hyperglycemia in severe combined immunodeficient (SCID/non-obese diabetic (NOD mice, an animal model of diabetes.We generated pancreatic IPCs from two hESC lines, YT1 and YT2, using an optimized four-stage differentiation protocol in a chemically defined culture system. Then, about 5-7 × 10(6 differentiated cells were transplanted into the epididymal fat pad of SCID/NOD mice (n = 20. The control group were transplanted with undifferentiated hESCs (n = 6. Graft survival and function were assessed using immunohistochemistry, and measuring serum human C-peptide and blood glucose levels.The pancreatic IPCs were generated by the four-stage differentiation protocol using hESCs. About 17.1% of differentiated cells expressed insulin, as determined by flow cytometry. These cells secreted insulin/C-peptide following glucose stimulation, similarly to adult human islets. Most of these IPCs co-expressed mature β cell-specific markers, including human C-peptide, GLUT2, PDX1, insulin, and glucagon. After implantation into the epididymal fat pad of SCID/NOD mice, the hESC-derived pancreatic IPCs corrected hyperglycemia for ≥ 8 weeks. None of the animals transplanted with pancreatic IPCs developed tumors during the time. The mean survival of recipients was increased by implanted IPCs as compared to implanted undifferentiated hESCs (P<0.0001.The results of this study confirmed that human terminally differentiated pancreatic IPCs derived from hESCs can correct

  10. [Genetic and humoral autoimmunity markers of type 1 diabetes: from theory to practice].

    Science.gov (United States)

    Silva, Maria Elizabeth Rossi da; Mory, Denise; Davini, Elaine

    2008-03-01

    Type 1 A diabetes mellitus (T1AD) results from the autoimmune destruction of the insulin producing pancreatic beta-cells. The largest contribution to genetic susceptibility comes from several genes located in the major histocompatibility complex on chromosome 6p21.3 (IDDM1 locus), accounting for at least 40% of the family aggregation of this disease. The highest-risk human leukocyte antigen HLA genotype for T1AD is DR3-DQA1*0501-DQB1*0201/DR4-DQA1*0301-DQB1*0302, whereas -DR15-DQA1*0102-DQB1*0602 haplotype is associated with dominant protection. Three other T1D loci associated with predisposition are the Variable Number for Tandem Repeats (VNTR) near the insulin gene (IDDM2), which accounts to 10% of genetic susceptibility, the Cytotoxic T-Lymphocyte-associated Antigen (CTLA-4)(IDDM 12) and the Protein Tyrosine Phosphatasis Nonreceptor-type 22 (PTPN22). Many other gene suspected to predispose to autoimmunity have been investigated. T1AD is frequently associated with autoimmune thyroid disease, celiac disase, Addison s disease and many other autoimmune diseases, characterized by organ-specific autoantibodies and related to the same genetic background. Using these autoantibodies, organ specific autoimmunity may be detected before the development of clinical disease preventing significant morbidity. PMID:18438527

  11. Childhood malignancy and maternal diabetes or other auto-immune disease during pregnancy

    OpenAIRE

    Westbom, L; Åberg, A; Källén, B

    2002-01-01

    Among 4380 children born in 1987–1997 of women with a diagnosis of diabetes and alive at the age of one, 10 were registered in the Swedish Cancer Registry before the end of 1998. The odds ratio for having a childhood cancer after maternal diabetes, stratified for year of birth, maternal age, parity, multiple birth, and 500 g birth weight class was 2.25 (95%CI 1.22–4.15). Among 5842 children born during the period 1973–1997 whose mothers had other auto-immune diseases (SLE, rheumatoid arthriti...

  12. Identification and Antioxidant Activity of the Extracts of Eugenia uniflora Leaves. Characterization of the Anti-Inflammatory Properties of Aqueous Extract on Diabetes Expression in an Experimental Model of Spontaneous Type 1 Diabetes (NOD Mice

    Directory of Open Access Journals (Sweden)

    Nayara Simon Gonzalez Schumacher

    2015-10-01

    Full Text Available Medical and folklore reports suggest that Eugenia uniflora (E. uniflora is a functional food that contains numerous compounds in its composition, with anti-inflammatory, antioxidant and anti-diabetic effects. In the present study, we investigated the best solvents (water, ethanol and methanol/acetone for extracting bioactive compounds of E. uniflora leaves, assessing total phenols and the antioxidant activity of the extracts by 2,2-Diphenyl-1-picrylhydrazyl (DPPH, Ferric Reducing Antioxidant Power (FRAP, 2,2′-Azinobis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS and Oxygen Radical Absorbance Capacity (ORAC assays, identifying hydrolysable tannins and three phenolic compounds (ellagic acid, gallic acid and rutin present in the leaves. In addition, we evaluated the incidence of diabetes, degree of insulitis, serum insulin, hepatic glutathione and tolerance test glucose in non-obese diabetic (NOD mice. Our results suggest that the aqueous extract presents antioxidant activity and high total phenols, which were used as a type 1 diabetes mellitus (DM-1 treatment in NOD mice. We verified that the chronic consumption of aqueous extract reduces the inflammatory infiltrate index in pancreatic islets, maintaining serum insulin levels and hepatic glutathione, and reducing serum lipid peroxidation as well as the risk for diabetes.

  13. Identification and Antioxidant Activity of the Extracts of Eugenia uniflora Leaves. Characterization of the Anti-Inflammatory Properties of Aqueous Extract on Diabetes Expression in an Experimental Model of Spontaneous Type 1 Diabetes (NOD Mice).

    Science.gov (United States)

    Schumacher, Nayara Simon Gonzalez; Colomeu, Talita Cristina; de Figueiredo, Daniella; Carvalho, Virginia de Campos; Cazarin, Cinthia Baú Betim; Prado, Marcelo Alexandre; Meletti, Laura Maria Molina; Zollner, Ricardo de Lima

    2015-01-01

    Medical and folklore reports suggest that Eugenia uniflora (E. uniflora) is a functional food that contains numerous compounds in its composition, with anti-inflammatory, antioxidant and anti-diabetic effects. In the present study, we investigated the best solvents (water, ethanol and methanol/acetone) for extracting bioactive compounds of E. uniflora leaves, assessing total phenols and the antioxidant activity of the extracts by 2,2-Diphenyl-1-picrylhydrazyl (DPPH), Ferric Reducing Antioxidant Power (FRAP), 2,2'-Azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and Oxygen Radical Absorbance Capacity (ORAC) assays, identifying hydrolysable tannins and three phenolic compounds (ellagic acid, gallic acid and rutin) present in the leaves. In addition, we evaluated the incidence of diabetes, degree of insulitis, serum insulin, hepatic glutathione and tolerance test glucose in non-obese diabetic (NOD) mice. Our results suggest that the aqueous extract presents antioxidant activity and high total phenols, which were used as a type 1 diabetes mellitus (DM-1) treatment in NOD mice. We verified that the chronic consumption of aqueous extract reduces the inflammatory infiltrate index in pancreatic islets, maintaining serum insulin levels and hepatic glutathione, and reducing serum lipid peroxidation as well as the risk for diabetes. PMID:26783951

  14. The Gut Microbiota Modulates Glycaemic Control and Serum Metabolite Profiles in Non-Obese Diabetic Mice

    Science.gov (United States)

    Greiner, Thomas U.; Hyötyläinen, Tuulia; Knip, Mikael; Bäckhed, Fredrik; Orešič, Matej

    2014-01-01

    Islet autoimmunity in children who later progress to type 1 diabetes is preceded by dysregulated serum metabolite profiles, but the origin of these metabolic changes is unknown. The gut microbiota affects host metabolism and changes in its composition contribute to several immune-mediated diseases; however, it is not known whether the gut microbiota is involved in the early metabolic disturbances in progression to type 1 diabetes. We rederived non-obese diabetic (NOD) mice as germ free to explore the potential role of the gut microbiota in the development of diabetic autoimmunity and to directly investigate whether the metabolic profiles associated with the development of type 1 diabetes can be modulated by the gut microbiota. The absence of a gut microbiota in NOD mice did not affect the overall diabetes incidence but resulted in increased insulitis and levels of interferon gamma and interleukin 12; these changes were counterbalanced by improved peripheral glucose metabolism. Furthermore, we observed a markedly increased variation in blood glucose levels in the absence of a microbiota in NOD mice that did not progress to diabetes. Additionally, germ-free NOD mice had a metabolite profile similar to that of pre-diabetic children. Our data suggest that germ-free NOD mice have reduced glycaemic control and dysregulated immunologic and metabolic responses. PMID:25390735

  15. Humanizing Animal Models: A Key to Autoimmune Diabetes Treatment

    OpenAIRE

    Bresson, Damien; von Herrath, Matthias

    2011-01-01

    Preclinical evaluation of antibody-based immunotherapies for the treatment of type 1 diabetes (T1D) in animal models is often hampered by the fact that the human antibody drug does not cross-react with its mouse counterpart. In this issue of Science Translational Medicine, researchers describe a new mouse model that expresses the human isoform of a molecule targeted by T1D antibody therapies that are currently being tested in clinical trials—the human epsilon chain of the CD3 complex expresse...

  16. Decrease of FOXP3 mRNA in CD4~+ T cells in latent autoimmune diabetes in adult

    Institute of Scientific and Technical Information of China (English)

    杨治芳

    2006-01-01

    Objective To study the percentage of peripheral blood CD4+ CD25+ T cells and the expression of F0XP3 mRNA in patients with latent autoimmune diabetes in adult (LADA). Methods Fresh peripheral blood samples were obtained from 60 patients with LADA,30 patients with type 2 diabetes and 30 age- and sex-matched

  17. Effect of Associated Autoimmune Diseases on Type 1 Diabetes Mellitus Incidence and Metabolic Control in Children and Adolescents

    Science.gov (United States)

    2016-01-01

    Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases developing in childhood. The incidence of the disease in children increases for unknown reasons at a rate from 3 to 5% every year worldwide. The background of T1DM is associated with the autoimmune process of pancreatic beta cell destruction, which leads to absolute insulin deficiency and organ damage. Complex interactions between environmental and genetic factors contribute to the development of T1DM in genetically predisposed patients. The T1DM-inducing autoimmune process can also affect other organs, resulting in development of additional autoimmune diseases in the patient, thereby impeding diabetes control. The most common T1DM comorbidities include autoimmune thyroid diseases, celiac disease, and autoimmune gastritis; additionally, diabetes can be a component of PAS (Polyglandular Autoimmune Syndrome). The aim of this review is to assess the prevalence of T1DM-associated autoimmune diseases in children and adolescents and their impact on the course of T1DM. We also present suggestions concerning screening tests. PMID:27525273

  18. Toxin coupled MHC class I tetramers can specifically ablate autoreactive CD8+ T cells and delay diabetes in NOD mice1

    OpenAIRE

    Vincent, Benjamin G.; Young, Ellen F.; Buntzman, Adam S.; Stevens, Rosemary; Kepler, Thomas B.; Tisch, Roland; Frelinger, Jeffrey A.; Hess, Paul R.

    2010-01-01

    There is compelling evidence that self reactive CD8+ T cells are a major factor in development and progression of Type 1 diabetes in animals and humans. Hence, great effort has been expended to define the specificity of autoimmune CD8+ T cells, and to alter their responses. Much work has focused on tolerization of T cells using proteins or peptides. A weakness in this approach is residual autoreactive T cells may be activated and exacerbate disease.

  19. NOD2: Ethnic and geographic differences

    Institute of Scientific and Technical Information of China (English)

    Juleen Cavanaugh

    2006-01-01

    Investigations into the inheritance of the three risk alleles R702W, G908R and 1007fsInsC in NOD2 associated with susceptibility to Crohn's disease have demonstrated a remarkable amount of heterogeneity across ethnicities and populations, with regional variation across Europe for example, suggesting local founder effects. In nonCaucasian populations Crohn's disease continues to increase in incidence but this increase appears not to be a consequence of variation in NOD2, further advancing the accumulating evidence for other susceptibility loci.Frequencies of the known alleles are compared across populations in health and disease and evidence for additional alleles in NOD2 is reviewed. Based on its position on chromosome 16 coincident with some other autoimmune disease susceptibility localizations, research has targeted NOD2 variation as the potential cause of other autoimmune disorders. While these investigations have mostly returned negative findings, two diseases,Blau Syndrome and Graft versus Host Disease, have been shown to be caused by risk alleles in NOD2. As is frequent in complex disease investigations, some results await validation, but the identification of NOD2 and the differences within and across population raises intriguing questions about the population genetics of the variation at this locus.

  20. Where CD4 + CD25 + T reg cells impinge on autoimmune diabetes

    OpenAIRE

    Chen, Zhibin; Herman, Ann E.; Matos, Michael; Mathis, Diane; Benoist, Christophe

    2005-01-01

    Foxp3 is required for the generation and activity of CD4 + CD25 + regulatory T (T reg) cells, which are important controllers of autoimmunity, including type-1 diabetes. To determine where T reg cells affect the diabetogenic cascade, we crossed the Foxp3 scurfy mutation, which eliminates T reg cells, with the BDC2.5 T cell receptor (TCR) transgenic mouse line. In this model, the absence of T reg cells did not augment the initial activation or phenotypic characteristics of effector T cells in ...

  1. Prevalence of celiac disease autoimmunity in children with type 1 diabetes

    DEFF Research Database (Denmark)

    Adlercreutz, Emma H; Svensson, Jannet; Hansen, Dorte;

    2015-01-01

    OBJECTIVES: The aim was to determine the prevalence of celiac disease autoimmunity in children with type 1 diabetes (T1D) diagnosed in Denmark and Sweden. METHODS: A total of 662 Swedish children with T1D were matched with 1080 Danish children with T1D and 309 healthy children from Sweden and 283...... from Denmark served as controls. Sera were analyzed for the presence of IgA and IgG (IgAG) autoantibodies against deamidated gliadin peptide (DGP) and tissue transglutaminase (tTG) with enzyme-linked immunosorbent assay (ELISA) and IgG-tTG separately in a radioligand binding assay (RBA). Human...

  2. HLA, NFKB1 and NFKBIA gene polymorphism profile in autoimmune diabetes mellitus patients.

    Science.gov (United States)

    Katarina, K; Daniela, P; Peter, N; Marianna, R; Pavlina, C; Stepanka, P; Jan, L; Ludmila, T; Michal, A; Marie, C

    2007-02-01

    Type 1 diabetes mellitus (T1DM) is one of the long-time studied autoimmune disorders. The triggering of the autoimmune process has been ascribed to various genes active in the regulation of the cytokine gene transcription including the Rel/NF-kappaB gene family. In our study the gene polymorphism of HLA class II, NFKB1 (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) and NFKBIA (inhibitor of nuclear factor kappa B) was tested. Patients were divided into the subgroups in relation to the disease type: T1DM in children, T1DM in adults, and Latent Autoimmune Diabetes in Adults (LADA). HLA-DRB1 (*)04 and HLA-DQB1 (*)0302 have been detected as risk factors for T1DM in adults and particularly in children (P<0.0001, OR=22.9 and 46.5 respectively). HLA-DRB1 (*)03 has been found as a single risk factor for LADA (P<0.0001, OR=4.9). We detected 15 alleles for the NFKB1 gene polymorphism (CA-repeats) in the Czech population. The alleles were ranging in size from 114-142 bp corresponding to 10-25 CA repeats. Frequency of the A7 allele of NFKB1 gene has been significantly increased in T1DM adults (P<0.01). There was no difference in A and a G allele frequency of NFKBIA gene between the control group and patients, but the association of the AA genotype of NFKBIA gene has been found for LADA (P<0.05). Summarizing our results we concluded that there is a high probability of association of gene polymorphism from Rel/NF-kappaB family with an autoimmune diabetes course. Due to the results obtained in the epidemiological study we have been looking also for the function significance of the genetic predisposition. No significant changes have been observed by real time PCR testing of HLA-DRB1 (*)04 gene and NFKB1 gene expression between T1DM diabetic group with different HLA, NFKB1, NFKBIA genetic background. PMID:17318773

  3. Evidence of association with type 1 diabetes in the SLC11A1 gene region

    OpenAIRE

    Walker Neil M; Stevens Helen E; Nutland Sarah; Howson Joanna MM; Downes Kate; Yang Jennie HM; Todd John A

    2011-01-01

    Abstract Background Linkage and congenic strain analyses using the nonobese diabetic (NOD) mouse as a model for human type 1 autoimmune diabetes (T1D) have identified several NOD mouse Idd (insulin dependent diabetes) loci, including Slc11a1 (formerly known as Nramp1). Genetic variants in the orthologous region encompassing SLC11A1 in human chromosome 2q35 have been reported to be associated with various immune-related diseases including T1D. Here, we have conducted association analysis of th...

  4. Multiple endocrinopathies (growth hormone deficiency, autoimmune hypothyroidism and diabetes mellitus in Kearns-Sayre syndrome

    Directory of Open Access Journals (Sweden)

    A. Berio

    2013-06-01

    Full Text Available Kearns-Sayre syndrome is characterized by onset before 20 years, chronic progressive external opthalmoplegia, pigmentary retinal degeneration, and ataxia (and/or hearth block, and/or high protein content in the cerebrospinal fluid in the presence of mtDNA rearrangements. Multiple endocrine dysfunction associated with this syndrome was rarely reported. In this paper, the Authors report on a female patient with Kearns-Sayre syndrome with large heteroplasmic mtDNA deletion, absence of cytochrome c oxidase in many muscle fibers, partial GH deficiency, hypothyroidism and subsequently insulin dependent diabetes mellitus (IDDM. Anti-thyroid peroxidase and antithyreoglobulin antibodies were present in high titer in serum while anti-islet cell antibodies were absent. The patient developed thyroiditis with Hashimoto encephalopathy. The presence of GH deficiency, autoimmune thyroiditis with hypothyroidism and IDDM distinguishes this case from others and confirms the association of Kearns-Sayre syndrome with multiple endocrine dysfunction. Hashimoto encephalopathy and anti-thyroideal antibodies suggest that in this patient, predisposed by a genetic factor (a mitochondrial deletion anti-thyroideal antibodies may have contributed to the hypothyroidism and, by interfering with cerebral mitochondrial function, may have caused the encephalopathy. GH deficiency and IDDM can be attributed to oxidative phosphorylation deficiency but the autoimmunity may also have played a role in the production of glandular insufficiencies. It seems important to search for endocrine autoimmunity in every case of KSS.

  5. Gut mucosa and mucosal immunity as a gateway for autoimmunity in type 1 diabetes; the NOD mouse model

    Czech Academy of Sciences Publication Activity Database

    Funda, David; Fundová, Petra; Kozáková, Hana; Jirsa, M.; Tlaskalová, Helena; Buschard, K.

    Boston: Springer, 2009. s. 16-16. [International Congress of Mucosal Immunology /14./. 05.07.2006-09.09.2009, Boston] Institutional research plan: CEZ:AV0Z50200510 Keywords : gut mucosa * immunity Subject RIV: EC - Immunology

  6. DIABETOGENIC T CELLS INDUCE AUTOIMMUNE DIABETES IN BALB/c MICE

    Institute of Scientific and Technical Information of China (English)

    Xiao-lei Zou; Zeng-yu Zhao; Yun-yang Wang; Zhi-qiang Su; Ming Xiang

    2008-01-01

    Objective To investigate the role of T cell and its subsets in the induction of insulitis and type 1 diabetes meilitus(T1DM) in BALB/c mice.Methods Autoimmune diabetes mellitus was developed by intraperitoneal injection of 40 mg/kg streptozotocin(STZ) daily for 5 consecutive days in BALB/c mice as sources of donor cells. Spleen cells from diabetic mice were then cultured for 7 days in the stimulation of interleukin-2 ( IL-2 ) to harvest diabetogenic T cells, which were subsequently transferred into normal BALB/c mice recipients. MTr, ELISA, and HE staining were used to analyze the lymphocyte proliferation, cytokine (IL-2, interferon-γ, IL-4, and IL-10) levels, and pathological changes in pancreatic islets.Results As few as 3 × 106 diabetogenic T cells successfully induced diabetes meilitus in recipients pretreated with STZ twice, whereas transfer of equal amount of normal splenocytes, T cell-depleted diabetogenie splenocytes, or diabetogenic CD4+ T cells alone in recipients receiving STZ twice pretreatment was proved not to induce diabetes mellitus either. A markedly increased lymphocyte proliferation, high levels of interferon-γ and IL-2 in the supematants of diabetogenie T cells were observed. In addition, a markedly enhanced lymphocyte proliferation, a high level of interferon-γ secretion in serum, and numerous lymphocytes infiltration in pancreatic islets were detected in the diabetic mice induced by diabetogenic T cells transfer.Conclusions A novel T1DM murine model is established in STZ-pretreated BALB/c mice by adoptive transfer of diabetogenic T cells. CD4M+ T cells with interferon-γ may promote the onset of diabetes mellitus.

  7. Glutamic acid decarboxylase 65 autoantibody levels discriminate two subtypes of latent autoimmune diabetes in adults

    Institute of Scientific and Technical Information of China (English)

    李霞; 杨琳; 周智广; 黄干; 颜湘

    2003-01-01

    Objective To compare the clinical characteristics between type 2 diabetes mellitus (T2DM) and latent autoimmune diabetes in adults (LADA) with different titers of glutamic acid decarboxylase autoantibody (GADA) and to define the two distinct subtypes of LADA.Methods Sera of 750 patients with an initial diagnosis of T2DM from central south of China were screened for GADA using a radioligand assay. The distribution and frequency of GADA levels were described. Two hundred and ninety-five patients were divided into the T2DM group (n=233) and the LADA group (n=62) to compare the age of onset, body mass index, HbA1c, C-peptide, hypertension, dyslipidemia and chronic diabetic complications. Furthermore, LADA patients with different GADA titers were subdivided to analyze the same indexes as the above. Results The prevalence of LADA (defined as GADA≥0.05, namely GADA positive) was 9.7% in the 750 initially diagnosed type 2 diabetic patients. Compared with T2DM, LADA patients were younger at their ages of onset, had lower C-peptide and body mass index, and also had less cases with hypertension and with dyslipidemia. However, only patients with high titer of GADA had poorer beta cell functions and less diabetic complications compared to T2DM and low GADA titer of LADA patients. Patients with low GADA titer were similar to T2DM patients, except that they were prone to develop ketosis more frequently.Conclusions Two clinically distinct subtypes of LADA can be identified by GADA levels in patients initially-diagnosed as type 2 diabetes. Patients with high titer of GADA (GADA≥0.5) subsequently develop more insulin dependency, which are classified as LADA-type 1; while those with lower GADA titer (0.05≤GADA<0.5) and having clinical and metabolic phenotypes of type 2 diabetes are classified as LADA-type 2.

  8. Latent autoimmune diabetes of adults: From oral hypoglycemic agents to early insulin

    Directory of Open Access Journals (Sweden)

    Resham R Poudel

    2012-01-01

    Full Text Available Approximately 10% of phenotypic type 2 diabetics have islet autoantibodies and are referred to as having latent autoimmune diabetes of adults (LADA, and they land on early sulfonylurea failure and require insulin. Diagnosing LADA has treatment implications because of high risk of progression to insulin dependency. But often there is delay in insulin therapy, as there are no recommendations for islet antibody testing in adult-onset diabetes currently. LADA clinical risk score can identify adults at high risk who may benefit from antibody testing. The optimal treatment of LADA is not established. Early insulin therapy helps to achieve good metabolic control and better long-term outcomes by preserving b-cells and endogenous C-peptide secretion. Sulfonylureas are better avoided as they exhaust b-cells; glitazones and exenatide have favorable outcomes, whereas metformin needs to be used with caution. Understanding LADA will also bring new windows in managing type 1 diabetes. Information acquisition was done by reviewing the medical literature published since 1987, with particular attention to the natural history, genetic factors, and treatment of LADA.

  9. Autoimmune Diseases

    Science.gov (United States)

    ... Some examples of CAM are herbal products, chiropractic , acupuncture , and hypnosis . If you have an autoimmune disease, ... Toll-Free: 877-226-4267 National Institute of Diabetes and Digestive and Kidney Diseases, NIH, HHS Phone: ...

  10. Investigation of the vitamin D receptor gene (VDR) and its interaction with protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2) on risk of islet autoimmunity and type 1 diabetes : The Diabetes Autoimmunity Study in the Young (DAISY)

    NARCIS (Netherlands)

    Frederiksen, B.; Liu, E.; Romanos, J.; Steck, A. K.; Yin, X.; Kroehl, M.; Fingerlin, T. E.; Erlich, H.; Eisenbarth, G. S.; Rewers, M.; Norris, J. M.

    2013-01-01

    The present study investigated the association between variants in the vitamin D receptor gene (VDR) and protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2), as well as an interaction between VDR and PTPN2 and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D). T

  11. Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset.

    Science.gov (United States)

    Costa, Frederico R C; Françozo, Marcela C S; de Oliveira, Gabriela G; Ignacio, Aline; Castoldi, Angela; Zamboni, Dario S; Ramos, Simone G; Câmara, Niels O; de Zoete, Marcel R; Palm, Noah W; Flavell, Richard A; Silva, João S; Carlos, Daniela

    2016-06-27

    Type 1 diabetes (T1D) is an autoimmune disease that is triggered by both genetic and environmental factors, resulting in the destruction of pancreatic β cells. The disruption of the intestinal epithelial barrier and consequent escape of microbial products may be one of these environmental triggers. However, the immune receptors that are activated in this context remain elusive. We show here that during streptozotocin (STZ)-induced T1D, the nucleotide-binding oligomerization domain containing 2 (NOD2), but not NOD1, participates in the pathogenesis of the disease by inducing T helper 1 (Th1) and Th17 cells in the pancreatic LNs (PLNs) and pancreas. Additionally, STZ-injected wild-type (WT) diabetic mice displayed an altered gut microbiota compared with vehicle-injected WT mice, together with the translocation of bacteria to the PLNs. Interestingly, WT mice treated with broad-spectrum antibiotics (Abx) were fully protected from STZ-induced T1D, which correlated with the abrogation of bacterial translocation to the PLNs. Notably, when Abx-treated STZ-injected WT mice received the NOD2 ligand muramyl dipeptide, both hyperglycemia and the proinflammatory immune response were restored. Our results demonstrate that the recognition of bacterial products by NOD2 inside the PLNs contributes to T1D development, establishing a new putative target for intervention during the early stages of the disease. PMID:27325889

  12. Lessons From Pancreas Transplantation in Type 1 Diabetes: Recurrence of Islet Autoimmunity.

    Science.gov (United States)

    Burke, George W; Vendrame, Francesco; Virdi, Sahil K; Ciancio, G; Chen, Linda; Ruiz, Phillip; Messinger, Shari; Reijonen, Helena K; Pugliese, Alberto

    2015-12-01

    Type 1 diabetes recurrence (T1DR) affecting pancreas transplants was first reported in recipients of living-related pancreas grafts from twins or HLA identical siblings; given HLA identity, recipients received no or minimal immunosuppression. This observation provided critical evidence that type 1 diabetes (T1D) is an autoimmune disease. However, T1DR is traditionally considered very rare in immunosuppressed recipients of pancreas grafts from organ donors, representing the majority of recipients, and immunological graft failures are ascribed to chronic rejection. We have been performing simultaneous pancreas-kidney (SPK) transplants for over 25 years and find that 6-8 % of our recipients develop T1DR, with symptoms usually becoming manifest on extended follow-up. T1DR is typically characterized by (1) variable degree of insulitis and loss of insulin staining, on pancreas transplant biopsy (with most often absent), minimal to moderate and rarely severe pancreas, and/or kidney transplant rejection; (2) the conversion of T1D-associated autoantibodies (to the autoantigens GAD65, IA-2, and ZnT8), preceding hyperglycemia by a variable length of time; and (3) the presence of autoreactive T cells in the peripheral blood, pancreas transplant, and/or peripancreatic transplant lymph nodes. There is no therapeutic regimen that so far has controlled the progression of islet autoimmunity, even when additional immunosuppression was added to the ongoing chronic regimens; we hope that further studies and, in particular, in-depth analysis of pancreas transplant biopsies with recurrent diabetes will help identify more effective therapeutic approaches. PMID:26547222

  13. Growth and Risk for Islet Autoimmunity and Progression to Type 1 Diabetes in Early Childhood: The Environmental Determinants of Diabetes in the Young Study.

    Science.gov (United States)

    Elding Larsson, Helena; Vehik, Kendra; Haller, Michael J; Liu, Xiang; Akolkar, Beena; Hagopian, William; Krischer, Jeffrey; Lernmark, Åke; She, Jin-Xiong; Simell, Olli; Toppari, Jorma; Ziegler, Anette-G; Rewers, Marian

    2016-07-01

    Increased growth in early childhood has been suggested to increase the risk of type 1 diabetes. This study explored the relationship between weight or height and development of persistent islet autoimmunity and progression to type 1 diabetes during the first 4 years of life in 7,468 children at genetic risk for type 1 diabetes followed in Finland, Germany, Sweden, and the U.S. Growth data collected every third month were used to estimate individual growth curves by mixed models. Cox proportional hazards models were used to evaluate body size and risk of islet autoimmunity and type 1 diabetes. In the overall cohort, development of islet autoimmunity (n = 575) was related to weight z scores at 12 months (hazard ratio [HR] 1.16 per 1.14 kg in males or per 1.02 kg in females, 95% CI 1.06-1.27, P development of multiple islet autoantibodies (1 year: HR 1.21, 95% CI 1.08-1.35, P = 0.001, FDR = 0.008; 2 years: HR 1.18, 95% CI 1.06-1.32, P = 0.004, FDR = 0.02). No association was found between weight or height and type 1 diabetes (n = 169). In conclusion, greater weight in the first years of life was associated with an increased risk of islet autoimmunity. PMID:26993064

  14. The Effect of Diabetes-Associated Autoantigens on Cell Processes in Human PBMCs and Their Relevance to Autoimmune Diabetes Development

    Directory of Open Access Journals (Sweden)

    Jana Vcelakova

    2013-01-01

    Full Text Available Type 1 Diabetes (T1D is considered to be a T-helper- (Th- 1 autoimmune disease; however, T1D pathogenesis likely involves many factors, and sufficient tools for autoreactive T cell detection for the study of this disease are currently lacking. In this study, using gene expression microarrays, we analysed the effect of diabetes-associated autoantigens on peripheral blood mononuclear cells (PBMCs with the purpose of identifying (prediabetes-associated cell processes. Twelve patients with recent onset T1D, 18 first-degree relatives of the TD1 patients (DRL; 9/18 autoantibody positive, and 13 healthy controls (DV were tested. PBMCs from these individuals were stimulated with a cocktail of diabetes-associated autoantigens (proinsulin, IA-2, and GAD65-derived peptides. After 72 hours, gene expression was evaluated by high-density gene microarray. The greatest number of functional differences was observed between relatives and controls (69 pathways, from which 15% of the pathways belonged to “immune response-related” processes. In the T1D versus controls comparison, more pathways (24% were classified as “immune response-related.” Important pathways that were identified using data from the T1D versus controls comparison were pathways involving antigen presentation by MHCII, the activation of Th17 and Th22 responses, and cytoskeleton rearrangement-related processes. Genes involved in Th17 and TGF-beta cascades may represent novel, promising (prediabetes biomarkers.

  15. Association of type 1 diabetes mellitus and autoimmune disorders in Brazilian children and adolescents

    Science.gov (United States)

    Alves, Crésio; Santos, Larissa Siqueira; Toralles, Maria Betânia P.

    2016-01-01

    Context: Type 1 diabetes mellitus (T1DM) is caused by an immune-mediated destruction of pancreatic beta cells. Other autoimmune diseases can be observed in association with T1DM. The screening for celiac disease (CD) and Hashimoto's thyroiditis is necessary due to the increased prevalence of these pathologies in T1DM patients. Aims: This study aimed to investigate the prevalence of autoimmune markers for pancreatitis, thyroiditis, and CD in racially admixtured children and adolescents with T1DM. Settings and Design: Cross-sectional clinic-based study. Methods: Seventy-one patients with T1DM (average: 11.6 ± 5.1 years). In all patients, the following antibodies were surveyed: Anti-glutamic acid decarboxylase (anti-GAD), immunoglobulin A (IgA) anti-transglutaminase (anti-tTG), Antithyroglobulin (AAT), anti-thyroid peroxidase (anti-TPO), and IgA. Statistical Analysis Used: The quantitative variables were expressed as a mean and standard deviation and the qualitative variables in contingency tables. Student's t-test and χ2 tests were used to assess the differences between the groups. The level of significance was established as P adolescents with T1DM have increased the prevalence of antithyroid and CD-related antibodies. The positivity for anti-GAD and antithyroid antibodies was less frequent than in other studies. The prevalence of anti-tTG antibodies was similar to the literature.

  16. Harnessing memory adaptive regulatory T cells to control autoimmunity in type 1 diabetes

    Institute of Scientific and Technical Information of China (English)

    Cheng-Rui Li; Bas J.G. Baaten; Linda M. Bradley

    2012-01-01

    Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing β-cells in the pancreatic islets.There is an immediate need to restore both β-cell function and immune tolerance to control disease progression and ultimately cure T1D.Currently,there is no effective treatment strategy to restore glucose regulation in patients with T1D.FoxP3-expressing CD4+ regulatory T cells (Tregs) are potential candidates to control autoimmunity because they play a central role in maintaining self-tolerance.However,deficiencies in either naturally occurring Tregs (nTregs) themselves and/or their ability to control pathogenic effector T cells have been associated with T1D.Here,we hypothesize that nTregs can be replaced by FoxP3+ adaptive Tregs (aTregs),which are uniquely equipped to combat autoreactivity in T1D.Unlike nTregs,aTregs are stable and provide long-lived protection.In this review,we summarize the current understanding of aTregs and their potential for use as an immunological intervention to treat T1D.

  17. Helicobacter pylori infection might be responsible for the interconnection between type 1 diabetes and autoimmune thyroiditis

    Directory of Open Access Journals (Sweden)

    El-Eshmawy Mervat M

    2011-10-01

    Full Text Available Abstract Background Higher serological prevalence rates of helicobacter pylori (H. pylori infection have been reported in patients with type 1 diabetes (T1DM and autoimmune thyroiditis (AT. Patients with T1DM are at increased risk for developing other autoimmune diseases, most commonly AT. It is unknown whether H. pylori infection could explain the high prevalence of thyroid autoantibodies and AT in T1DM. The aim of the current study was to evaluate anti-thyroid peroxidase (anti-TPO and anti-thyroglobulin (anti-Tg autoantibodies in correlation with anti-H. pylori IgG and IgA in young patients with T1DM. Methods Anti-H. Pylori IgG, IgA, anti-TPO and anti-Tg antibodies titers were measured in 162 euthyroid patients with T1DM and 80 healthy controls matched for age, sex and socioeconomic status. Results Seroprevalence of H. pylori was significantly higher in patients with T1DM than in healthy controls; 79% vs. 51.2%, p Conclusion our results support the idea of a connection between H. pylori infection and the occurrence of anti-TPO, anti-Tg autoantibodies and AT in young patients with T1DM. So, H. pylori infection could be considered as an environmental trigger for development of AT in T1DM. Young patients with T1DM should be screened for H. pylori infection.

  18. Prevention of Autoimmune Diabetes by Pentoxifylline is Associated with Target Tissue Modulation of Cytokines and the Expression of Fas-FasL

    Institute of Scientific and Technical Information of China (English)

    刘云峰; 章毅; 任如枫; 孙辽; 张志利

    2004-01-01

    The effect of Pentoxifylline (PTX) on type 1 diabetes was investigated by means of the studies on the expressions of cytokine mRNA in pancreas and the Fas-Fasl, on islet cells of NOD mice. NOD mice were treated with FFX from 4-6 wk, and then from 8-12 wk. After treatment, it was found that the incidence of diabetes in NOD mice at ages of 30 wk was reduced to 25% in group of mice treated with PTX, in comparison to 73.3% in case of mice injected with PBS, and the degree of insulitis in the PTX treated mice was lower than that of the PBS injected mice. RT-PCR analysis revealed down-regulatory effect on the expressions of IFN-γ and TNF-α mRNA in PTX treated mice, but there was no any effect on the expression of IL-10. As to the expression of Fas, there was marked decrease in the mean cytoplasmic integral optical density (IOD) in PTX treated mice, but there was little difference between FIX and PBS groups in the expression of FasL. These results indicated that FIX could prevent the development of diabetes in NOD mice, which might be related to the regulation of Th1/Th2 imbalance and the decreased expression of Fas in islet cells.

  19. Autoimmune disease

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    2005164 Optimal cut-point of glutamic acid decar-boxylase antibody (GAD-Ab) for differentiating two subtypes of latent autoimmune diabetes in adults (LADA). LI Xia(李霞), et al. Dept Endocrinol, 2nd Xiangya Hosp, Central South Univ, Changsha, 410011. Chin J Diabetes, 2005;13(1) :34-38. Objective: To investigate the optimal cut-point of glutamate decarboxylase antibody (GAD-Ab) for differentiating two subtypes of latent autoimmune diabetes in adults (I. ADA). Methods: The frequency

  20. Oral delivery of glutamic acid decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice.

    Science.gov (United States)

    Robert, Sofie; Gysemans, Conny; Takiishi, Tatiana; Korf, Hannelie; Spagnuolo, Isabella; Sebastiani, Guido; Van Huynegem, Karolien; Steidler, Lothar; Caluwaerts, Silvia; Demetter, Pieter; Wasserfall, Clive H; Atkinson, Mark A; Dotta, Francesco; Rottiers, Pieter; Van Belle, Tom L; Mathieu, Chantal

    2014-08-01

    Growing insight into the pathogenesis of type 1 diabetes (T1D) and numerous studies in preclinical models highlight the potential of antigen-specific approaches to restore tolerance efficiently and safely. Oral administration of protein antigens is a preferred method for tolerance induction, but degradation during gastrointestinal passage can impede such protein-based therapies, reducing their efficacy and making them cost-ineffective. To overcome these limitations, we generated a tolerogenic bacterial delivery technology based on live Lactococcus lactis (LL) bacteria for controlled secretion of the T1D autoantigen GAD65370-575 and the anti-inflammatory cytokine interleukin-10 in the gut. In combination with short-course low-dose anti-CD3, this treatment stabilized insulitis, preserved functional β-cell mass, and restored normoglycemia in recent-onset NOD mice, even when hyperglycemia was severe at diagnosis. Combination therapy did not eliminate pathogenic effector T cells, but increased the presence of functional CD4(+)Foxp3(+)CD25(+) regulatory T cells. These preclinical data indicate a great therapeutic potential of orally administered autoantigen-secreting LL for tolerance induction in T1D. PMID:24677716

  1. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse

    DEFF Research Database (Denmark)

    Hansen, Camilla Hartmann Friis; Krych, Lukasz; Nielsen, Dennis Sandris;

    2012-01-01

    another group received vancomycin from 8 weeks of age until onset of diabetes. Pyrosequencing of the gut microbiota and flow cytometry of intestinal immune cells was used to investigate the effect of vancomycin treatment. Results: At the end of the study, the cumulative diabetes incidence was found to be...... small intestinal lymphocytes, which displayed an increase in cluster of differentiation (CD)4+ T cells producing pro-inflammatory cytokines in the neonatally treated mice. Furthermore, bacteriological examination of the gut microbiota composition by pyrosequencing revealed that vancomycin depleted many...... major genera of Gram-positive and Gram-negative microbes while, interestingly, one single species, Akkermansia muciniphila, became dominant. Conclusions/interpretation: The early postnatal period is a critical time for microbial protection from type 1 diabetes and it is suggested that the mucolytic...

  2. Resistance to Streptozotocin-Induced Autoimmune Diabetes in Absence of Complement C3: Myeloid-Derived Suppressor Cells Play a Role

    OpenAIRE

    Gao, Xiaogang; Liu, Huanhai; He, Bin; Fu, Zhiren

    2013-01-01

    The contribution of complement to the development of autoimmune diabetes has been proposed recently. The underlying mechanisms, however, remain poorly understood. We hypothesize that myeloid-derived suppressor cells (MDSC), which act as regulators in autoimmunity, play a role in resistance to diabetes in absence of complement C3. Indeed, MDSC number was increased significantly in STZ-treated C3−/− mice. These cells highly expressed arginase I and inducible nitric oxide synthase (iNOS). Import...

  3. Serum fatty acids and risk of advanced β cell autoimmunity: a nested case-control study among children with HLA-conferred susceptibility to type 1 diabetes

    OpenAIRE

    Virtanen, SM; Niinistö, Sari; Nevalainen, Jaakko; Salminen, Irma; Takkinen, Hanna-Mari; Kääriä, Suvi; Uusitalo, Liisa; Alfthan, Georg; Kenward, Mike; Veijola, Riitta; Simell, O.; Ilonen, Jorma; Knip, Mikael

    2010-01-01

    Abstract Background/ Objectives: N-3 (omega-3) fatty acids have been reported to decrease the risk for development of ? cell autoimmunity and clinical type 1 diabetes. We set out to examine whether different serum fatty acids are associated with the development of advanced ? cell autoimmunity in children carrying HLA-DQB1-conferred susceptibility to type 1 diabetes. Subjects/Methods: Within a cohort, serum total fatty acid composition of 108 children with advanced ? cell autoimm...

  4. Gut microbial markers are associated with diabetes onset, regulatory imbalance, and IFN-γ level in NOD mice

    DEFF Research Database (Denmark)

    Krych, Lukasz; Nielsen, Dennis Sandris; Hansen, Axel Kornerup; Hansen, Camilla Hartmann Friis

    2015-01-01

    Gut microbiota regulated imbalances in the host's immune profile seem to be an important factor in the etiology of type 1 diabetes (T1D), and identifying bacterial markers for T1D may therefore be useful in diagnosis and prevention of T1D. The aim of the present study was to investigate the link ...

  5. Type 1 diabetes: can exercise impair the autoimmune event? The L-arginine/glutamine coupling hypothesis.

    Science.gov (United States)

    Krause, Maurício da Silva; de Bittencourt, Paulo Ivo Homem

    2008-06-01

    Prevention of type 1 diabetes mellitus (T1DM) requires early intervention in the autoimmune process directed against beta-cells of the pancreatic islets of Langerhans, which is believed to result from a disorder of immunoregulation. According to this concept, a T-helper lymphocyte of type 1 (Th1) subset of T-lymphocytes and their cytokine products, the type 1 cytokines [e.g. interleukin 2 (IL-2), interferon gamma (IFN-gamma) and tumour necrosis factor beta (TNF-beta)] prevail over immunoregulatory (anti-inflammatory) Th2 subset and its cytokine products, i.e. type 2 cytokines (e.g. IL-4, IL-6 and IL-10). This allows type 1 cytokines to initiate a cascade of immune/inflammatory processes in the islet (insulitis), culminating in beta-cell destruction. Activation of sympathetic-corticotropin-releasing hormone (CRH) axis by psychological stress induces specifically Th1 cell overactivity that determines enhanced glutamine utilization and consequent poor L-arginine supply for nitric oxide (NO)-assisted insulin secretion. This determines the shift of intraislet glutamate metabolism from the synthesis of glutathione (GSH) to that of L-arginine, leading to a redox imbalance that activates nuclear factor kappaB exacerbating inflammation and NO-mediated cytotoxicity. Physical exercise is capable of inducing changes in the pattern of cytokine production and release towards type 2 class and to normalize the glutamine supply to the circulation, which reduces the need for glutamate, whose metabolic fate may be restored in the direction of GSH synthesis and antioxidant defence. Also, the 70-kDa heat shock protein (hsp70), which is immunoregulatory, may modulate exercise-induced anti-inflammation. In this work, we envisage how exercise can intervene in the mechanisms involved in the autoimmune process against beta-cells and how novel therapeutic approaches may be inferred from these observations. PMID:18383559

  6. Regulatory T and B lymphocytes in a spontaneous autoimmune polyneuropathy.

    Science.gov (United States)

    Quan, S; Sheng, J R; Abraham, P M; Soliven, B

    2016-04-01

    B7-2(-/-) non-obese diabetic (NOD) mice develop a spontaneous autoimmune polyneuropathy (SAP) that mimics the progressive form of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In this study, we focused on the role of regulatory T cells (Tregs ) and regulatory B cells (Bregs ) in SAP. We found that deletion of B7-2 in female NOD mice led to a lower frequency and number of Tregs and Bregs in spleens and lymph nodes. Tregs but not Bregs suppressed antigen-stimulated splenocyte proliferation, whereas Bregs inhibited the T helper type 1 (Th1) cytokine response. Both Tregs and Bregs induced an increase in CD4(+) interleukin (IL)-10(+) cells, although less effectively in the absence of B7-2. Adoptive transfer studies revealed that Tregs , but not Bregs , suppressed SAP, while Bregs attenuated disease severity when given prior to symptom onset. B cell deficiency in B cell-deficient (muMT)/B7-2(-/-) NOD mice prevented the development of SAP, which would indicate that the pathogenic role of B cells predominates over its regulatory role in this model. We conclude that Bregs and Tregs control the immunopathogenesis and progression of SAP in a non-redundant fashion, and that therapies aimed at expansion of Bregs and Tregs may be an effective approach in autoimmune neuropathies. PMID:26671281

  7. Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Ana M. C. Faria

    2006-01-01

    Full Text Available Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10 and Th3 (TGF-β regulatory T cells (Tregs plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-β, cholera toxin B subunit (CTB, Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE, uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral, formulation, mucosal adjuvants, combination therapy and early therapy.

  8. Lack of association of type 2 diabetes susceptibility genotypes and body weight on the development of islet autoimmunity and type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Christiane Winkler

    Full Text Available AIM: To investigate whether type 2 diabetes susceptibility genes and body weight influence the development of islet autoantibodies and the rate of progression to type 1 diabetes. METHODS: Genotyping for single nucleotide polymorphisms (SNP of the type 2 diabetes susceptibility genes CDKAL1, CDKN2A/2B, FTO, HHEX-IDE, HMGA2, IGF2BP2, KCNJ11, KCNQ1, MTNR1B, PPARG, SLC30A8 and TCF7L2 was obtained in 1350 children from parents with type 1 diabetes participating in the BABYDIAB study. Children were prospectively followed from birth for islet autoantibodies and type 1 diabetes. Data on weight and height were obtained at 9 months, 2, 5, 8, 11, and 14 years of age. RESULTS: None of type 2 diabetes risk alleles at the CDKAL1, CDKN2A/2B, FTO, HHEX-IDE, HMGA2, IGF2BP2, KCNJ11, KCNQ1, MTNR1B, PPARG and SLC30A8 loci were associated with the development of islet autoantibodies or diabetes. The type 2 diabetes susceptible genotype of TCF7L2 was associated with a lower risk of islet autoantibodies (7% vs. 12% by age of 10 years, P = 0.015, P(corrected = 0.18. Overweight children at seroconversion did not progress to diabetes faster than non-overweight children (HR: 1.08; 95% CI: 0.48-2.45, P>0.05. CONCLUSIONS: These findings do not support an association of type 2 diabetes risk factors with islet autoimmunity or acceleration of diabetes in children with a family history of type 1 diabetes.

  9. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Christopher T Brown

    Full Text Available Recent studies have suggested a bacterial role in the development of autoimmune disorders including type 1 diabetes (T1D. Over 30 billion nucleotide bases of Illumina shotgun metagenomic data were analyzed from stool samples collected from four pairs of matched T1D case-control subjects collected at the time of the development of T1D associated autoimmunity (i.e., autoantibodies. From these, approximately one million open reading frames were predicted and compared to the SEED protein database. Of the 3,849 functions identified in these samples, 144 and 797 were statistically more prevalent in cases and controls, respectively. Genes involved in carbohydrate metabolism, adhesions, motility, phages, prophages, sulfur metabolism, and stress responses were more abundant in cases while genes with roles in DNA and protein metabolism, aerobic respiration, and amino acid synthesis were more common in controls. These data suggest that increased adhesion and flagella synthesis in autoimmune subjects may be involved in triggering a T1D associated autoimmune response. Extensive differences in metabolic potential indicate that autoimmune subjects have a functionally aberrant microbiome. Mining 16S rRNA data from these datasets showed a higher proportion of butyrate-producing and mucin-degrading bacteria in controls compared to cases, while those bacteria that produce short chain fatty acids other than butyrate were higher in cases. Thus, a key rate-limiting step in butyrate synthesis is more abundant in controls. These data suggest that a consortium of lactate- and butyrate-producing bacteria in a healthy gut induce a sufficient amount of mucin synthesis to maintain gut integrity. In contrast, non-butyrate-producing lactate-utilizing bacteria prevent optimal mucin synthesis, as identified in autoimmune subjects.

  10. Treated Autoimmune Thyroid Disease Is Associated with a Decreased Quality of Life among Young Persons with Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    Alena Spirkova

    2015-01-01

    Full Text Available Type 1 diabetes (T1D in children and adolescents is relatively often accompanied by other immunopathological diseases, autoimmune thyroid disease (AITD or celiac disease (CD. Our aim was to assess whether these conditions are associated with changes in the health-related quality of life (HRQOL in pediatric patients with T1D. In a cross-sectional study we identified eligible 332 patients with T1D aged 8–18 years, of whom 248 (75% together with their parents responded to the PedsQL Generic and Diabetes Modules. Compared to 143 patients without thyroid autoantibodies, 40 patients with a thyroxine-treated AITD scored lower in the overall generic HRQOL (P=0.014, as well as in the overall diabetes-specific HRQOL (P=0.013. After adjustment for age, gender, duration of diabetes, type of diabetes treatment, and diabetes control, this association remained statistically significant for the generic HRQOL (P=0.023. Celiac disease was not associated with a change in the generic or diabetes-specific HRQOL (P=0.07  and   P=0.63, resp.. Parental scores showed no association with AITD or celiac disease, except a marginally significant decrease in the overall generic HRQOL (P=0.039 in the T1D + AITD compared to T1D group. Our study indicates that, in pediatric patients with T1D, concomitant thyroxine-treated AITD is associated with lower quality of life.

  11. Improved function and proliferation of adult human beta cells engrafted in diabetic immunodeficient NOD-scid IL2rγnull mice treated with alogliptin

    Directory of Open Access Journals (Sweden)

    Jurczyk A

    2013-12-01

    Full Text Available Agata Jurczyk,1 Philip diIorio,1 Dean Brostowin,1 Linda Leehy,1 Chaoxing Yang,1 Fumihiko Urano,2 David M Harlan,3 Leonard D Shultz,4 Dale L Greiner,1 Rita Bortell1 1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 2Department of Medicine, Washington University School of Medicine, St Louis, MO, 3Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 4The Jackson Laboratory, Bar Harbor, ME, USA Purpose: Dipeptidyl-peptidase-4 (DPP-4 inhibitors are known to increase insulin secretion and beta cell proliferation in rodents. To investigate the effects on human beta cells in vivo, we utilize immunodeficient mice transplanted with human islets. The study goal was to determine the efficacy of alogliptin, a DPP-4 inhibitor, to enhance human beta cell function and proliferation in an in vivo context using diabetic immunodeficient mice engrafted with human pancreatic islets. Methods: Streptozotocin-induced diabetic NOD-scid IL2rγnull (NSG mice were transplanted with adult human islets in three separate trials. Transplanted mice were treated daily by gavage with alogliptin (30 mg/kg/day or vehicle control. Islet graft function was compared using glucose tolerance tests and non-fasting plasma levels of human insulin and C-peptide; beta cell proliferation was determined by bromodeoxyuridine (BrdU incorporation. Results: Glucose tolerance tests were significantly improved by alogliptin treatment for mice transplanted with islets from two of the three human islet donors. Islet-engrafted mice treated with alogliptin also had significantly higher plasma levels of human insulin and C-peptide compared to vehicle controls. The percentage of insulin+BrdU+ cells in human islet grafts from alogliptin-treated mice was approximately 10-fold more than from vehicle control mice, consistent with a significant increase in human beta cell proliferation. Conclusion: Human islet-engrafted immunodeficient mice

  12. Are insights gained from NOD mice sufficient to guide clinical translation? Another inconvenient truth.

    Science.gov (United States)

    Roep, Bart O

    2007-04-01

    Despite decades of research using various animal models for type 1 diabetes, we are still struggling to define the initiating autoantigens, the precise mechanisms of beta cell destruction, and suitable immune-based interventions to prevent or treat human diabetes. Animal models, such as the non-obese diabetic (NOD) mouse and the biobreeding (BB) rat, develop immune-mediated diseases with features resembling type 1 diabetes in humans. Although these animal models of autoimmune diabetes have proved to be valuable tools to study certain aspects of the disease process, they have also led to misconceptions and erroneous extrapolations, as well as false expectations with regard to the efficacy of immunotherapy. It is therefore time to ask ourselves whether we are making major strategic mistakes when employing rodent models for the study of type 1 diabetes. This review will describe where rodent models have provided us with proper guidance and where they have misled us, concluding that each model only offers partial information with undefined clinical value. Therefore, a more critical attitude and repetition of crucial observations in different model settings will be necessary in the future. I will argue that animal models have limited but evident value when it comes to teaching us about type 1 diabetes in humans, and we can take advantage of this value more efficiently. PMID:17376838

  13. A Maternal Gluten-Free Diet Reduces Inflammation and Diabetes Incidence in the Offspring of NOD Mice

    DEFF Research Database (Denmark)

    Hansen, Camilla Hartmann Friis; Krych, Lukasz; Buschard, Karsten;

    2014-01-01

    pronounced difference between both mothers and their offspring on different diets, characterized by increased numbers of Akkermansia, Proteobacteria, and TM7 in the GF diet group. In addition, pancreatic forkhead box P3 regulatory T cells were increased in GF-fed offspring, as were M2 macrophage gene markers...... and tight junction-related genes in the gut, while intestinal gene expression of proinflammatory cytokines was reduced. An increased proportion of T cells in the pancreas expressing the mucosal integrin alpha 4 beta 7 suggests that the mechanism involves increased trafficking of gut-primed immune...... cells to the pancreas. In conclusion, a GF diet during fetal and early postnatal life reduces the incidence of diabetes. The mechanism may involve changes in gut microbiota and shifts to a less proinflammatory immunological milieu in the gut and pancreas....

  14. Regulatory CD8{sup +} T cells induced by exposure to all-trans retinoic acid and TGF-{beta} suppress autoimmune diabetes

    Energy Technology Data Exchange (ETDEWEB)

    Kishi, Minoru [Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Yasuda, Hisafumi, E-mail: yasuda@med.kobe-u.ac.jp [Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Abe, Yasuhisa; Sasaki, Hirotomo; Shimizu, Mami; Arai, Takashi; Okumachi, Yasuyo; Moriyama, Hiroaki; Hara, Kenta; Yokono, Koichi; Nagata, Masao [Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan)

    2010-03-26

    Antigen-specific regulatory CD4{sup +} T cells have been described but there are few reports on regulatory CD8{sup +} T cells. We generated islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific regulatory CD8{sup +} T cells from 8.3-NOD transgenic mice. CD8{sup +} T cells from 8.3-NOD splenocytes were cultured with IGRP, splenic dendritic cells (SpDCs), TGF-{beta}, and all-trans retinoic acid (ATRA) for 5 days. CD8{sup +} T cells cultured with either IGRP alone or IGRP and SpDCs in the absence of TGF-{beta} and ATRA had low Foxp3{sup +} expression (1.7 {+-} 0.9% and 3.2 {+-} 4.5%, respectively). In contrast, CD8{sup +} T cells induced by exposure to IGRP, SpDCs, TGF-{beta}, and ATRA showed the highest expression of Foxp3{sup +} in IGRP-reactive CD8{sup +} T cells (36.1 {+-} 10.6%), which was approximately 40-fold increase compared with that before induction culture. CD25 expression on CD8{sup +} T cells cultured with IGRP, SpDCs, TGF-{beta}, and ATRA was only 7.42%, whereas CD103 expression was greater than 90%. These CD8{sup +} T cells suppressed the proliferation of diabetogenic CD8{sup +} T cells from 8.3-NOD splenocytes in vitro and completely prevented diabetes onset in NOD-scid mice in cotransfer experiments with diabetogenic splenocytes from NOD mice in vivo. Here we show that exposure to ATRA and TGF-{beta} induces CD8{sup +}Foxp3{sup +} T cells ex vivo, which suppress diabetogenic T cells in vitro and in vivo.

  15. Regulatory CD8+ T cells induced by exposure to all-trans retinoic acid and TGF-β suppress autoimmune diabetes

    International Nuclear Information System (INIS)

    Antigen-specific regulatory CD4+ T cells have been described but there are few reports on regulatory CD8+ T cells. We generated islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific regulatory CD8+ T cells from 8.3-NOD transgenic mice. CD8+ T cells from 8.3-NOD splenocytes were cultured with IGRP, splenic dendritic cells (SpDCs), TGF-β, and all-trans retinoic acid (ATRA) for 5 days. CD8+ T cells cultured with either IGRP alone or IGRP and SpDCs in the absence of TGF-β and ATRA had low Foxp3+ expression (1.7 ± 0.9% and 3.2 ± 4.5%, respectively). In contrast, CD8+ T cells induced by exposure to IGRP, SpDCs, TGF-β, and ATRA showed the highest expression of Foxp3+ in IGRP-reactive CD8+ T cells (36.1 ± 10.6%), which was approximately 40-fold increase compared with that before induction culture. CD25 expression on CD8+ T cells cultured with IGRP, SpDCs, TGF-β, and ATRA was only 7.42%, whereas CD103 expression was greater than 90%. These CD8+ T cells suppressed the proliferation of diabetogenic CD8+ T cells from 8.3-NOD splenocytes in vitro and completely prevented diabetes onset in NOD-scid mice in cotransfer experiments with diabetogenic splenocytes from NOD mice in vivo. Here we show that exposure to ATRA and TGF-β induces CD8+Foxp3+ T cells ex vivo, which suppress diabetogenic T cells in vitro and in vivo.

  16. Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetes

    Czech Academy of Sciences Publication Activity Database

    Funda, David; Kaas, A.; Tlaskalová, Helena; Buschard, K.

    2007-01-01

    Roč. 24, - (2007), s. 59-63. ISSN 1520-7552 R&D Projects: GA AV ČR IAA5020405; GA ČR GA303/06/1329 Institutional research plan: CEZ:AV0Z50200510 Keywords : gluten * gluten -free * type 1 diabetes Subject RIV: EE - Microbiology, Virology Impact factor: 3.087, year: 2007

  17. Moderate Intensity Training Impact on the Inflammatory Status and Glycemic Profiles in NOD Mice

    Directory of Open Access Journals (Sweden)

    Roberto Codella

    2015-01-01

    Full Text Available The nonobese diabetic (NOD mouse represents a well-established experimental model analogous to human type 1 diabetes mellitus (T1D as it is characterized by progressive autoimmune destruction of pancreatic β-cells. Experiments were designed to investigate the impact of moderate-intensity training on T1D immunomodulation and inflammation. Under a chronic exercise regime, NOD mice were trained on a treadmill for 12 weeks (12 m/min for 30 min, 5 d/wk while age-matched, control animals were left untrained. Prior to and upon completion of the training period, fed plasma glucose and immunological soluble factors were monitored. Both groups showed deteriorated glycemic profiles throughout the study although trained mice tended to be more compensated than controls after 10 weeks of training. An exercise-induced weight loss was detected in the trained mice with respect to the controls from week 6. After 12 weeks, IL-6 and MIP-1β were decreased in the trained animals compared to their baseline values and versus controls, although not significantly. Morphometric analysis of pancreata revealed the presence of larger infiltrates along with decreased α-cells areas in the control mice compared to trained mice. Exercise may exert positive immunomodulation of systemic functions with respect to both T1D and inflammation, but only in a stringent therapeutic window.

  18. NOD1 and NOD2 signalling links ER stress with inflammation.

    Science.gov (United States)

    Keestra-Gounder, A Marijke; Byndloss, Mariana X; Seyffert, Núbia; Young, Briana M; Chávez-Arroyo, Alfredo; Tsai, April Y; Cevallos, Stephanie A; Winter, Maria G; Pham, Oanh H; Tiffany, Connor R; de Jong, Maarten F; Kerrinnes, Tobias; Ravindran, Resmi; Luciw, Paul A; McSorley, Stephen J; Bäumler, Andreas J; Tsolis, Renée M

    2016-04-21

    Endoplasmic reticulum (ER) stress is a major contributor to inflammatory diseases, such as Crohn disease and type 2 diabetes. ER stress induces the unfolded protein response, which involves activation of three transmembrane receptors, ATF6, PERK and IRE1α. Once activated, IRE1α recruits TRAF2 to the ER membrane to initiate inflammatory responses via the NF-κB pathway. Inflammation is commonly triggered when pattern recognition receptors (PRRs), such as Toll-like receptors or nucleotide-binding oligomerization domain (NOD)-like receptors, detect tissue damage or microbial infection. However, it is not clear which PRRs have a major role in inducing inflammation during ER stress. Here we show that NOD1 and NOD2, two members of the NOD-like receptor family of PRRs, are important mediators of ER-stress-induced inflammation in mouse and human cells. The ER stress inducers thapsigargin and dithiothreitol trigger production of the pro-inflammatory cytokine IL-6 in a NOD1/2-dependent fashion. Inflammation and IL-6 production triggered by infection with Brucella abortus, which induces ER stress by injecting the type IV secretion system effector protein VceC into host cells, is TRAF2, NOD1/2 and RIP2-dependent and can be reduced by treatment with the ER stress inhibitor tauroursodeoxycholate or an IRE1α kinase inhibitor. The association of NOD1 and NOD2 with pro-inflammatory responses induced by the IRE1α/TRAF2 signalling pathway provides a novel link between innate immunity and ER-stress-induced inflammation. PMID:27007849

  19. Thymic negative selection is functional in NOD mice

    Science.gov (United States)

    Mingueneau, Michael; Jiang, Wenyu; Feuerer, Markus

    2012-01-01

    Based on analyses of multiple TCR transgenic (tg) models, the emergence of pathogenic T cells in diabetes-prone NOD mice has been ascribed to a failure to censure autoreactive clones in the thymus. In contrast, using isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic variation impairs neither clonal deletion nor downstream transcriptional programs. However, we find that NOD genetic variation influences αβ/γδ-lineage decisions promoted by early expression of tg αβ-TCRs at the double-negative (DN) stage. In B6 and other genetic backgrounds, tg αβ-TCRs behave like γδ-TCRs and commit a large fraction of DNs toward the γδ-lineage, thereby decreasing the size of the double-positive (DP) pool, which is efficiently positively and negatively selected. In NOD DNs, αβ-TCR signalosomes instead behave like pre-TCRs, resulting in high numbers of DPs competing for limited selection niches, and poor positive and negative selection. Once niche effects are neutralized in mixed bone marrow chimeras, positive and negative selection are equally efficient on B6 and NOD backgrounds. Biochemical analysis revealed a selective defect in the activation of Erk1/2 downstream of NOD αβ-TCR signalosomes. Therefore, NOD genetic variation influences αβ/γδ-lineage decisions when the αβ-TCR heterodimer is prematurely expressed, but not the process of negative selection. PMID:22329992

  20. Evidence that MHC I-E dampens thyroid autoantibodies and prevents spreading to a second thyroid autoantigen in I-Ak NOD mice

    Science.gov (United States)

    Pelletier, Adam-Nicolas; Aliesky, Holly A.; Banuelos, Bianca; Chabot-Roy, Geneviève; Rapoport, Basil; Lesage, Sylvie; McLachlan, Sandra M

    2015-01-01

    NOD.H2k and NOD.H2h4 mice carry the MHC class II molecule I-Ak associated with susceptibility to experimentally-induced thyroiditis. Dietary iodine enhanced spontaneous thyroid autoimmunity, well known in NOD.H2h4 mice, has not been investigated in NOD.H2k mice. We compared NOD.H2h4 and NOD.H2k strains for thyroiditis and autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) without or with dietary sodium iodide (NaI) for up to 32 weeks. TgAb levels were significantly higher in NOD.H2h4 than NOD.H2k mice on NaI and TPOAb developed in NOD.H2h4 but not NOD.H2k mice. DNA exome analysis revealed, in addition to the differences in the chromosome (Chr) 17 MHC regions, that NOD.H2k and particularly NOD.H2h4 mice have substantial non-MHC parental DNA. KEGG pathway-analysis highlighted thyroid autoimmunity and immune-response genes on Chr 17 but not on Chr 7 and 15 parental B10.A4R DNA. Studies of parental strains provided no evidence for non-MHC gene contributions. The exon 10 thyroglobulin haplotype, associated with experimentally-induced thyroiditis, is absent in NOD.H2h4 and NOD.H2k mice and is not a marker for spontaneous murine thyroid autoimmunity. In conclusion, the absence of I-E is a likely explanation for the difference between NOD.H2h4 and NOD.H2k mice in TgAb levels and, as in humans, autoantibody spreading to TPO. PMID:25811933

  1. Role of Fas-FasL in insulitis in nonobese diabetic mouse

    Institute of Scientific and Technical Information of China (English)

    曹峻洋; 王姮

    2004-01-01

    @@ Type 1 diabetes results from autoimmune damage to βcells and insulitis typically characterizes its pathological presentation. Apoptosis could be a main mechanism.There are several pathways of apoptosis including FasFasL. 1 Fas is a type 1 transmembrane glycoprotein in the super family of TNF/NGF receptors and FasL (the specific ligand for Fas in vivo) is a type 2 transmembrane glycoprotein in the super family of TNF. 2 Their interaction for inducing apoptosis is important in many processes. 3 Their malfunction can lead to the overproliferation of the autoreactive immune cells in mice or humans. 4-5 In autoimmune diabetes, specific CDs + T cells may kill β cells by FasL and perforin-granuzyme.Moreover, Fas-FasL also mediates the elimination of autoreactive T cells. 6-11 Diabetes in nonobese diabetic (NOD) mice is a result of autoimmune damage to βcells. 12 Our study aims at analyzing the significance of Fas-FasL in NOD insulitis, specifically discussing the mechanism of autoimmune diabetes.

  2. Weight Gain in Early Life Predicts Risk of Islet Autoimmunity in Children With a First-Degree Relative With Type 1 Diabetes

    OpenAIRE

    Couper, Jennifer J.; Beresford, Sarah; Hirte, Craig; Baghurst, Peter A; Pollard, Angie; Tait, Brian D.; Harrison, Leonard C.; Colman, Peter G.

    2009-01-01

    OBJECTIVE—In a prospective birth cohort study, we followed infants who had a first-degree relative with type 1 diabetes to investigate the relationship between early growth and infant feeding and the risk of islet autoimmunity. RESEARCH DESIGN AND METHODS—Infants with a first-degree relative with type 1 diabetes were identified during their mother's pregnancy. Dietary intake was recorded prospectively to determine duration of breast-feeding and age at introduction of cow's milk protein, cerea...

  3. TRANSPLANTATION OF BONE MARROW CELLS AND UMBILICAL CORD BLOOD CELLS AS A WAY FOR CORRECTION OF AUTOIMMUNE MECHANISMS IN DEVELOPMENT OF DIABETES MELLITUS TYPE I

    Directory of Open Access Journals (Sweden)

    D. A. Velikiy

    2009-05-01

    Full Text Available In this review the modern conception of development of autoimmune diabetes mellitus was presented. Possibilities of immune disturbances correction and β-cells regeneration at transplantation of bone marrow and umbilical cord blood cells were considered. 

  4. Altered BCR signalling quality predisposes to autoimmune disease and a pre-diabetic state

    OpenAIRE

    Königsberger, Sebastian; Prodöhl, Jan; Stegner, David; Weis, Vanessa; Andreas, Martin; Stehling, Martin; Schumacher, Theresa; Böhmer, Ruben; Thielmann, Ina; van Eeuwijk, Judith M M; Nieswandt, Bernhard; Kiefer, Friedemann

    2012-01-01

    The related tyrosine kinases Syk and Zap-70 are key signalling proteins downstream of antigen receptors. A knock-in strategy reveals that the two kinases differentially affect BCR signalling, leading to aberrant B cell section and increased risk of autoimmune disease.

  5. Resistance to Streptozotocin-Induced Autoimmune Diabetes in Absence of Complement C3: Myeloid-Derived Suppressor Cells Play a Role.

    Directory of Open Access Journals (Sweden)

    Xiaogang Gao

    Full Text Available The contribution of complement to the development of autoimmune diabetes has been proposed recently. The underlying mechanisms, however, remain poorly understood. We hypothesize that myeloid-derived suppressor cells (MDSC, which act as regulators in autoimmunity, play a role in resistance to diabetes in absence of complement C3. Indeed, MDSC number was increased significantly in STZ-treated C3-/- mice. These cells highly expressed arginase I and inducible nitric oxide synthase (iNOS. Importantly, depletion of MDSC led to the occurrence of overt diabetes in C3-/- mice after STZ. Furthermore, C3-/- MDSC actively suppressed diabetogenic T cell proliferation and prevented/delayed the development of diabetes in arginase and/or iNOS-dependent manner. Both Tregs and transforming growth factor-β (TGF-β are crucial for MDSC induction in STZ-treated C3-/- mice as depletion of Tregs or blocking TGF-β bioactivity dramatically decreased MDSC number. These findings indicate that MDSC are implicated in resistance to STZ-induced diabetes in the absence of complement C3, which may be helpful for understanding of mechanisms underlying preventive effects of complement deficiency on autoimmune diseases.

  6. 1,25-Dihydroxyvitamin D3 promotes tolerogenic dendritic cells with functional migratory properties in NOD mice.

    Science.gov (United States)

    Ferreira, Gabriela B; Gysemans, Conny A; Demengeot, Jocelyne; da Cunha, João Paulo M C M; Vanherwegen, An-Sofie; Overbergh, Lut; Van Belle, Tom L; Pauwels, Femke; Verstuyf, Annemieke; Korf, Hannelie; Mathieu, Chantal

    2014-05-01

    The biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], is able to promote the generation of tolerogenic mature dendritic cells (mDCs) with an impaired ability to activate autoreactive T cells. These cells could represent a reliable tool for the promotion or restoration of Ag-specific tolerance through vaccination strategies, for example in type 1 diabetes patients. However, successful transfer of 1,25(OH)2D3-treated mDCs (1,25D3-mDCs) depends on the capacity of 1,25(OH)2D3 to imprint a similar tolerogenic profile in cells derived from diabetes-prone donors as from diabetes-resistant donors. In this study, we examined the impact of 1,25(OH)2D3 on the function and phenotype of mDCs originating from healthy (C57BL/6) and diabetes-prone (NOD) mice. We show that 1,25(OH)2D3 is able to imprint a phenotypic tolerogenic profile on DCs derived from both mouse strains. Both NOD- and C57BL/6-derived 1,25D3-mDCs decreased the proliferation and activation of autoreactive T cells in vitro, despite strain differences in the regulation of cytokine/chemokine expression. In addition, 1,25D3-mDCs from diabetes-prone mice expanded CD25(+)Foxp3(+) regulatory T cells and induced intracellular IL-10 production by T cells in vitro. Furthermore, 1,25D3-mDCs exhibited an intact functional migratory capacity in vivo that favors homing to the liver and pancreas of adult NOD mice. More importantly, when cotransferred with activated CD4(+) T cells into NOD.SCID recipients, 1,25D3-mDCs potently dampened the proliferation of autoreactive donor T cells in the pancreatic draining lymph nodes. Altogether, these results argue for the potential of 1,25D3-mDCs to restore Ag-specific immune tolerance and arrest autoimmune disease progression in vivo. PMID:24663679

  7. Nel Noddings och omsorgsetiken

    Directory of Open Access Journals (Sweden)

    Gunnel Colnerud

    2006-01-01

    Full Text Available NEL NODDINGS AND THE ETHICS OF CARE. Nel Noddings is one of the premierphilosophers of the ethics of care. Her elaboration of this ethics has resul-ted in a complex relation-based theory. Noddings defines care as a conti-nuing, reciprocal relationship between the carer and the cared-for. Thecaring relation is complete only if the cared-for confirms the value of thecare. The ethics of care attaches no importance to principles, since thecarer looks for guidance to the needs of the cared-for, rather than toprinciples of justice. Local and particular ethical decisions are seen as morevalid than universal principles. In this article I discuss a number of pro-blems by applying the ethics of care to all levels and aspects of schooling,from policy to the teacher–student relationship. More recently, Noddingsand philosophers who defend an ethics of justice, e.g. Strike, have agreedthat these theories are complementary. Noddings still argues, though, thatcare is the most adequate ethical theory for moral events in schools. Theconclusion drawn here is that neither the ethics of care nor the ethics ofjustice may be enough to guide teachers in their ethically demanding andcomplex practice.

  8. Liposome-mediated transfer of IL-1 receptor antagonist gene to dispersed islet cells does not prevent recurrence of disease in syngeneically transplanted NOD mice

    DEFF Research Database (Denmark)

    Saldeen, J; Sandler, S; Bendtzen, K; Welsh, N

    2000-01-01

    transplanted non-obese diabetic (NOD) mice. NOD mouse islet cells were transfected using liposome-mediated gene transfer with a human IL-1ra cDNA construct and transplanted two days later to prediabetic NOD mice. Graft infiltration and destruction were monitored three, five and eight days posttransplantation...

  9. WJD 5th Anniversary Special Issues(3): Type 1 diabetes Distinct clinical and laboratory characteristics of latent autoimmune diabetes in adults in relation to type 1 and type 2 diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    Elena; Pipi; Marietta; Marketou; Alexandra; Tsirogianni

    2014-01-01

    Ever since its first appearance among the multiple forms of diabetes,latent autoimmune diabetes in adults(LADA),has been the focus of endless discussions concerning mainly its existence as a special type of diabetes.In this mini-review,through browsing important peer-reviewed publications,(original articles and reviews),we will attempt to refresh our knowledge regarding LADA hoping to enhance our understanding of this controversial diabetes entity.A unique combination of immunological,clinical and metabolic characteristics has been identified in this group of patients,namely persistent islet cell antibodies,high frequency of thyroid and gastric autoimmunity,DR3 and DR4 human leukocyte antigen haplotypes,progressive loss of beta cells,adult disease onset,normal weight,defective glycaemic control,and without tendency to ketoacidosis.Although anthropomorphic measurements are useful as a first line screening,the detection of C-peptide levels and the presence of glutamic acid decarboxylase(GAD)autoantibodies is undoubtedly the sine qua non condi-tion for a confirmatory LADA diagnosis.In point of fact,GAD autoantibodies are far from being solely a biomarker and the specific role of these autoantibodies in disease pathogenesis is still to be thoroughly studied.Nevertheless,the lack of diagnostic criteria and guidelines still puzzle the physicians,who struggle between early diagnosis and correct timing for insulin treatment.

  10. Dynamic changes of the Th17/Tc17 and regulatory T cell populations interfere in the experimental autoimmune diabetes pathogenesis.

    Science.gov (United States)

    Yaochite, Juliana Navarro Ueda; Caliari-Oliveira, Carolina; Davanso, Mariana Rodrigues; Carlos, Daniela; Malmegrim, Kelen Cristina Ribeiro; Cardoso, Cristina Ribeiro de Barros; Ramalho, Leandra Naira Zambelli; Palma, Patricia Vianna Bonini; da Silva, João Santana; Cunha, Fernando Queiróz; Covas, Dimas Tadeu; Voltarelli, Júlio César

    2013-03-01

    A balance between proinflammatory (Th17 and Tc17) and anti-inflammatory (regulatory T cells) subsets of T cells is essential to maintain immunological tolerance and prevent the onset of several autoimmune diseases, including type 1 diabetes. However, the kinetics of these subsets and disease severity during the streptozotocin (STZ)-induced diabetes course has not been determined. Thus, susceptible C57BL/6 mice were administrated with multiple low doses of STZ and we evaluated the frequency/absolute number of these T cell subsets in the pancreatic lymph nodes (PLNs) and spleen and Th1, Th17, Treg cytokine production in the pancreatic tissue. At different time points of the disease progression (6, 11, 18 and 25 days after the last STZ administration), the histopathological alterations were also evaluated by H&E and immunohistochemistry staining. During the initial phase of diabetes development (day 6), we noted increased numbers of CD4(+) and CD8(+) T cells in spleen and PLNs. At the same time, the frequencies of Th17 and Tc17 cells in PLNs were also enhanced. In addition, the early augment of interferon gamma (IFN-γ), tumoral necrosis factor (TNF-α), IL-6 and IL-17 levels in pancreatic tissue correlated with pancreatic islet inflammation and mild β-cell damage. Notably, the absolute number of Treg cells increased in PLNs during over time when compared to control group. Interestingly, increased IL-10 levels were associated with control of the inflammatory process during the late phase of the type 1 diabetes (day 25). In agreement, mice lacking the expression of IL-17 receptor (Il17r) showed impairment in STZ-induced diabetes progression, reduced peri-insulitis and beta cells preservation when compared with wild-type mice. Our findings suggest that dynamic changes of pathogenic Th17/Tc17 and regulatory T cell subsets numbers is associated with early strong inflammation in the pancreatic islets followed by late regulatory profile during the experimental STZ

  11. Linking chronic infection and autoimmune diseases: Mycobacterium avium subspecies paratuberculosis, SLC11A1 polymorphisms and type-1 diabetes mellitus.

    Directory of Open Access Journals (Sweden)

    Daniela Paccagnini

    Full Text Available BACKGROUND: The etiology of type 1 diabetes mellitus (T1DM is still unknown; numerous studies are performed to unravel the environmental factors involved in triggering the disease. SLC11A1 is a membrane transporter that is expressed in late endosomes of antigen presenting cells involved in the immunopathogenic events leading to T1DM. Mycobacterium avium subsp. paratuberculosis (MAP has been reported to be a possible trigger in the development of T1DM. METHODOLOGY/PRINCIPAL FINDINGS: Fifty nine T1DM patients and 79 healthy controls were genotyped for 9 polymorphisms of SLC11A1 gene, and screened for the presence of MAP by PCR. Differences in genotype frequency were evaluated for both T1DM patients and controls. We found a polymorphism in the SLC11A1 gene (274C/T associated to type 1 diabetic patients and not to controls. The presence of MAP DNA was also significantly associated with T1DM patients and not with controls. CONCLUSIONS/SIGNIFICANCE: The 274C/T SCL11A1 polymorphism was found to be associated with T1DM as well as the presence of MAP DNA in blood. Since MAP persists within macrophages and it is also processed by dendritic cells, further studies are necessary to evaluate if mutant forms of SLC11A1 alter the processing or presentation of MAP antigens triggering thereby an autoimmune response in T1DM patients.

  12. Etiopathogenesis of insulin autoimmunity.

    OpenAIRE

    Åke Lenmark; Moustakas, Antonis K; Papadopoulos, George K; Norio Kanatsuna

    2012-01-01

    Autoimmunity against pancreatic islet beta cells is strongly associated with proinsulin, insulin, or both. The insulin autoreactivity is particularly pronounced in children with young age at onset of type 1 diabetes. Possible mechanisms for (pro)insulin autoimmunity may involve beta-cell destruction resulting in proinsulin peptide presentation on HLA-DR-DQ Class II molecules in pancreatic draining lymphnodes. Recent data on proinsulin peptide binding to type 1 diabetes-associated HLA-DQ2 and ...

  13. Clustering of immunological, metabolic and genetic features in latent autoimmune diabetes in adults: evidence from principal component analysis.

    Science.gov (United States)

    Pes, Giovanni Mario; Delitala, Alessandro Palmerio; Errigo, Alessandra; Delitala, Giuseppe; Dore, Maria Pina

    2016-06-01

    Latent autoimmune diabetes in adults (LADA) which accounts for more than 10 % of all cases of diabetes is characterized by onset after age 30, absence of ketoacidosis, insulin independence for at least 6 months, and presence of circulating islet-cell antibodies. Its marked heterogeneity in clinical features and immunological markers suggests the existence of multiple mechanisms underlying its pathogenesis. The principal component (PC) analysis is a statistical approach used for finding patterns in data of high dimension. In this study the PC analysis was applied to a set of variables from a cohort of Sardinian LADA patients to identify a smaller number of latent patterns. A list of 11 variables including clinical (gender, BMI, lipid profile, systolic and diastolic blood pressure and insulin-free time period), immunological (anti-GAD65, anti-IA-2 and anti-TPO antibody titers) and genetic features (predisposing gene variants previously identified as risk factors for autoimmune diabetes) retrieved from clinical records of 238 LADA patients referred to the Internal Medicine Unit of University of Sassari, Italy, were analyzed by PC analysis. The predictive value of each PC on the further development of insulin dependence was evaluated using Kaplan-Meier curves. Overall 4 clusters were identified by PC analysis. In component PC-1, the dominant variables were: BMI, triglycerides, systolic and diastolic blood pressure and duration of insulin-free time period; in PC-2: genetic variables such as Class II HLA, CTLA-4 as well as anti-GAD65, anti-IA-2 and anti-TPO antibody titers, and the insulin-free time period predominated; in PC-3: gender and triglycerides; and in PC-4: total cholesterol. These components explained 18, 15, 12, and 12 %, respectively, of the total variance in the LADA cohort. The predictive power of insulin dependence of the four components was different. PC-2 (characterized mostly by high antibody titers and presence of predisposing genetic markers

  14. Preventative effects of the flowers of Inula britannica on autoimmune diabetes in C57BL/KsJ mice induced by multiple low doses of streptozotocin.

    Science.gov (United States)

    Kobayashi, Takao; Song, Qing-Hua; Hong, Tie; Kitamura, Hajime; Cyong, Jong-Chol

    2002-06-01

    We have reported that an aqueous extract from the flowers of Inula britannica L. subsp. japonica Kitam. (IB) prevented immunologically induced experimental hepatitis in mice and suggested that the antihepatitic effect of IB is due to inhibition of IFN-gamma production. We then investigated the effects of IB on diabetes in mice induced by multiple low doses of streptozotocin (MLDSTZ), which is a mouse model for IFN-gamma-dependent autoimmune diabetes. C57BL/KsJ mice (male, 7 weeks) were provided with IB extract (500 mg/ kg/ day) in drinking water ad libitum, starting 7 days before the first STZ injection. Autoimmune diabetes was induced by MLDSTZ (40 mg/kg/day for 5 daily doses, i.p.). The IB treatment significantly suppressed the increase of blood glucose levels. Histological analysis of the pancreas showed that the degree of insulitis and destruction of beta-cells were reduced by IB treatment. The IFN-gamma production from stimulated splenic T lymphocytes was inhibited by the IB treatment. Moreover, the proportion of IFN-gamma-producing cells in the CD4(+) population, which was increased by MLDSTZ, was significantly decreased by the IB treatment. These results suggest that IB has a preventative effect on autoimmune diabetes by regulating cytokine production. PMID:12112297

  15. Exploring the induction of preproinsulin-specific Foxp3+ CD4+ Treg cells that inhibit CD8+ T cell-mediated autoimmune diabetes by DNA vaccination

    Science.gov (United States)

    Stifter, Katja; Schuster, Cornelia; Schlosser, Michael; Boehm, Bernhard Otto; Schirmbeck, Reinhold

    2016-01-01

    DNA vaccination is a promising strategy to induce effector T cells but also regulatory Foxp3+ CD25+ CD4+ Treg cells and inhibit autoimmune disorders such as type 1 diabetes. Little is known about the antigen requirements that facilitate priming of Treg cells but not autoreactive effector CD8+ T cells. We have shown that the injection of preproinsulin (ppins)-expressing pCI/ppins vector into PD-1- or PD-L1-deficient mice induced Kb/A12-21-monospecific CD8+ T cells and autoimmune diabetes. A pCI/ppinsΔA12-21 vector (lacking the critical Kb/A12-21 epitope) did not induce autoimmune diabetes but elicited a systemic Foxp3+ CD25+ Treg cell immunity that suppressed diabetes induction by a subsequent injection of the diabetogenic pCI/ppins. TGF-β expression was significantly enhanced in the Foxp3+ CD25+ Treg cell population of vaccinated/ppins-primed mice. Ablation of Treg cells in vaccinated/ppins-primed mice by anti-CD25 antibody treatment abolished the protective effect of the vaccine and enabled diabetes induction by pCI/ppins. Adoptive transfer of Treg cells from vaccinated/ppins-primed mice into PD-L1−/− hosts efficiently suppressed diabetes induction by pCI/ppins. We narrowed down the Treg-stimulating domain to a 15-residue ppins76–90 peptide. Vaccine-induced Treg cells thus play a crucial role in the control of de novo primed autoreactive effector CD8+ T cells in this diabetes model. PMID:27406624

  16. Exploring the induction of preproinsulin-specific Foxp3(+) CD4(+) Treg cells that inhibit CD8(+) T cell-mediated autoimmune diabetes by DNA vaccination.

    Science.gov (United States)

    Stifter, Katja; Schuster, Cornelia; Schlosser, Michael; Boehm, Bernhard Otto; Schirmbeck, Reinhold

    2016-01-01

    DNA vaccination is a promising strategy to induce effector T cells but also regulatory Foxp3(+) CD25(+) CD4(+) Treg cells and inhibit autoimmune disorders such as type 1 diabetes. Little is known about the antigen requirements that facilitate priming of Treg cells but not autoreactive effector CD8(+) T cells. We have shown that the injection of preproinsulin (ppins)-expressing pCI/ppins vector into PD-1- or PD-L1-deficient mice induced K(b)/A12-21-monospecific CD8(+) T cells and autoimmune diabetes. A pCI/ppinsΔA12-21 vector (lacking the critical K(b)/A12-21 epitope) did not induce autoimmune diabetes but elicited a systemic Foxp3(+) CD25(+) Treg cell immunity that suppressed diabetes induction by a subsequent injection of the diabetogenic pCI/ppins. TGF-β expression was significantly enhanced in the Foxp3(+) CD25(+) Treg cell population of vaccinated/ppins-primed mice. Ablation of Treg cells in vaccinated/ppins-primed mice by anti-CD25 antibody treatment abolished the protective effect of the vaccine and enabled diabetes induction by pCI/ppins. Adoptive transfer of Treg cells from vaccinated/ppins-primed mice into PD-L1(-/-) hosts efficiently suppressed diabetes induction by pCI/ppins. We narrowed down the Treg-stimulating domain to a 15-residue ppins76-90 peptide. Vaccine-induced Treg cells thus play a crucial role in the control of de novo primed autoreactive effector CD8(+) T cells in this diabetes model. PMID:27406624

  17. Randomized, controlled, parallel-group prospective study to investigate the clinical effectiveness of early insulin treatment in patients with latent autoimmune diabetes in adults

    Directory of Open Access Journals (Sweden)

    Lloyd Janet

    2008-07-01

    Full Text Available Abstract Background Latent autoimmune diabetes in adults [LADA] is a type 1 diabetes that is slowly developing. This means many people are treated as having type 2 diabetes at diagnosis as they are adults who are not immediately insulin dependent. LADA can be distinguished from type 2 diabetes by antibody tests. Patients who are antibody positive have an autoimmune reaction which is similar to that of type 1 diabetes and is not found in type 2 diabetes. We would like to examine the best way of treating LADA in the early phase of the conditions, with tablets (similar to type 2 diabetes or with insulin (similar to type 1 diabetes. Methods/design This is an open parallel group prospective randomised trial. Participants need to have a GAD antibody test results of 101 WHO units or more and a diagnosis of diabetes not requiring insulin at diagnosis. Participants will need to have been diagnosed within 12 months and not treated with insulin at study entry. They will be randomised to receive either insulin (NovoMix 30 or tablets (diet treated followed by metformin followed by glitazone (with or without metformin followed by insulin. Primary outcome assessment will be for change in HbA1c and change in fasting C-peptide over 24 months. Secondary outcome measures will include Quality of life, GAD antibody levels, adverse events, inflammatory markers, insulin resistance, and markers of the metabolic syndrome. Discussion This study seeks the best treatment for early LADA in terms of maintaining glycaemic control and maintaining natural insulin production. Trial registration ISRCTN63815121

  18. Invariant Natural Killer T-Cell Control of Type 1 Diabetes: A Dendritic Cell Genetic Decision of a Silver Bullet or Russian Roulette

    OpenAIRE

    Driver, John P.; Scheuplein, Felix; Chen, Yi-Guang; Grier, Alexandra E.; Wilson, S. Brian; Serreze, David V.

    2009-01-01

    OBJECTIVE In part, activation of invariant natural killer T (iNKT)-cells with the superagonist α-galactosylceramide (α-GalCer) inhibits the development of T-cell–mediated autoimmune type 1 diabetes in NOD mice by inducing the downstream differentiation of antigen-presenting dendritic cells (DCs) to an immunotolerogenic state. However, in other systems iNKT-cell activation has an adjuvant-like effect that enhances rather than suppresses various immunological responses. Thus, we tested whether ...

  19. PECULIARITIES OF THE CYTOKINE PROFILE OF PATIENTS WITH TYPE 2 DIABETES MELLITUS IN COMBINATION WITH AUTOIMMUNE THYROIDITIS

    Directory of Open Access Journals (Sweden)

    N. A. Kravchun

    2014-01-01

    Full Text Available Study objective: study of the nature of changes in the immune system of patients with type 2 diabetes mellitus (DM in combination with autoimmune thyroiditis (AIT and without it; comparative analysis of similar indicators of patients with type 1 DM in combination with AIT and without it.Materials and methods. 104 patients at the age of 22 to 62 y.o. (57 women and 47 men took part in the study. They were divided into 4 groups (type 2 DM, type 2 DM and AIT, type 1 DM, type 1 DM and AIT. Groups of patients who were examined regarding the state of carbohydrate and lipid metabolism, indicators of the T-cell link of the immune system, concentration of interleukin 4 (IL-4, IL-6, interferon-gamma, and leptin level, were comparable regarding their sex, age, duration of disease.Results. Unidirectional relationship between body mass index (BMI, amount of CD4 +-, CD8+- lymphocytes, level of leptin, IL-4, IL-6 concentrations and BMI and immunoregulatory index of patients with type 2 DM both with AIT and without it was determined. Patients with type 2 DM displayed decreasing activity of the T-cell link of the immune system and increasing of the concentration of pro-inflammatory cytokines irrespectively of the availability of accompanying AIT, which evidenced primary development of autoimmune processes. At the same time, positivecorrelating relationship between the level of leptin and BMI and immunoregulatory index of patients with type 2 DM both with AIT and without it was revealed (r = 0.83; р < 0.005; r = 0.77; р < 0.01; r = 0.9; р < 0.001, and r = 0.53; р < 0.05 respectively, which demonstrates autoimmune directivity of immune system disorders in combination with metabolic shifts.Conclusion. For the purpose of performance of simultaneous correction of metabolic and immunological disorders of patients with type 2 DM, it is necessary to determine immunological indicators (of the CD+- range of lymphocytes. The latter is caused with higher

  20. PECULIARITIES OF THE CYTOKINE PROFILE OF PATIENTS WITH TYPE 2 DIABETES MELLITUS IN COMBINATION WITH AUTOIMMUNE THYROIDITIS

    Directory of Open Access Journals (Sweden)

    N. A. Kravchun

    2015-01-01

    Full Text Available Study objective: study of the nature of changes in the immune system of patients with type 2 diabetes mellitus (DM in combination with autoimmune thyroiditis (AIT and without it; comparative analysis of similar indicators of patients with type 1 DM in combination with AIT and without it.Materials and methods. 104 patients at the age of 22 to 62 y.o. (57 women and 47 men took part in the study. They were divided into 4 groups (type 2 DM, type 2 DM and AIT, type 1 DM, type 1 DM and AIT. Groups of patients who were examined regarding the state of carbohydrate and lipid metabolism, indicators of the T-cell link of the immune system, concentration of interleukin 4 (IL-4, IL-6, interferon-gamma, and leptin level, were comparable regarding their sex, age, duration of disease.Results. Unidirectional relationship between body mass index (BMI, amount of CD4 +-, CD8+- lymphocytes, level of leptin, IL-4, IL-6 concentrations and BMI and immunoregulatory index of patients with type 2 DM both with AIT and without it was determined. Patients with type 2 DM displayed decreasing activity of the T-cell link of the immune system and increasing of the concentration of pro-inflammatory cytokines irrespectively of the availability of accompanying AIT, which evidenced primary development of autoimmune processes. At the same time, positivecorrelating relationship between the level of leptin and BMI and immunoregulatory index of patients with type 2 DM both with AIT and without it was revealed (r = 0.83; р < 0.005; r = 0.77; р < 0.01; r = 0.9; р < 0.001, and r = 0.53; р < 0.05 respectively, which demonstrates autoimmune directivity of immune system disorders in combination with metabolic shifts.Conclusion. For the purpose of performance of simultaneous correction of metabolic and immunological disorders of patients with type 2 DM, it is necessary to determine immunological indicators (of the CD+- range of lymphocytes. The latter is caused with higher

  1. Longitudinal three-dimensional visualisation of autoimmune diabetes by functional optical coherence imaging

    OpenAIRE

    Berclaz, Corinne; Schmidt-Christensen, Anja; Szlag, Daniel; Extermann, Jerome; Hansen, Lisbeth; Bouwens, Arno; Villiger, Martin; Goulley, Joan; Schuit, Frans; Grapin-Botton, Anne; Lasser, Theo; Holmberg, Dan

    2016-01-01

    It is generally accepted that structural and functional quantitative imaging of individual islets would be beneficial to elucidate the pathogenesis of type 1 diabetes. We here introduce functional optical coherence imaging (FOCI) for fast, label-free monitoring of beta cell destruction and associated alterations of islet vascularisation.

  2. Generation of Stable Pluripotent Stem Cells From NOD Mouse Tail-Tip Fibroblasts

    OpenAIRE

    Liu, Jun; Ashton, Michelle P.; Sumer, Huseyin; O’Bryan, Moira K.; Brodnicki, Thomas C.; Verma, Paul J.

    2011-01-01

    OBJECTIVE The NOD mouse strain has been widely used to investigate the pathology and genetic susceptibility for type 1 diabetes. Induced pluripotent stem cells (iPSCs) derived from this unique mouse strain would enable new strategies for investigating type 1 diabetes pathogenesis and potential therapeutic targets. The objective of this study was to determine whether somatic fibroblasts from NOD mice could be reprogrammed to become iPSCs, providing an alternative source of stem cells for the p...

  3. Peculiarities of antithyroid autoimmunity indicators in type 2 diabetic patients depending on leptin level in blood serum and their dynamics as a result of sodium selenite treatment

    OpenAIRE

    ABRAMOVA N.O.; PASHKOVSKA N.V.; BEREZOVA M.S.

    2015-01-01

    There were studied 46 patients with diabetes mellitus type 2 in order to identify the autoimmune processes directed against thyroid tissue and dependence of those changes on the level of leptin in blood serum. It was established that in patients with high leptin serum level antithyroid antibody titer increased. In order to adjust the levels of antithyroid antibodies sodium selenite was prescribed against the background of standard therapy. Statistically significant reduction in antibodies exp...

  4. Rhizobium nodM and nodN genes are common nod genes: nodM encodes functions for efficiency of nod signal production and bacteroid maturation.

    OpenAIRE

    Baev, N; Schultze, M; Barlier, I; Ha, D C; Virelizier, H.; Kondorosi, E.; Kondorosi, A

    1992-01-01

    Earlier, we showed that Rhizobium meliloti nodM codes for glucosamine synthase and that nodM and nodN mutants produce strongly reduced root hair deformation activity and display delayed nodulation of Medicago sativa (Baev et al., Mol. Gen. Genet. 228:113-124, 1991). Here, we demonstrate that nodM and nodN genes from Rhizobium leguminosarum biovar viciae restore the root hair deformation activity of exudates of the corresponding R. meliloti mutant strains. Partial restoration of the nodulation...

  5. Genetically Engineered Islets and Alternative Sources of Insulin-Producing Cells for Treating Autoimmune Diabetes: Quo Vadis?

    Directory of Open Access Journals (Sweden)

    Feng-Cheng Chou

    2012-01-01

    Full Text Available Islet transplantation is a promising therapy for patients with type 1 diabetes that can provide moment-to-moment metabolic control of glucose and allow them to achieve insulin independence. However, two major problems need to be overcome: (1 detrimental immune responses, including inflammation induced by the islet isolation/transplantation procedure, recurrence autoimmunity, and allorejection, can cause graft loss and (2 inadequate numbers of organ donors. Several gene therapy approaches and pharmaceutical treatments have been demonstrated to prolong the survival of pancreatic islet grafts in animal models; however, the clinical applications need to be investigated further. In addition, for an alternative source of pancreatic β-cell replacement therapy, the ex vivo generation of insulin-secreting cells from diverse origins of stem/progenitor cells has become an attractive option in regenerative medicine. This paper focuses on the genetic manipulation of islets during transplantation therapy and summarizes current strategies to obtain functional insulin-secreting cells from stem/progenitor cells.

  6. New tricks for old NODs

    OpenAIRE

    Pietras, Eric M.; Cheng, Genhong

    2008-01-01

    Recent work has identified the human NOD-like receptor NLRX1 as a negative regulator of intracellular signaling leading to type I interferon production. Here we discuss these findings and the questions and implications they raise regarding the function of NOD-like receptors in the antiviral response.

  7. Autoimmune polyglandular syndrome type 2 - a case report

    Directory of Open Access Journals (Sweden)

    Bănică Diana

    2014-03-01

    Full Text Available Autoimmune polyglandular syndromes are characterized by the association of two or more autoimmune diseases. They are classified into two major subtypes, each having its own characteristics. The autoimmune polyglandular syndrome type 2 is defined by the presence of at least two of the following diseases: Addison’s disease, type 1 diabetes mellitus and thyroid autoimmune disease. Other autoimmune diseases belonging to the autoimmune polyglandular syndrome type 2 are: primary hypogonadism, myasthenia gravis, celiac disease, pernicious anemia, alopecia, vitiligo. We are going to present the case of a patient, aged 40, with diabetes mellitus (probably latent autoimmune diabetes of the adult, chronic autoimmune thyroiditis and celiac disease.

  8. Rotavirus activates lymphocytes from non-obese diabetic mice by triggering toll-like receptor 7 signaling and interferon production in plasmacytoid dendritic cells.

    Directory of Open Access Journals (Sweden)

    Jessica A Pane

    2014-03-01

    Full Text Available It has been proposed that rotavirus infection promotes the progression of genetically-predisposed children to type 1 diabetes, a chronic autoimmune disease marked by infiltration of activated lymphocytes into pancreatic islets. Non-obese diabetic (NOD mice provide a model for the human disease. Infection of adult NOD mice with rhesus monkey rotavirus (RRV accelerates diabetes onset, without evidence of pancreatic infection. Rather, RRV spreads to the pancreatic and mesenteric lymph nodes where its association with antigen-presenting cells, including dendritic cells, induces cellular maturation. RRV infection increases levels of the class I major histocompatibility complex on B cells and proinflammatory cytokine expression by T cells at these sites. In autoimmunity-resistant mice and human mononuclear cells from blood, rotavirus-exposed plasmacytoid dendritic cells contribute to bystander polyclonal B cell activation through type I interferon expression. Here we tested the hypothesis that rotavirus induces bystander activation of lymphocytes from NOD mice by provoking dendritic cell activation and proinflammatory cytokine secretion. NOD mouse splenocytes were stimulated with rotavirus and assessed for activation by flow cytometry. This stimulation activated antigen-presenting cells and B cells independently of virus strain and replicative ability. Instead, activation depended on virus dose and was prevented by blockade of virus decapsidation, inhibition of endosomal acidification and interference with signaling through Toll-like receptor 7 and the type I interferon receptor. Plasmacytoid dendritic cells were more efficiently activated than conventional dendritic cells by RRV, and contributed to the activation of B and T cells, including islet-autoreactive CD8+ T cells. Thus, a double-stranded RNA virus can induce Toll-like receptor 7 signaling, resulting in lymphocyte activation. Our findings suggest that bystander activation mediated by type I

  9. IL-2 as a therapeutic target for the restoration of Foxp3+ regulatory T cell function in organ-specific autoimmunity: implications in pathophysiology and translation to human disease

    Directory of Open Access Journals (Sweden)

    Piccirillo Ciriaco A

    2010-11-01

    Full Text Available Abstract Peripheral immune tolerance requires a finely controlled balance between tolerance to self-antigens and protective immunity against enteric and invading pathogens. Self-reactive T cells sometimes escape thymic clonal deletion, and can subsequently provoke autoimmune diseases such as type 1 diabetes (T1D unless they are controlled by a network of tolerance mechanisms in the periphery, including CD4+ regulatory T cells (Treg cells. CD4+ Treg cells are characterized by the constitutive expression of the IL-2Rα chain (CD25 and preferentially express the forkhead winged helix transcriptional regulator Foxp3. These cells have been shown to possess immunosuppressive properties towards various immune cell subsets and their defects are thought to contribute to many autoimmune disorders. Strong evidence shows that IL-2 is one of the important stimulatory signals for the development, function and fitness of Treg cells. The non-obese diabetic (NOD mouse model, a prototypic model of spontaneous autoimmunity, mimics many features of human T1 D. Using this model, the contribution of the IL-2-IL-2R pathway to the development of T1 D and other autoimmune disorders has been extensively studied. In the past years, strong genetic and molecular evidence has indicated an essential role for the IL-2/IL-2R pathway in autoimmune disorders. Thus, the major role of IL-2 is to maintain immune tolerance by promoting Treg cell development, functional fitness and stability. Here we first summarize the genetic and experimental evidence demonstrating a role for IL-2 in autoimmunity, mainly through the study of the NOD mouse model, and analyze the cellular and molecular mechanisms of its action on Treg cells. We then move on to describe how this data can be translated to applications for human autoimmune diseases by using IL-2 as a therapeutic agent to restore Treg cell fitness, numbers and functions.

  10. Tc17 CD8+ T cells potentiate Th1-mediated autoimmune diabetes in a mouse model.

    Science.gov (United States)

    Saxena, Amit; Desbois, Sabine; Carrié, Nadège; Lawand, Myriam; Mars, Lennart T; Liblau, Roland S

    2012-09-15

    An increase in IL-17-producing CD8+ T (Tc17) cells has been reported in the peripheral blood of children with recent onset type 1 diabetes (T1D), but their contribution to disease pathogenesis is still unknown. To directly study the pathogenic potential of β cell-specific Tc17 cells, we used an experimental model of T1D based on the expression of the neo-self Ag hemagglutinin (HA) in the β cells of the pancreas. When transferred alone, the IL-17-producing HA-specific CD8+ T cells homed to the pancreatic lymph nodes without causing any pancreatic infiltration or tissue destruction. When transferred together with small numbers of diabetogenic HA-specific CD4+ T cells, a strikingly different phenotype developed. Under these conditions, Tc17 cells sustained disease progression, driving the destruction of β-islet cells, causing hyperglycemia and ultimately death. Disease progression did not correlate with functional or numerical alterations among the HA-specific CD4+ T cells. Rather, the transferred CD8+ T cells accumulated in the pancreatic islets and a considerable fraction converted, under the control of IL-12, to an IFN-γ-producing phenotype. Our data indicate that Tc17 cells are not diabetogenic but can potentiate a Th1-mediated disease. Plasticity of the Tc17 lineage is associated with transition to overt disease in this experimental model of T1D. PMID:22904307

  11. A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production

    DEFF Research Database (Denmark)

    Nachbur, Ueli; Stafford, Che A; Bankovacki, Aleksandra;

    2015-01-01

    , WEHI-345 prevents cytokine production in vitro and in vivo and ameliorates experimental autoimmune encephalomyelitis in mice. Our study highlights the importance of the kinase activity of RIPK2 for proper immune responses and demonstrates the therapeutic potential of inhibiting RIPK2 in NOD...

  12. Detection of GAD65 antibodies in diabetes and other autoimmune diseases using a simple radioligand assay.

    Science.gov (United States)

    Petersen, J S; Hejnaes, K R; Moody, A; Karlsen, A E; Marshall, M O; Høier-Madsen, M; Boel, E; Michelsen, B K; Dyrberg, T

    1994-03-01

    Autoantibodies to glutamic acid decarboxylase (GAD) are frequent at or before the onset of insulin-dependent diabetes mellitus (IDDM). We have developed a simple, reproducible, and quantitative immunoprecipitation radioligand assay using as antigen in vitro transcribed and translated [35S]methionine-labeled human islet GAD65. By using this assay, 77% (77 of 100) of serum samples from recent-onset IDDM patients were positive for GAD65 antibodies compared with 4% (4 of 100) of serum samples from healthy control subjects. In competition analysis with unlabeled purified recombinant human islet GAD65, binding to tracer was inhibited in 74% (74 of 100) of the GAD65-positive IDDM serum samples compared with 2% of the control samples. The levels of GAD antibodies expressed as an index value relative to a standard serum, analyzed with or without competition, were almost identical (r = 0.991). The intra- and interassay variations of a positive control serum sample were 2.9 and 7.6%, respectively (n = 4). The frequency of GAD antibodies was significantly higher with IDDM onset before the age of 30 (80%, 59 of 74) than after the age of 30 (48%, 10 of 21) (P DNA autoantibodies (8% [2 of 25] and 4% [1 of 25] in competition analysis) or rheuma factor autoantibodies [12% (4 of 35) and 3% (1 of 35) in competition analysis] was not different from that in control samples. In contrast, in sera positive for ribonucleoprotein antibodies the frequency of GAD antibodies was significantly increased (73% [51 of 70] and 10% [7 of 70] in competition analysis [P history of IDDM for the presence of this marker. PMID:8314020

  13. Screening of endocrine organ-specific humoral autoimmunity in 47,XXY Klinefelter's syndrome reveals a significant increase in diabetes-specific immunoreactivity in comparison with healthy control men.

    Science.gov (United States)

    Panimolle, Francesca; Tiberti, Claudio; Granato, Simona; Semeraro, Antonella; Gianfrilli, Daniele; Anzuini, Antonella; Lenzi, Andrea; Radicioni, Antonio

    2016-04-01

    The aim of this study was to evaluate the frequency of humoral endocrine organ-specific autoimmunity in 47,XXY Klinefelter's syndrome (KS) by investigating the autoantibody profile specific to type 1 diabetes (T1DM), Addison's disease (AD), Hashimoto thyroiditis (HT), and autoimmune chronic atrophic gastritis (AG). Sixty-one adult Caucasian 47,XXY KS patients were tested for autoantibodies specific to T1DM (Insulin Abs, GAD Abs, IA-2 Abs, Znt8 Abs), HT (TPO Abs), AD (21-OH Abs), and AG (APC Abs). Thirty-five of these patients were not undergoing testosterone replacement therapy TRT (Group 1) and the remaining 26 patients started TRT before the beginning of the study (Group 2). KS autoantibody frequencies were compared to those found in 122 control men. Six of 61 KS patients (9.8 %) were positive for at least one endocrine autoantibody, compared to 6.5 % of controls. Interestingly, KS endocrine immunoreactivity was directed primarily against diabetes-specific autoantigens (8.2 %), with a significantly higher frequency than in controls (p = 0.016). Two KS patients (3.3 %) were TPO Ab positive, whereas no patients were positive for AD- and AG-related autoantigens. The autoantibody endocrine profile of untreated and treated KS patients was not significantly different. Our findings demonstrate for the first time that endocrine humoral immunoreactivity is not rare in KS patients and that it is more frequently directed against type 1 diabetes-related autoantigens, thus suggesting the importance of screening for organ-specific autoimmunity in clinical practice. Follow-up studies are needed to establish if autoantibody-positive KS patients will develop clinical T1DM. PMID:25935328

  14. Islet-specific CTL cloned from a type 1 diabetes patient cause beta-cell destruction after engraftment into HLA-A2 transgenic NOD/scid/IL2RG null mice.

    Directory of Open Access Journals (Sweden)

    Wendy W J Unger

    Full Text Available Despite increasing evidence that autoreactive CD8 T-cells are involved in both the initiation of type 1 diabetes (T1D and the destruction of beta-cells, direct evidence for their destructive role in-vivo is lacking. To address a destructive role for autoreactive CD8 T-cells in human disease, we assessed the pathogenicity of a CD8 T-cell clone derived from a T1D donor and specific for an HLA-A2-restricted epitope of islet-specific glucose-6-phosphatase catalytic-subunit related protein (IGRP. HLA-A2/IGRP tetramer staining revealed a higher frequency of IGRP-specific CD8 T-cells in the peripheral blood of recent onset human individuals than of healthy donors. IGRP(265-273-specific CD8 T-cells that were cloned from the peripheral blood of a recent onset T1D individual were shown to secrete IFNγ and Granzyme B after antigen-specific activation and lyse HLA-A2-expressing murine islets in-vitro. Lytic capacity was also demonstrated in-vivo by specific killing of peptide-pulsed target cells. Using the HLA-A2 NOD-scid IL2rγ(null mouse model, HLA-A2-restricted IGRP-specific CD8 T-cells induced a destructive insulitis. Together, this is the first evidence that human HLA-restricted autoreactive CD8 T-cells target HLA-expressing beta-cells in-vivo, demonstrating the translational value of humanized mice to study mechanisms of disease and therapeutic intervention strategies.

  15. Cutting Edge: Commensal Microbiota Has Disparate Effects on Manifestations of Polyglandular Autoimmune Inflammation.

    Science.gov (United States)

    Hansen, Camilla H F; Yurkovetskiy, Leonid A; Chervonsky, Alexander V

    2016-08-01

    Polyglandular autoimmune inflammation accompanies type 1 diabetes (T1D) in NOD mice, affecting organs like thyroid and salivary glands. Although commensals are not required for T1D progression, germ-free (GF) mice had a very low degree of sialitis, which was restored by colonization with select microbial lineages. Moreover, unlike T1D, which is blocked in mice lacking MyD88 signaling adaptor under conventional, but not GF, housing conditions, sialitis did not develop in MyD88(-/-) GF mice. Thus, microbes and MyD88-dependent signaling are critical for sialitis development. The severity of sialitis did not correlate with the degree of insulitis in the same animal and was less sensitive to a T1D-reducing diet, but it was similar to T1D with regard to microbiota-dependent sexual dimorphism. The unexpected distinction in requirements for the microbiota for different autoimmune pathologies within the same organism is crucial for understanding the nature of microbial involvement in complex autoimmune disorders, including human autoimmune polyglandular syndromes. PMID:27324130

  16. Nod-like receptors have a grip on stem cells.

    Science.gov (United States)

    Fritz, Jörg H

    2014-06-11

    Two reports in this issue of Cell Host & Microbe establish that Nod-like receptor proteins NOD1 and NOD2 regulate stem cell function. Burberry et al. (2014) demonstrate that NOD1 and NOD2 synergize with TLRs to mobilize hematopoietic stem cells. Nigro et al. (2014) report that NOD2 provides cytoprotection to intestinal stem cells. PMID:24922568

  17. IDO-Expressing Fibroblasts Protect Islet Beta Cells From Immunological Attack and Reverse Hyperglycemia in Non-Obese Diabetic Mice.

    Science.gov (United States)

    Zhang, Yun; Jalili, Reza B; Kilani, Ruhangiz T; Elizei, Sanam Salimi; Farrokhi, Ali; Khosravi-Maharlooei, Mohsen; Warnock, Garth L; Ao, Ziliang; Marzban, Lucy; Ghahary, Aziz

    2016-09-01

    Indoleamine 2,3-dioxygenase (IDO) induces immunological tolerance in physiological and pathological conditions. Therefore, we used dermal fibroblasts with stable IDO expression as a cell therapy to: (i) Investigate the factors determining the efficacy of this cell therapy for autoimmune diabetes in non-obese diabetic (NOD) mice; (ii) Scrutinize the potential immunological mechanisms. Newly diabetic NOD mice were randomly injected with either 10 × 10(6) (10M) or 15 × 10(6) (15M) IDO-expressing dermal fibroblasts. Blood glucose levels (BGLs), body weight, plasma kynurenine levels, insulitis severity, islet beta cell function, autoreactive CD8(+) T cells, Th17 cells and regulatory T cells (Tregs) were then investigated in these mice. IL-1β and cleaved caspase-3 levels were assessed in islets co-cultured with IDO-expressing fibroblasts. BGLs in 83% mice treated with 15M IDO-expressing fibroblasts recovered to normal up to 120 days. However, only 17% mice treated with 10M IDO-expressing cells were reversed to normoglycemia. A 15M IDO-expressing fibroblasts significantly reduced infiltrated immune cells in islets and recovered the functionality of remaining islet beta cells in NOD mice. Additionally, they successfully inhibited autoreactive CD8(+) T cells and Th17 cells as well as increased Tregs in different organs of NOD mice. Islet beta cells co-cultured with IDO-expressing fibroblasts had reduced IL-1β levels and cell apoptosis. Both cell number and IDO enzymatic activity contributes to the efficiency of IDO cell therapy. Optimized IDO-expressing fibroblasts successfully reverse the progression of diabetes in NOD mice through induction of Tregs as well as inhibition of beta cell specific autoreactive CD8(+) T cells and Th17 cells. J. Cell. Physiol. 231: 1964-1973, 2016. © 2016 Wiley Periodicals, Inc. PMID:26743772

  18. DMPD: Nod1 and Nod2 in innate immunity and human inflammatory disorders. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18031249 Nod1 and Nod2 in innate immunity and human inflammatory disorders. Le Bour...w Nod1 and Nod2 in innate immunity and human inflammatory disorders. PubmedID 18031249 Title Nod1 and Nod2 in innate immunity and hum...an inflammatory disorders. Authors Le Bourhis L, Benko S

  19. Autoimmune polyglandular syndrome type 2 - a case report

    OpenAIRE

    Bănică Diana; Frăţilă Ramona; Sima Alexandra; Vlad Adrian; Timar Romulus

    2014-01-01

    Autoimmune polyglandular syndromes are characterized by the association of two or more autoimmune diseases. They are classified into two major subtypes, each having its own characteristics. The autoimmune polyglandular syndrome type 2 is defined by the presence of at least two of the following diseases: Addison’s disease, type 1 diabetes mellitus and thyroid autoimmune disease. Other autoimmune diseases belonging to the autoimmune polyglandular syndrome type 2 are: primary hypogonadism, myast...

  20. In vivo islet protection by a nuclear import inhibitor in a mouse model of type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Daniel J Moore

    Full Text Available BACKGROUND: Insulin-dependent Type 1 diabetes (T1D is a devastating autoimmune disease that destroys beta cells within the pancreatic islets and afflicts over 10 million people worldwide. These patients face life-long risks for blindness, cardiovascular and renal diseases, and complications of insulin treatment. New therapies that protect islets from autoimmune destruction and allow continuing insulin production are needed. Increasing evidence regarding the pathomechanism of T1D indicates that islets are destroyed by the relentless attack by autoreactive immune cells evolving from an aberrant action of the innate, in addition to adaptive, immune system that produces islet-toxic cytokines, chemokines, and other effectors of islet inflammation. We tested the hypothesis that targeting nuclear import of stress-responsive transcription factors evoked by agonist-stimulated innate and adaptive immunity receptors would protect islets from autoimmune destruction. PRINCIPAL FINDINGS: Here we show that a first-in-class inhibitor of nuclear import, cSN50 peptide, affords in vivo islet protection following a 2-day course of intense treatment in NOD mice, which resulted in a diabetes-free state for one year without apparent toxicity. This nuclear import inhibitor precipitously reduces the accumulation of islet-destructive autoreactive lymphocytes while enhancing activation-induced cell death of T and B lymphocytes derived from autoimmune diabetes-prone, non-obese diabetic (NOD mice that develop T1D. Moreover, in this widely used model of human T1D we noted attenuation of pro-inflammatory cytokine and chemokine production in immune cells. CONCLUSIONS: These results indicate that a novel form of immunotherapy that targets nuclear import can arrest inflammation-driven destruction of insulin-producing beta cells at the site of autoimmune attack within pancreatic islets during the progression of T1D.

  1. GCN2 and FGF21 are likely mediators of the protection from cancer, autoimmunity, obesity, and diabetes afforded by vegan diets.

    Science.gov (United States)

    McCarty, Mark F

    2014-09-01

    Third World quasi-vegan cultures have been characterized by low risks for "Western" cancers, autoimmune disorders, obesity, and diabetes. The relatively low essential amino acid contents of many vegan diets may play a role in this regard. It is proposed that such diets modestly activate the kinase GCN2 - a physiological detector of essential amino acid paucity - within the liver, resulting in up-regulated production of fibroblast growth factor 21 (FGF21). FGF21, by opposing the stimulatory effect of growth hormone on hepatic IGF-I production, may be responsible for the down-regulation of plasma IGF-I observed in vegans consuming diets of modest protein content. Decreased IGF-I bioactivity throughout life can be expected to have a favorable impact on cancer risk, as observed in rodents that are calorie restricted or genetically defective in IGF-I activity. Increased FGF21 in vegans might also contribute to their characteristic leanness and low LDL cholesterol by promoting hepatic lipid oxidation while inhibiting lipogenesis. Direct trophic effects of FGF21 on pancreatic beta-cells may help to explain the low risk for diabetes observed in vegans, and the utility of vegan diets in diabetes management. And up-regulation of GCN2 in immune cells, by boosting T regulatory activity, might play some role in the reduced risk for autoimmunity reported in some quasi-vegan cultures. The fact that bone density tends to be no greater in vegans than omnivores, despite consumption of a more "alkaline" diet, might be partially attributable to the fact that FGF21 opposes osteoblastogenesis and decreases IGF-I. If these speculations have merit, it should be possible to demonstrate that adoption of a vegan diet of modest protein content increases plasma FGF21 levels. PMID:25015767

  2. [Polyglandular autoimmune syndromes : An overview].

    Science.gov (United States)

    Komminoth, P

    2016-05-01

    Polyglandular autoimmune syndromes (PGAS), also known as autoimmune polyendocrinopathy syndromes (APS), are a heterogeneous group of rare, genetically caused diseases of the immune system which lead to inflammatory damage of various endocrine glands resulting in malfunctions. In addition, autoimmune diseases of non-endocrine organs may also be found. Early diagnosis of PGAS is often overlooked because of heterogeneous symptoms and the progressive occurrence of the individual diseases. The two most important forms of PGAS are the juvenile and adult types. The juvenile type (PGAS type 1) is caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21, exhibits geographic variations in incidence and is defined by the combination of mucocutaneous candidiasis, Addison's disease and hypoparathyroidism. In addition, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome and other autoimmune diseases can also occur. The adult form of PGAS (PGAS type 2) is a multigenetic disorder associated with some HLA haplotypes, is more common than the juvenile type, shows female predominance and exhibits the combination of type 1 diabetes, autoimmune thyroid disease, Addison's disease and other autoimmune disorders. The histological alterations in affected organs of PGAS patients are similar to findings in sporadically occurring autoimmune diseases of these organs but there are no pathognomic fine tissue findings. If patients exhibit autoimmune changes in two different endocrine glands or if there are indications of several autoimmune disorders from the patient history, it is important to consider PGAS and inform the clinicians of this suspicion. PMID:27099223

  3. Identifying type 1 diabetes candidate genes by DNA microarray analysis of islet-specific CD4+ T cells

    Directory of Open Access Journals (Sweden)

    Gregory J. Berry

    2015-09-01

    Full Text Available Type 1 diabetes (T1D is a T cell-mediated autoimmune disease resulting from the destruction of insulin-producing pancreatic beta cells and is fatal unless treated with insulin. During the last four decades, multiple insulin-dependent diabetes (Idd susceptibility/resistance loci that regulate T1D development have been identified in humans and non-obese diabetic (NOD mice, an established animal model for T1D. However, the exact mechanisms by which these loci confer diabetes risk and the identity of the causative genes remain largely elusive. To identify genes and molecular mechanisms that control the function of diabetogenic T cells, we conducted DNA microarray analysis in islet-specific CD4+ T cells from BDC2.5 TCR transgenic NOD mice that contain the Idd9 locus from T1D-susceptible NOD mice or T1D-resistant C57BL/10 mice. Here we describe in detail the contents and analyses for these gene expression data associated with our previous study [1]. Gene expression data are available at the Gene Expression Omnibus (GEO repository from the National Center for Biotechnology Information (accession number GSE64674.

  4. Autoimmune Hepatitis

    Science.gov (United States)

    ... diagnosed? A health care provider will make a diagnosis of autoimmune hepatitis based on symptoms, a physical exam, blood tests, ... 2. A health care provider will make a diagnosis of autoimmune hepatitis based on symptoms, a physical exam, blood tests, ...

  5. A new model defines the minimal set of polymorphism in HLA-DQ and -DR that determines susceptibility and resistance to autoimmune diabetes

    Directory of Open Access Journals (Sweden)

    Brooks Bernard R

    2008-10-01

    Full Text Available Abstract Background The mechanism underlying autoimmune diabetes has been difficult to define. There is a strong genetic contribution and numerous studies associate the major histocompatibility complex, especially the class II region, with predisposition or resistance. However, how these molecules are implicated remains obscure. Presentation of the hypothesis We have supplemented structural analysis with computational biophysical and sequence analyses and propose an heuristic for distinguishing between human leukocyte antigen molecules that predispose to insulin dependent diabetes mellitus and those that are protective. Polar residues at both β37 and β9 suffice to distinguish accurately between class II alleles that predispose to type 1 diabetes and those that do not. The electrostatic potential within the peptide binding pocket exerts a strong influence on diabetogenic epitopes with basic residues. Diabetes susceptibility alleles are predicted to bind autoantigens strongly with tight affinity, prolonged association and altered cytokine expression profile. Protective alleles bind moderately, and neutral alleles poorly or not at all. Non-Asp β57 is a modifier that supplements disease risk but only in the presence of the polymorphic, polar pair at β9 and β37. The nature of β37 determines resistance on one hand, and susceptibility or dominant protection on the other. Conclusion The proposed ideas are illustrated with structural, functional and population studies from the literature. The hypothesis, in turn, rationalizes their results. A plausible mechanism of immune mediated diabetes based on binding affinity and peptide kinetics is discussed. The number of the polymorphic markers present correlates with onset of disease and severity. The molecular elucidation of disease susceptibility and resistance paves the way for risk prediction, treatment and prevention of disease based on analogue peptides. Reviewers This article was reviewed by Eugene

  6. Sialoadenitis progression in nonobese diabetic mice and its correlation with expression of apoptosis-associated proteins in salivary glands and serum IgG levels

    Institute of Scientific and Technical Information of China (English)

    QI Ge; HUA Hong; GAO Yan; LIN Qin; YU Guang-yan

    2007-01-01

    Background Sj(o)gren syndrome (SS) is an autoimmune disorder characterized by chronic lymphocytic infiltration and decreased secretion in salivary glands. Apoptosis is one of the possible mechanisms involved in acinar epithelial destruction in SS. The role of apoptosis in the initiation and effect phase of sialoadenitis is still controversial. The aim of this study was to observe the roles of apoptosis-associated proteins and serum IgG levels in sialoadenitis progression in nonobese diabetic (NOD) mice.Methods 2-, 5-, 10-, 15-, 20-week female NOD and matched BALB/c control mice were selected. Saliva and tear flow rate were measured. Serum IgG level was tested by enzyme-linked immunosorbent assay (ELISA). Number of lymphocyte foci (NLF) in submandibular glands (SMGs) was counted under routine hematoxylin/eosin-stained sections.Expression of Fas, Bcl-2 and procaspase3 proteins as well as apoptotic cells in the SMGs were detected by immunohistochemical staining and by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay respectively.Results Decreased stimulated total flow rate (STFR) and lymphocyte foci in SMGs were first observed in the 10-week NOD group. STFR was negatively correlated with NLF (P<0.05). Serum IgG in NOD mice was significantly higher than that of the control group (P<0.05) and showed a positive correlation with NLF (P<0.05). Fas expression in SMGs acinar cells in NOD mice increased with age and was significantly higher compared with that in the control group. Bcl-2 expression and procaspase3 expression in SMG acinar cells in each NOD group were lower compared with those of the age-matched control mice.Conclusion Abnormal expression of Fas and Bcl-2 in the SMGs and higher level of serum IgG may contribute to the initiation of sialoadenitis and cause the glandular destruction in NOD mice.

  7. Autoimmune pancreatitis

    Directory of Open Access Journals (Sweden)

    Bo-Guang Fan

    2009-01-01

    Full Text Available Since the autoimmune pancreatitis was introduced in 1995, it has been recognized as a form of chronic pancreatitis, which is always associated with autoimmune manifestations. As the improvement of technical and instrumental made in ultrasonography, computed tomography and magnetic resonance imaging, the diagnoses of autoimmune pancreatitis is no longer such difficult. Even though the treatment of autoimmune pancreatitis is available with a conservative therapy, there are many points that are still unclearly. These have stimulated widespread interest in this disease from gastroenterologists, endoscopists, pathologists, and prevalent research. The present article provides with our better understanding of the diagnosis and treatment of autoimmune pancreatitis.

  8. Autoimmune pancreatitis

    Directory of Open Access Journals (Sweden)

    Bo-Guang Fan

    2009-09-01

    Full Text Available Since the autoimmune pancreatitis was introduced in 1995, it has been recognized as a form of chronic pancreatitis, which is always associated with autoimmune manifestations. As the improvement of technical and instrumental made in ultrasonography, computed tomography and magnetic resonance imaging, the diagnoses of autoimmune pancreatitis is no longer such difficult. Even though the treatment of autoimmune pancreatitis is available with a conservative therapy, there are many points that are still unclearly. These have stimulated widespread interest in this disease from gastroenterologists, endoscopists, pathologists, and prevalent research. The present article provides with our better understanding of the diagnosis and treatment of autoimmune pancreatitis.

  9. Autoimmune liver disease, autoimmunity and liver transplantation.

    Science.gov (United States)

    Carbone, Marco; Neuberger, James M

    2014-01-01

    Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent the three major autoimmune liver diseases (AILD). PBC, PSC, and AIH are all complex disorders in that they result from the effects of multiple genes in combination with as yet unidentified environmental factors. Recent genome-wide association studies have identified numerous risk loci for PBC and PSC that host genes involved in innate or acquired immune responses. These loci may provide a clue as to the immune-based pathogenesis of AILD. Moreover, many significant risk loci for PBC and PSC are also risk loci for other autoimmune disorders, such type I diabetes, multiple sclerosis and rheumatoid arthritis, suggesting a shared genetic basis and possibly similar molecular pathways for diverse autoimmune conditions. There is no curative treatment for all three disorders, and a significant number of patients eventually progress to end-stage liver disease requiring liver transplantation (LT). LT in this context has a favourable overall outcome with current patient and graft survival exceeding 80% at 5years. Indications are as for other chronic liver disease although recent data suggest that while lethargy improves after transplantation, the effect is modest and variable so lethargy alone is not an indication. In contrast, pruritus rapidly responds. Cholangiocarcinoma, except under rigorous selection criteria, excludes LT because of the high risk of recurrence. All three conditions may recur after transplantation and are associated with a greater risk of both acute cellular and chronic ductopenic rejection. It is possible that a crosstalk between alloimmune and autoimmune response perpetuate each other. An immunological response toward self- or allo-antigens is well recognised after LT in patients transplanted for non-autoimmune indications and sometimes termed "de novo autoimmune hepatitis". Whether this is part of the spectrum of rejection or an autoimmune

  10. Types of pediatric diabetes mellitus defined by anti-islet autoimmunity and random C-peptide at diagnosis

    Science.gov (United States)

    The objective of this study was to test the hypothesis that anti-islet autoantibody expression and random serum C-peptide obtained at diagnosis define phenotypes of pediatric diabetes with distinct clinical features. We analyzed 607 children aged diabetes after ex...

  11. The Effects of Exogenous and Endogenous Ligands of the Aryl Hydrocarbon Receptor on the Activation of Autoimmune Diabetes

    OpenAIRE

    Abu-Rizq, Hana'A

    2012-01-01

    The aryl-hydrocarbon receptor (AhR) is an important receptor found in immune cells. Itfunctions as a detector of environmental toxins, naturally occurring dietary products, andendogenous tryptophan derivatives for induction of gene transcription responses. Previousreports have implicated stimulation of AhR by various ligands in promoting T cellactivation or regulatory function, with effects on autoimmune disease models. Also, effectsof Ah toxins or natural products on increasing or suppressin...

  12. Selective destruction of mouse islet beta cells by human T lymphocytes in a newly-established humanized type 1 diabetic model

    International Nuclear Information System (INIS)

    Research highlights: → Establish a human immune-mediated type 1 diabetic model in NOD-scid IL2rγnull mice. → Using the irradiated diabetic NOD mouse spleen mononuclear cells as trigger. → The islet β cells were selectively destroyed by infiltrated human T cells. → The model can facilitate translational research to find a cure for type 1 diabetes. -- Abstract: Type 1 diabetes (T1D) is caused by a T cell-mediated autoimmune response that leads to the loss of insulin-producing β cells. The optimal preclinical testing of promising therapies would be aided by a humanized immune-mediated T1D model. We develop this model in NOD-scid IL2rγnull mice. The selective destruction of pancreatic islet β cells was mediated by human T lymphocytes after an initial trigger was supplied by the injection of irradiated spleen mononuclear cells (SMC) from diabetic nonobese diabetic (NOD) mice. This resulted in severe insulitis, a marked loss of total β-cell mass, and other related phenotypes of T1D. The migration of human T cells to pancreatic islets was controlled by the β cell-produced highly conserved chemokine stromal cell-derived factor 1 (SDF-1) and its receptor C-X-C chemokine receptor (CXCR) 4, as demonstrated by in vivo blocking experiments using antibody to CXCR4. The specificity of humanized T cell-mediated immune responses against islet β cells was generated by the local inflammatory microenvironment in pancreatic islets including human CD4+ T cell infiltration and clonal expansion, and the mouse islet β-cell-derived CD1d-mediated human iNKT activation. The selective destruction of mouse islet β cells by a human T cell-mediated immune response in this humanized T1D model can mimic those observed in T1D patients. This model can provide a valuable tool for translational research into T1D.

  13. Lack of Association of Type 2 Diabetes Susceptibility Genotypes and Body Weight on the Development of Islet Autoimmunity and Type 1 Diabetes

    OpenAIRE

    Winkler, Christiane; Raab, Jennifer; Grallert, Harald; Ziegler, Anette-Gabriele

    2012-01-01

    Aim To investigate whether type 2 diabetes susceptibility genes and body weight influence the development of islet autoantibodies and the rate of progression to type 1 diabetes. Methods Genotyping for single nucleotide polymorphisms (SNP) of the type 2 diabetes susceptibility genes CDKAL1, CDKN2A/2B, FTO, HHEX-IDE, HMGA2, IGF2BP2, KCNJ11, KCNQ1, MTNR1B, PPARG, SLC30A8 and TCF7L2 was obtained in 1350 children from parents with type 1 diabetes participating in the BABYDIAB study. Children were ...

  14. Identification and Antioxidant Activity of the Extracts of Eugenia uniflora Leaves. Characterization of the Anti-Inflammatory Properties of Aqueous Extract on Diabetes Expression in an Experimental Model of Spontaneous Type 1 Diabetes (NOD Mice)

    OpenAIRE

    Nayara Simon Gonzalez Schumacher; Talita Cristina Colomeu; Daniella de Figueiredo; Virginia de Campos Carvalho; Cinthia Baú Betim Cazarin; Marcelo Alexandre Prado; Laura Maria Molina Meletti; Ricardo de Lima Zollner

    2015-01-01

    Medical and folklore reports suggest that Eugenia uniflora (E. uniflora) is a functional food that contains numerous compounds in its composition, with anti-inflammatory, antioxidant and anti-diabetic effects. In the present study, we investigated the best solvents (water, ethanol and methanol/acetone) for extracting bioactive compounds of E. uniflora leaves, assessing total phenols and the antioxidant activity of the extracts by 2,2-Diphenyl-1-picrylhydrazyl (DPPH), Ferric Reducing Antioxid...

  15. Nodding syndrome, western Uganda, 1994.

    Science.gov (United States)

    Kaiser, Christoph; Rubaale, Tom; Tukesiga, Ephraim; Kipp, Walter; Asaba, George

    2015-07-01

    Nodding syndrome (NS) is a poorly understood condition, which was delineated in 2008 as a new epilepsy syndrome. So far, confirmed cases of NS have been observed in three circumscribed African areas: southern Tanzania, southern Sudan, and northern Uganda. Case-control studies have provided evidence of an association between NS and infection with Onchocerca volvulus, but the causation of NS is still not fully clarified. We report a case of a 15-year old boy with head nodding seizures and other characteristic features of NS from an onchocerciasis endemic area in western Uganda, with no contiguity to the hitherto known areas. We suggest that the existence of NS should be systematically investigated in other areas. PMID:25918208

  16. Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes

    OpenAIRE

    Achenbach, Peter; Koczwara, Kerstin; Knopff, Annette; Naserke, Heike; Ziegler, Anette-G.; Bonifacio, Ezio

    2004-01-01

    Children at risk for type 1 diabetes can develop early insulin autoantibodies (IAAs). Many, but not all, of these children subsequently develop multiple islet autoantibodies and diabetes. To determine whether disease progression is reflected by autoantibody maturity, IAA affinity was measured by competitive radiobinding assay in first and subsequent IAA-positive samples from children followed from birth in the BABYDIAB cohort. IAA affinity in first positive samples ranged from less than 106 l...

  17. Is pancreas development abnormal in the non-obese diabetic mouse, a spontaneous model of type I diabetes?

    Directory of Open Access Journals (Sweden)

    F. Homo-Delarche

    2001-04-01

    Full Text Available Despite extensive genetic and immunological research, the complex etiology and pathogenesis of type I diabetes remains unresolved. During the last few years, our attention has been focused on factors such as abnormalities of islet function and/or microenvironment, that could interact with immune partners in the spontaneous model of the disease, the non-obese diabetic (NOD mouse. Intriguingly, the first anomalies that we noted in NOD mice, compared to control strains, are already present at birth and consist of 1 higher numbers of paradoxically hyperactive ß cells, assessed by in situ preproinsulin II expression; 2 high percentages of immature islets, representing islet neogenesis related to neonatal ß-cell hyperactivity and suggestive of in utero ß-cell stimulation; 3 elevated levels of some types of antigen-presenting cells and FasL+ cells, and 4 abnormalities of extracellular matrix (ECM protein expression. However, the colocalization in all control mouse strains studied of fibroblast-like cells (anti-TR-7 labeling, some ECM proteins (particularly, fibronectin and collagen I, antigen-presenting cells and a few FasL+ cells at the periphery of islets undergoing neogenesis suggests that remodeling phenomena that normally take place during postnatal pancreas development could be disturbed in NOD mice. These data show that from birth onwards there is an intricate relationship between endocrine and immune events in the NOD mouse. They also suggest that tissue-specific autoimmune reactions could arise from developmental phenomena taking place during fetal life in which ECM-immune cell interaction(s may play a key role.

  18. 皮下注射胰岛素抑制胰岛β细胞凋亡预防NOD鼠糖尿病%Inhibition of islet β cell apoptosis and prevention diabetes by subcutaneous administration of insulin in NOD mice

    Institute of Scientific and Technical Information of China (English)

    蒋铁建; 周智广; 苏恒

    2006-01-01

    目的:观察皮下注射胰岛素免疫干预对非肥胖糖尿病(non-obese diabetic,NOD)鼠胰岛炎、β细胞凋亡和糖尿病的影响,并探讨其诱导免疫耐受的机制.方法:60只NOD雌鼠随机分为胰岛素处理组(n=34)和磷酸盐缓冲液(phosphate buffered saline,PBS)对照组(n=28),分别于4周、12周、20周、28周皮下注射中效胰岛素优泌林N(Humulin N)6 U(60 μL)+不完全弗氏佐剂(incomplete Freund's adjuvant,IFA)60 μL,对照组予PBS(60 μL)+IFA(60μL).于12周龄观察胰岛炎和胰岛β细胞凋亡;检测胰岛Fas和FasL的表达;测定血清IL-4和IFN-γ浓度,以及胰岛内I-Aβg7,IL-1β,IFN-γ,Fas,IL-4mRNA的表达水平.结果:NOD鼠皮下注射胰岛素加IFA组30周龄和52周龄时发病率仅为21.4%和28.6%,而皮下PBS加IFA组为71.4%和85.7%(P<0.05).胰岛素组胰岛炎积分比对照组低,但差异无统计学意义(P>0.05).胰岛素组胰岛Fas抗原表达和β细胞凋亡率均比PBS对照组低(均P<0.05).胰岛素组胰岛内I-Aβg7,IFN-γ,IL-1β,Fas mRNA表达较PBS对照组低(均P<0.05),而IL-4mRNA表达较对照组高(P<0.05);胰岛素组血清IL-4比PBS组高,IFN-γ比PBS组低(均P<0.05).结论:皮下注射胰岛素能诱导NOD鼠的免疫耐受而预防糖尿病的发生,但不能阻断胰岛炎的进展.皮下注射胰岛素能诱导调节性T细胞产生,使全身和胰岛局部T细胞由Th1向Th2转型,从而抑制Fas介导的β细胞凋亡而预防糖尿病.

  19. Sex differences in autoimmune diseases

    Directory of Open Access Journals (Sweden)

    Voskuhl Rhonda

    2011-01-01

    Full Text Available Abstract Women are more susceptible to a variety of autoimmune diseases including systemic lupus erythematosus (SLE, multiple sclerosis (MS, primary biliary cirrhosis, rheumatoid arthritis and Hashimoto's thyroiditis. This increased susceptibility in females compared to males is also present in animal models of autoimmune diseases such as spontaneous SLE in (NZBxNZWF1 and NZM.2328 mice, experimental autoimmune encephalomyelitis (EAE in SJL mice, thyroiditis, Sjogren's syndrome in MRL/Mp-lpr/lpr mice and diabetes in non-obese diabetic mice. Indeed, being female confers a greater risk of developing these diseases than any single genetic or environmental risk factor discovered to date. Understanding how the state of being female so profoundly affects autoimmune disease susceptibility would accomplish two major goals. First, it would lead to an insight into the major pathways of disease pathogenesis and, secondly, it would likely lead to novel treatments which would disrupt such pathways.

  20. A cluster of coregulated genes determines TGF-beta-induced regulatory T-cell (Treg) dysfunction in NOD mice.

    Science.gov (United States)

    D'Alise, Anna Morena; Ergun, Ayla; Hill, Jonathan A; Mathis, Diane; Benoist, Christophe

    2011-05-24

    Foxp3(+) regulatory T cells (Tregs) originate in the thymus, but the Treg phenotype can also be induced in peripheral lymphoid organs or in vitro by stimulation of conventional CD4(+) T cells with IL-2 and TGF-β. There have been divergent reports on the suppressive capacity of these TGF-Treg cells. We find that TGF-Tregs derived from diabetes-prone NOD mice, although expressing normal Foxp3 levels, are uniquely defective in suppressive activity, whereas TGF-Tregs from control strains (B6g7) or ex vivo Tregs from NOD mice all function normally. Most Treg-typical transcripts were shared by NOD or B6g7 TGF-Tregs, except for a small group of differentially expressed genes, including genes relevant for suppressive activity (Lrrc32, Ctla4, and Cd73). Many of these transcripts form a coregulated cluster in a broader analysis of T-cell differentiation. The defect does not map to idd3 or idd5 regions. Whereas Treg cells from NOD mice are normal in spleen and lymph nodes, the NOD defect is observed in locations that have been tied to pathogenesis of diabetes (small intestine lamina propria and pancreatic lymph node). Thus, a genetic defect uniquely affects a specific Treg subpopulation in NOD mice, in a manner consistent with a role in determining diabetes susceptibility. PMID:21543717

  1. Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: Application to nonobese diabetic (NOD) mouse and human insulin-dependent diabetes mellitus (IDDM)

    Energy Technology Data Exchange (ETDEWEB)

    Risch, N. (Yale Univ. School of Medicine, New Haven, CT (United States)); Ghosh, S.; Todd, J.A.

    1993-09-01

    Common, familial human disorders generally do not follow Mendelian inheritance patterns, presumably because multiple loci are involved in disease susceptibility. One approach to mapping genes for such traits in humans is to first study an analogous form in an animal model, such as mouse, by using inbred strains and backcross experiments. Here the authors describe methodology for analyzing multiple-locus linkage data from such experimental backcrosses, particularly in light of multilocus genetic models, including the effects of epistasis. They illustrate these methods by using data from backcrosses involving nonobese diabetic mouse, which serves as an animal model for human insulin-dependent diabetes mellitus. They show that it is likely that a minimum of nine loci contribute to susceptibility, with strong epistasis effects among these loci. Three of the loci actually confer a protective effect in the homozygote, compared with the heterozygote. Further, they discuss the relevance of these studies for analogous studies of the human form of the trait. Specifically, they show that the magnitude of the gene effect in the experimental backcross is likely to correlate only weakly, at best, with the expected magnitude of effect for a human form, because in humans the gene effect will depend more heavily on disease allele frequencies than on the observed penetrance ratios; such allele frequencies are unpredictable. Hence, the major benefit from animal studies may be a better understanding of the disease process itself, rather than identification of cells through comparison mapping in humans by using regions of homology. 12 refs., 7 tabs.

  2. Etiopathogenesis of Insulin Autoimmunity

    Directory of Open Access Journals (Sweden)

    Norio Kanatsuna

    2012-01-01

    Full Text Available Autoimmunity against pancreatic islet beta cells is strongly associated with proinsulin, insulin, or both. The insulin autoreactivity is particularly pronounced in children with young age at onset of type 1 diabetes. Possible mechanisms for (proinsulin autoimmunity may involve beta-cell destruction resulting in proinsulin peptide presentation on HLA-DR-DQ Class II molecules in pancreatic draining lymphnodes. Recent data on proinsulin peptide binding to type 1 diabetes-associated HLA-DQ2 and -DQ8 is reviewed and illustrated by molecular modeling. The importance of the cellular immune reaction involving cytotoxic CD8-positive T cells to kill beta cells through Class I MHC is discussed along with speculations of the possible role of B lymphocytes in presenting the proinsulin autoantigen over and over again through insulin-carrying insulin autoantibodies. In contrast to autoantibodies against other islet autoantigens such as GAD65, IA-2, and ZnT8 transporters, it has not been possible yet to standardize the insulin autoantibody test. As islet autoantibodies predict type 1 diabetes, it is imperative to clarify the mechanisms of insulin autoimmunity.

  3. Fatal Attraction: Interactions between antigen-presenting cells and islets of Langerhans in the pathogenesis of autoimmune diabetes

    NARCIS (Netherlands)

    J.G.M. Rosmalen (Judith)

    2000-01-01

    textabstractThe onset of diabetes mellitus is characterized by various symptoms, all the result of a disturbed glucose metabolism. The main symptoms are thirst and an excessive production of urine. The disturbed glucose metabolism underlying these symptoms is due to an absolute deficiency of insulin

  4. Achieving Consensus Through Professionalized Head Nods

    DEFF Research Database (Denmark)

    Oshima, Sae

    2014-01-01

    While the interactional functions of head nodding in everyday Japanese conversation have been frequently studied, a discourse on head nodding as a professional communicative practice has yet to be explored. With the method of multimodal conversation analysis, the current study examines the role...

  5. Usefulness of postmortem biochemistry in identification of ketosis: Diagnosis of ketoacidosis at the onset of autoimmune type 1 diabetes in an autopsy case with cold exposure and malnutrition.

    Science.gov (United States)

    Tani, Naoto; Michiue, Tomomi; Chen, Jian-Hua; Oritani, Shigeki; Ishikawa, Takaki

    2016-09-01

    A severely malnourished, Japanese female in her twenties was found dead in her apartment. On autopsy, most of the findings from the internal examination were suggestive of hypothermia. Postmortem biochemistry, however, showed severely increased levels of glycated hemoglobin (HbA1c) and blood and urine glucose levels. Levels of acetone, 3-hydroxybutyric acid, and acetoacetate in various body fluids were also highly increased, indicating ketosis. The serum insulin and c-peptide levels were severely low, and subsequent testing was positive for anti-GAD antibodies. Immunohistochemical examination of the pancreatic islet cells revealed few insulin-positive cells but many glucagon-positive cells on staining. Furthermore, slight invasion of CD8-positive lymphocytes in the pancreatic islets of Langerhans was observed. Results of immunostaining of the pancreatic and bronchial epithelial tissues were partly positive for the Influenza A virus. We concluded that severe ketoacidosis associated with rapid-onset hyperglycemia due to autoimmune type 1 diabetes (AT1D) had occurred shortly before death. However, the ketosis was accompanied by hypothermia and malnutrition as well as diabetic ketoacidosis (DKA). Therefore, we retrospectively collected biochemical data on cases of hypothermia and malnutrition and compared them with the present case. Serum glucose, acetone, 3-hydroxybutyric acid, and acetoacetic acid can be used for screening and diagnosis to distinguish DKA from ketosis due to hypothermia and malnutrition. Therefore, in the present case, we diagnosed that the natural cause of death was due to AT1D. In conclusion, screening investigations for relevant biochemical markers can provide essential information for the diagnosis of metabolic disturbances, which fail to demonstrate characteristic autopsy findings. PMID:27591535

  6. Oral ingestion of Capsaicin, the pungent component of chili pepper, enhances a discreet population of macrophages and confers protection from autoimmune diabetes.

    Science.gov (United States)

    Nevius, E; Srivastava, P K; Basu, S

    2012-01-01

    Vanilloid receptor 1 (VR1) is expressed on immune cells as well as on sensory neurons. Here we report that VR1 can regulate immunological events in the gut in response to its ligand Capsaicin (CP), a nutritional factor, the pungent component of chili peppers. Oral administration of CP attenuates the proliferation and activation of autoreactive T cells in pancreatic lymph nodes (PLNs) but not other lymph nodes, and protects mice from development of type 1 diabetes (T1D). This is a general phenomenon and not restricted to one particular strain of mice. Engagement of VR1 enhances a discreet population of CD11b(+)/F4/80(+) macrophages in PLN, which express anti-inflammatory factors interleukin (IL)-10 and PD-L1. This population is essential for CP-mediated attenuation of T-cell proliferation in an IL-10-dependent manner. Lack of VR1 expression fails to inhibit proliferation of autoreactive T cells, which is partially reversed in (VR1(+/+) → VR1(-/-)) bone marrow chimeric mice, implying the role of VR1 in crosstalk between neuronal and immunological responses in vivo. These findings imply that endogenous ligands of VR1 can have profound effect on gut-mediated immune tolerance and autoimmunity by influencing the nutrient-immune interactions. PMID:22113584

  7. Effect of 'antidiabetis' herbal preparation on serum glucose and fructosamine in NOD mice.

    Science.gov (United States)

    Petlevski, R; Hadzija, M; Slijepcevic, M; Juretic, D

    2001-05-01

    The antihyperglycemic effect of the Antidiabetis herbal preparation ((Myrtilli folium (Vaccinium myrtillus L.), Taraxaci radix (Taraxacum officinale Web.), Cichorii radix (Cichorium intybus L.), Juniperi fructus (Juniperus communis L.), Centaurii herba (Centaurium umbellatum Gilib.), Phaseoli pericarpium (Phaseolus vulgaris), Millefollii herba (Achillea millefolium L.), Morii folium (Morus nigra L.), Valeriane radix (Valleriana officinalis L.), Urticae herba et radix (Urtica dioica L.)), patent No. P-9801091 Zagreb, Croatia was investigated. Two extracts were prepared: ethanol extract (extract 1), and ethanol extract from which ethanol was evaporated on a rotatory evaporator at a temperature of 45 degrees C (extract 2). Extract 1 and extract 2 were administered (in experiment 1) to alloxan-induced non-obese diabetic (NOD) mice in the same dose of 20 mg/kg. Blood glucose was determined before, and 10, 30, 60 and 120 min after the preparation administration. Extract 1 and extract 2 decreased the level of blood glucose by 10 and 20%, respectively, of the initial value (at 0 min, mean = 22.6 +/- 8.3 mmol/l). Serum levels of glucose and fructosamine were determined in NOD mice, NOD mice administered extract 2 in a dose of 20 mg/kg of extract 2, and NOD mice administered acarbose in a dose of 25 mg/100 g chow, in order to verify the hypoglycemic action of extract 2 (in experiment 2). Extract 2 and acarbose were admixed to the chow. The duration of treatment was 7 days. Significantly lower glucose (P < 0.05) and fructosamine (P < 0.001) levels were recorded in extract 2 treated NOD mice as compared with NOD mice. Study results showed extract 2 to significantly decrease the level of glucose and fructosamine in alloxan induced NOD mice. Our future studies will be focused on the search of active principles of the extracts. PMID:11297848

  8. [Autoimmune encephalitis].

    Science.gov (United States)

    Davydovskaya, M V; Boyko, A N; Beliaeva, I A; Martynov, M Yu; Gusev, E I

    2015-01-01

    The authors consider the issues related to pathogenesis, clinical features, diagnosis and treatment of autoimmune encephalitis. It has been demonstrated that the development of autoimmune encephalitis can be associated with the oncologic process or be of idiopathic character. The pathogenesis of autoimmune encephalitis is caused by the production of antibodies that directly or indirectly (via T-cell mechanism) damage exo-and/or endocellular structures of the nerve cells. The presence of antobodies to endocellular structures of neurons in the cerebrospinal fluid of patients with autoimmune encephalitis in the vast majority of cases (> 95%) indicates the concomitant oncologic process, the presence of antibodies to membranes or neuronal synapses can be not associated with the oncologic process. Along with complex examination, including neuroimaging, EEG, cerebrospinal fluid and antibodies, the diagnostic algorithm in autoimmune encephalitis should include the search for the nidus of cancer. The treatment algorithm in autoimmune encephalitis included the combined immunosupressive therapy, plasmapheresis, immunoglobulines, cytostatics as well as treatment of the oncologic process. PMID:26322363

  9. A novel technique for the in vivo imaging of autoimmune diabetes development in the pancreas by two-photon microscopy.

    Directory of Open Access Journals (Sweden)

    Ken Coppieters

    Full Text Available Type 1 diabetes (T1D is characterized by the immune-mediated destruction of beta cells in the pancreas. Little is known about the in vivo dynamic interactions between T cells and beta cells or the kinetic behavior of other immune cell subsets in the pancreatic islets. Utilizing multiphoton microscopy we have designed a technique that allows for the real-time visualization of diabetogenic T cells and dendritic cells in pancreatic islets in a live animal, including their interplay with beta cells and the vasculature. Using a custom designed stage, the pancreas was surgically exposed under live conditions so that imaging of islets under intact blood pressure and oxygen supply became possible. We demonstrate here that this approach allows for the tracking of diabetogenic leukocytes as well as vascularization phenotype of islets and accumulation of dendritic cells in islets during diabetes pathogenesis. This technique should be useful in mapping crucial kinetic events in T1D pathogenesis and in testing the impact of immune based interventions on T cell migration, extravasation and islet destruction.

  10. Can CD44 Be a Mediator of Cell Destruction? The Challenge of Type 1 Diabetes.

    Science.gov (United States)

    Assayag-Asherie, Nathalie; Sever, Dror; Bogdani, Marika; Johnson, Pamela; Weiss, Talya; Ginzberg, Ariel; Perles, Sharon; Weiss, Lola; Sebban, Lora Eshkar; Turley, Eva A; Okon, Elimelech; Raz, Itamar; Naor, David

    2015-01-01

    CD44 is a multi-functional receptor with multiple of isoforms engaged in modulation of cell trafficking and transmission of apoptotic signals. We have previously shown that injection of anti-CD44 antibody into NOD mice induced resistance to type 1 diabetes (T1D). In this communication we describe our efforts to understand the mechanism underlying this effect. We found that CD44-deficient NOD mice develop stronger resistance to T1D than wild-type littermates. This effect is not explained by the involvement of CD44 in cell migration, because CD44-deficient inflammatory cells surprisingly had greater invasive potential than the corresponding wild type cells, probably owing to molecular redundancy. We have previously reported and we show here again that CD44 expression and hyaluronic acid (HA, the principal ligand for CD44) accumulation are detected in pancreatic islets of diabetic NOD mice, but not of non-diabetic DBA/1 mice. Expression of CD44 on insulin-secreting β cells renders them susceptible to the autoimmune attack, and is associated with a diminution in β-cells function (e.g., less insulin production and/or insulin secretion) and possibly also with an enhanced apoptosis rate. The diabetes-supportive effect of CD44 expression on β cells was assessed by the TUNEL assay and further strengthened by functional assays exhibiting increased nitric oxide release, reduced insulin secretion after glucose stimulation and decreased insulin content in β cells. All these parameters could not be detected in CD44-deficient islets. We further suggest that HA-binding to CD44-expressing β cells is implicated in β-cell demise. Altogether, these data agree with the concept that CD44 is a receptor capable of modulating cell fate. This finding is important for other pathologies (e.g., cancer, neurodegenerative diseases) in which CD44 and HA appear to be implicated. PMID:26624007

  11. Autoimmune synaptopathies.

    Science.gov (United States)

    Crisp, Sarah J; Kullmann, Dimitri M; Vincent, Angela

    2016-02-01

    Autoantibodies targeting proteins at the neuromuscular junction are known to cause several distinct myasthenic syndromes. Recently, autoantibodies targeting neurotransmitter receptors and associated proteins have also emerged as a cause of severe, but potentially treatable, diseases of the CNS. Here, we review the clinical evidence as well as in vitro and in vivo experimental evidence that autoantibodies account for myasthenic syndromes and autoimmune disorders of the CNS by disrupting the functional or structural integrity of synapses. Studying neurological and psychiatric diseases of autoimmune origin may provide new insights into the cellular and circuit mechanisms underlying a broad range of CNS disorders. PMID:26806629

  12. Autoimmun hypophysitis

    DEFF Research Database (Denmark)

    Krarup, Therese; Hagen, Claus

    2010-01-01

    Autoimmune hypophysitis (AH) - often referred to as lymphocytic hypophysitis - is a rare disease that affects the pituitary gland and causes inflammation. The disease enlarges the pituitary gland and the clinical presentations are lack of pituitary function and headaches. AH is mostly seen in women...... during pregnancy or postpartum, but also occurs in males and children. AH is often associated with other autoimmune diseases, most frequently with Hashimoto's thyroiditis. The symptoms are caused by enlargement of the pituitary gland and disturbances of the hormone function. Treatment is either...

  13. Achalasia in a Patient with Polyglandular Autoimmune Syndrome Type II

    OpenAIRE

    Amr, Bashar S.; Mamillapalli, Chaitanya

    2015-01-01

    Achalasia is a rare disease characterized by aperistalsis of the esophageal body and failure of the lower esophageal sphincter to relax. The etiology of this disease remains unknown. Polyglandular autoimmune syndrome type II is a well-identified disease characterized by the occurrence of autoimmune Addison's disease in combination with autoimmune thyroid disease and/or type 1 diabetes mellitus. We report a case that suggests autoimmunity and immunogenicity as a probable contributing factor fo...

  14. Autoimmun pankreatitis

    DEFF Research Database (Denmark)

    Fjordside, Eva; Novovic, Srdan; Schmidt, Palle Nordblad;

    2015-01-01

    Autoimmune pancreatitis (AIP) is a rare inflammatory disease. AIP has characteristic histology, serology and imaging findings. Two types of AIP exist, type 1, which is a part of the systemic immunoglobulin G4-related disease, and type 2, which is only localized to the pancreas. Patients with type 1...

  15. AML engraftment in the NOD/SCID assay reflects the outcome of AML: implications for our understanding of the heterogeneity of AML

    OpenAIRE

    Pearce, Daniel J.; Taussig, David; Zibara, Kazem; Smith, Lan-Lan; Ridler, Christopher M.; Preudhomme, Claude; Young, Bryan D.; Rohatiner, Ama Z; Lister, T. Andrew; Bonnet, Dominique

    2006-01-01

    The nonobese diabetic/severe combined immunodeficient (NOD/SCID) assay is the current model for assessment of human normal and leukemic stem cells. We explored why 51% of 59 acute myeloid leukemia (AML) patients were unable to initiate leukemia in NOD/SCID mice. Increasing the cell dose, using more permissive recipients, and alternative tissue sources did not cause AML engraftment in most previously nonengrafting AML samples. Homing of AML cells to the marrow was the same between engrafters a...

  16. Effect of dietary gluten on dendritic cells and innate immune subsets in BALB/c and NOD mice.

    Directory of Open Access Journals (Sweden)

    Jesper Larsen

    Full Text Available The innate immune system is known to play an important role in oral tolerance to dietary antigens. This is important in development of celiac disease (CD but may also be important in type 1 diabetes (T1D, and could potentially explain the reduced incidence of T1D in mice receiving a gluten-free (GF diet. The direct in vivo effect of gluten on innate cells, and particularly dendritic cells (DC is not sufficiently clarified. Therefore, we wished to investigate the innate cell populations of spontaneous diabetic NOD mice and healthy BALB/c mice kept on a GF or a standard (STD gluten containing diet. We studied, by flow cytometry and reverse transcription-quantitative polymerase chain reaction (qRT-PCR, if dietary gluten induces changes in the activation of DCs and distribution of selected innate cells in lymphoid, pancreatic and intestinal tissues in BALB/c and NOD mice. We found that a GF diet increased the percentage of macrophages in BALB/c spleen and of CD11c+ DCs in BALB/c and NOD spleen. Strictly gluten-free (SGF diet increased the percentage of CD103+ DCs in BALB/c mice and decreased percentages of CD11b+ DCs in mesenteric and pancreatic lymph nodes in BALB/c mice. SGF diet in BALB/c mice also decreased DC expression of CD40, CCR7 and MHC-II in pancreatic lymph nodes. In conclusion, GF diet changes the composition of the innate immune system in BALB/c and NOD mice and increases expression of DC activation markers in NOD mice. These results contribute to the explanation of the low diabetes incidence in GF NOD mice. This mechanism may be important in development of type 1 diabetes, celiac disease and non-celiac gluten sensitivity.

  17. The non-obese diabetic mouse strain as a model to study CD8+ T cell function in relapsing and progressive multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Prenitha Mercy eIgnatius Arokia Doss

    2015-10-01

    Full Text Available Multiple sclerosis (MS is a neurodegenerative disease resulting from an autoimmune attack on central nervous system myelin. While CD4+ T cell function in MS pathology has been extensively studied, there is also strong evidence that CD8+ T lymphocytes play a key role. Intriguingly, CD8+ T cells accumulate in great numbers in the CNS in progressive MS, a form of the disease that is refractory to current disease-modifying therapies which target the CD4+ T cell response. Here, we discuss the function of CD8+ T cells in experimental autoimmune encephalomyelitis (EAE, a mouse model of MS. In particular, we describe EAE in non-obese diabetic (NOD background mice, which develop a pattern of disease characterized by multiple attacks and remissions followed by a progressively worsening phase. This is highly reminiscent of the pattern of disease observed in nearly half of MS patients. Particular attention is paid to a newly described transgenic mouse strain (1C6 on the NOD background whose CD4+ and CD8+ T cells are directed against the encephalitogenic peptide MOG[35-55]. Use of this model will give us a more complete picture of the role(s played by distinct T cell subsets in CNS autoimmunity.

  18. Autoimmune Type 1 Diabetes Genetic Susceptibility Encoded by Human Leukocyte Antigen DRB1 and DQB1 Genes in Tunisia▿

    Science.gov (United States)

    Stayoussef, Mouna; Benmansour, Jihen; Al-Irhayim, Abdul-Qader; Said, Hichem B.; Rayana, Chiheb B.; Mahjoub, Touhami; Almawi, Wassim Y.

    2009-01-01

    Human leukocyte antigen (HLA) class II genes contribute to the genetic susceptibility to type 1 diabetes (T1D), and susceptible alleles and haplotypes were implicated in the pathogenesis of T1D. This study investigated the heterogeneity in HLA class II haplotype distribution among Tunisian patients with T1D. This was a retrospective case control study done in Monastir in central Tunisia. The subjects comprised 88 T1D patients and 112 healthy controls. HLA-DRB1 and -DQB1 genotyping was done by PCR-sequence-specific priming. Significant DRB1 and DQB1 allelic differences were seen between T1D patients and controls; these differences comprised DRB1*030101 and DQB1*0302, which were higher in T1D patients than in control subjects, and DRB1*070101, DRB1*110101, DQB1*030101, and DQB1*060101, which were lower in T1D patients than in control subjects. In addition, the frequencies of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 were higher in T1D patients than in control subjects, and the frequencies of DRB1*070101-DQB1*0201 and DRB1*110101-DQB1*030101 haplotypes were lower in T1D patients than in control subjects. Multiple logistic regression analysis revealed the positive association of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 and the negative association of only DRB1*070101-DQB1*0201 haplotypes with T1D. Furthermore, a significantly increased prevalence of DRB1*030101-DQB1*0201 homozygotes was seen for T1D subjects than for control subjects. Our results confirm the association of specific HLA-DR and -DQ alleles and haplotypes with T1D in Tunisians. The identification of similar and unique haplotypes in Tunisians compared to other Caucasians highlights the need for evaluating the contribution of HLA class II to the genetic susceptibility to T1D with regard to haplotype usage and also to ethnic origin and racial background. PMID:19553558

  19. Autoimmune type 1 diabetes genetic susceptibility encoded by human leukocyte antigen DRB1 and DQB1 genes in Tunisia.

    Science.gov (United States)

    Stayoussef, Mouna; Benmansour, Jihen; Al-Irhayim, Abdul-Qader; Said, Hichem B; Rayana, Chiheb B; Mahjoub, Touhami; Almawi, Wassim Y

    2009-08-01

    Human leukocyte antigen (HLA) class II genes contribute to the genetic susceptibility to type 1 diabetes (T1D), and susceptible alleles and haplotypes were implicated in the pathogenesis of T1D. This study investigated the heterogeneity in HLA class II haplotype distribution among Tunisian patients with T1D. This was a retrospective case control study done in Monastir in central Tunisia. The subjects comprised 88 T1D patients and 112 healthy controls. HLA-DRB1 and -DQB1 genotyping was done by PCR-sequence-specific priming. Significant DRB1 and DQB1 allelic differences were seen between T1D patients and controls; these differences comprised DRB1*030101 and DQB1*0302, which were higher in T1D patients than in control subjects, and DRB1*070101, DRB1*110101, DQB1*030101, and DQB1*060101, which were lower in T1D patients than in control subjects. In addition, the frequencies of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 were higher in T1D patients than in control subjects, and the frequencies of DRB1*070101-DQB1*0201 and DRB1*110101-DQB1*030101 haplotypes were lower in T1D patients than in control subjects. Multiple logistic regression analysis revealed the positive association of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 and the negative association of only DRB1*070101-DQB1*0201 haplotypes with T1D. Furthermore, a significantly increased prevalence of DRB1*030101-DQB1*0201 homozygotes was seen for T1D subjects than for control subjects. Our results confirm the association of specific HLA-DR and -DQ alleles and haplotypes with T1D in Tunisians. The identification of similar and unique haplotypes in Tunisians compared to other Caucasians highlights the need for evaluating the contribution of HLA class II to the genetic susceptibility to T1D with regard to haplotype usage and also to ethnic origin and racial background. PMID:19553558

  20. Cytotoxic T-cells from T-cell receptor transgenic NOD8.3 mice destroy beta-cells via the perforin and Fas pathways.

    Science.gov (United States)

    Dudek, Nadine L; Thomas, Helen E; Mariana, Lina; Sutherland, Robyn M; Allison, Janette; Estella, Eugene; Angstetra, Eveline; Trapani, Joseph A; Santamaria, Pere; Lew, Andrew M; Kay, Thomas W H

    2006-09-01

    Cytotoxic T-cells are the major mediators of beta-cell destruction in type 1 diabetes, but the molecular mechanisms are not definitively established. We have examined the contribution of perforin and Fas ligand to beta-cell destruction using islet-specific CD8(+) T-cells from T-cell receptor transgenic NOD8.3 mice. NOD8.3 T-cells killed Fas-deficient islets in vitro and in vivo. Perforin-deficient NOD8.3 T-cells were able to destroy wild-type but not Fas-deficient islets in vitro. These results imply that NOD8.3 T-cells use both pathways and that Fas is required for beta-cell killing only when perforin is missing. Consistent with this theory, transgenic NOD8.3 mice with beta-cells that do not respond to Fas ligation were not protected from diabetes. We next investigated the mechanism of protection provided by overexpression of suppressor of cytokine signaling-1 (SOCS-1) in beta-cells of NOD8.3 mice. SOCS-1 islets remained intact when grafted into NOD8.3 mice and were less efficiently killed in vitro. However, addition of exogenous peptide rendered SOCS-1 islets susceptible to 8.3 T-cell-mediated lysis. Therefore, NOD8.3 T-cells use both perforin and Fas pathways to kill beta-cells and the surprising blockade of NOD8.3 T-cell-mediated beta-cell death by SOCS-1 overexpression may be due in part to reduced target cell recognition. PMID:16936188

  1. Interaction between NOD2 and CARD9 involves the NOD2 NACHT and the linker region between the NOD2 CARDs and NACHT domain

    OpenAIRE

    Parkhouse, Rhiannon; Boyle, Joseph P; Mayle, Sophie; Sawmynaden, Kovilen; Rittinger, Katrin; Monie, Tom P.

    2014-01-01

    NOD2 activation by muramyl dipeptide causes a proinflammatory immune response in which the adaptor protein CARD9 works synergistically with NOD2 to drive p38 and c-Jun N-terminal kinase (JNK) signalling. To date the nature of the interaction between NOD2 and CARD9 remains undetermined. Here we show that this interaction is not mediated by the CARDs of NOD2 and CARD9 as previously suggested, but that NOD2 possesses two interaction sites for CARD9; one in the CARD–NACHT linker and one in the NA...

  2. Interaction between NOD2 and CARD9 involves the NOD2 NACHT and the linker region between the NOD2 CARDs and NACHT domain.

    Science.gov (United States)

    Parkhouse, Rhiannon; Boyle, Joseph P; Mayle, Sophie; Sawmynaden, Kovilen; Rittinger, Katrin; Monie, Tom P

    2014-08-25

    NOD2 activation by muramyl dipeptide causes a proinflammatory immune response in which the adaptor protein CARD9 works synergistically with NOD2 to drive p38 and c-Jun N-terminal kinase (JNK) signalling. To date the nature of the interaction between NOD2 and CARD9 remains undetermined. Here we show that this interaction is not mediated by the CARDs of NOD2 and CARD9 as previously suggested, but that NOD2 possesses two interaction sites for CARD9; one in the CARD-NACHT linker and one in the NACHT itself. PMID:24960071

  3. Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP

    OpenAIRE

    Krishnamurthy, Balasubramanian; Nadine L Dudek; McKenzie, Mark D.; Anthony W Purcell; Brooks, Andrew G.; Gellert, Shane; Colman, Peter G; Harrison, Leonard C.; Lew, Andrew M.; Helen E. Thomas; Kay, Thomas W.H.

    2006-01-01

    Type 1 diabetes (T1D) is characterized by immune responses against several autoantigens expressed in pancreatic β cells. T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP) can induce T1D in NOD mice. However, whether immune responses to multiple autoantigens are caused by spreading from one to another or whether they develop independently of each other is unknown. As cytotoxic T cells specific for IGRP were not detected in transge...

  4. Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rγnull mice.

    Directory of Open Access Journals (Sweden)

    Fang Xiao

    Full Text Available Type 1 diabetes mellitus (T1DM is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo.

  5. Autoimmune Encephalitis

    OpenAIRE

    Leypoldt, Frank; Wandinger, Klaus-Peter; Bien, Christian G; Dalmau, Josep

    2013-01-01

    The term autoimmune encephalitis is used to describe a group of disorders characterised by symptoms of limbic and extra-limbic dysfunction occurring in association with antibodies against synaptic antigens and proteins localised on the neuronal cell surface. In recent years there has been a rapidly expanding knowledge of these syndromes resulting in a shift in clinical paradigms and new insights into pathogenic mechanisms. Since many patients respond well to immunosuppressive treatment, the r...

  6. Autoimmun pankreatitis

    DEFF Research Database (Denmark)

    Fjordside, Eva; Novovic, Srdan; Schmidt, Palle Nordblad;

    2015-01-01

    Autoimmune pancreatitis (AIP) is a rare inflammatory disease. AIP has characteristic histology, serology and imaging findings. Two types of AIP exist, type 1, which is a part of the systemic immunoglobulin G4-related disease, and type 2, which is only localized to the pancreas. Patients with type 1...... are predominantly older men, have involvement of other organs and more often experience relapse than patients with type 2. Both types respond well to steroid treatment. The most important differential diagnose is pancreatic cancer....

  7. Alpha-1 antitrypsin protein and gene therapies decrease autoimmunity and delay arthritis development in mouse model

    Directory of Open Access Journals (Sweden)

    Atkinson Mark A

    2011-02-01

    Full Text Available Abstract Background Alpha-1 antitrypsin (AAT is a multi-functional protein that has anti-inflammatory and tissue protective properties. We previously reported that human AAT (hAAT gene therapy prevented autoimmune diabetes in non-obese diabetic (NOD mice and suppressed arthritis development in combination with doxycycline in mice. In the present study we investigated the feasibility of hAAT monotherapy for the treatment of chronic arthritis in collagen-induced arthritis (CIA, a mouse model of rheumatoid arthritis (RA. Methods DBA/1 mice were immunized with bovine type II collagen (bCII to induce arthritis. These mice were pretreated either with hAAT protein or with recombinant adeno-associated virus vector expressing hAAT (rAAV-hAAT. Control groups received saline injections. Arthritis development was evaluated by prevalence of arthritis and arthritic index. Serum levels of B-cell activating factor of the TNF-α family (BAFF, antibodies against both bovine (bCII and mouse collagen II (mCII were tested by ELISA. Results Human AAT protein therapy as well as recombinant adeno-associated virus (rAAV8-mediated hAAT gene therapy significantly delayed onset and ameliorated disease development of arthritis in CIA mouse model. Importantly, hAAT therapies significantly reduced serum levels of BAFF and autoantibodies against bCII and mCII, suggesting that the effects are mediated via B-cells, at least partially. Conclusion These results present a new drug for arthritis therapy. Human AAT protein and gene therapies are able to ameliorate and delay arthritis development and reduce autoimmunity, indicating promising potential of these therapies as a new treatment strategy for RA.

  8. NOD2 gene expression in Paneth cells and monocytes.

    OpenAIRE

    Lala, S. G.

    2006-01-01

    Introduction: Mutations in the NOD2 gene are associated with the development of Crohn's disease, an inflammatory disorder of the gastrointestinal tract. The NOD2 protein induces cellular activation in response to the bacterial antigen muramyl dipeptide (MDP). The NOD2 gene is mainly expressed by circulating blood monocytes although NOD2-associated Crohn's disease involves mainly the terminal ileum. Paneth cells, which are most numerous in the terminal ileum, are specialised intestinal epithel...

  9. Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP.

    Science.gov (United States)

    Krishnamurthy, Balasubramanian; Dudek, Nadine L; McKenzie, Mark D; Purcell, Anthony W; Brooks, Andrew G; Gellert, Shane; Colman, Peter G; Harrison, Leonard C; Lew, Andrew M; Thomas, Helen E; Kay, Thomas W H

    2006-12-01

    Type 1 diabetes (T1D) is characterized by immune responses against several autoantigens expressed in pancreatic beta cells. T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) can induce T1D in NOD mice. However, whether immune responses to multiple autoantigens are caused by spreading from one to another or whether they develop independently of each other is unknown. As cytotoxic T cells specific for IGRP were not detected in transgenic NOD mice tolerant to proinsulin, we determined that immune responses against proinsulin are necessary for IGRP-specific T cells to develop. On the other hand, transgenic overexpression of IGRP resulted in loss of intra-islet IGRP-specific T cells but did not protect NOD mice from insulitis or T1D, providing direct evidence that the response against IGRP is downstream of the response to proinsulin. Our results suggest that pathogenic proinsulin-specific immunity in NOD mice subsequently spreads to other antigens such as IGRP. PMID:17143333

  10. Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP

    Science.gov (United States)

    Krishnamurthy, Balasubramanian; Dudek, Nadine L.; McKenzie, Mark D.; Purcell, Anthony W.; Brooks, Andrew G.; Gellert, Shane; Colman, Peter G.; Harrison, Leonard C.; Lew, Andrew M.; Thomas, Helen E.; Kay, Thomas W.H.

    2006-01-01

    Type 1 diabetes (T1D) is characterized by immune responses against several autoantigens expressed in pancreatic β cells. T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP) can induce T1D in NOD mice. However, whether immune responses to multiple autoantigens are caused by spreading from one to another or whether they develop independently of each other is unknown. As cytotoxic T cells specific for IGRP were not detected in transgenic NOD mice tolerant to proinsulin, we determined that immune responses against proinsulin are necessary for IGRP-specific T cells to develop. On the other hand, transgenic overexpression of IGRP resulted in loss of intra-islet IGRP-specific T cells but did not protect NOD mice from insulitis or T1D, providing direct evidence that the response against IGRP is downstream of the response to proinsulin. Our results suggest that pathogenic proinsulin-specific immunity in NOD mice subsequently spreads to other antigens such as IGRP. PMID:17143333

  11. Altered connexin 43 expression underlies age-dependent decrease of regulatory T cell suppressor function in nonobese diabetic mice.

    Science.gov (United States)

    Kuczma, Michal; Wang, Cong-Yi; Ignatowicz, Leszek; Gourdie, Robert; Kraj, Piotr

    2015-06-01

    Type 1 diabetes is one of the most extensively studied autoimmune diseases, but the cellular and molecular mechanisms leading to T cell-mediated destruction of insulin-producing β cells are still not well understood. In this study, we show that regulatory T cells (T(regs)) in NOD mice undergo age-dependent loss of suppressor functions exacerbated by the decreased ability of activated effector T cells to upregulate Foxp3 and generate T(regs) in the peripheral organs. This age-dependent loss is associated with reduced intercellular communication mediated by gap junctions, which is caused by impaired upregulation and decreased expression of connexin 43. Regulatory functions can be corrected, even in T cells isolated from aged, diabetic mice, by a synergistic activity of retinoic acid, TGF-β, and IL-2, which enhance connexin 43 and Foxp3 expression in T(regs) and restore the ability of conventional CD4(+) T cells to upregulate Foxp3 and generate peripherally derived T(regs). Moreover, we demonstrate that suppression mediated by T(regs) from diabetic mice is enhanced by a novel reagent, which facilitates gap junction aggregation. In summary, our report identifies gap junction-mediated intercellular communication as an important component of the T(reg) suppression mechanism compromised in NOD mice and suggests how T(reg) mediated immune regulation can be improved. PMID:25911751

  12. Autoimmune liver disease panel

    Science.gov (United States)

    Liver disease test panel - autoimmune ... Autoimmune disorders are a possible cause of liver disease. The most common of these diseases are autoimmune hepatitis and primary biliary cirrhosis. This group of tests helps your health care provider ...

  13. Autoimmune hypophysitis or lymphocytic hypophysitis

    OpenAIRE

    Paiva, I; Gomes, L.; C. Ribeiro; Carvalheiro, M; Ruas, A

    2003-01-01

    This entity, due to the pituitary lymphoplasmacytic infiltrate, was described for the first time in 1962. The clinical suspicion relies on a rapidly progressing hypopituitarism, particularly with adrenal involvement, affecting women in the peripartum period or patients with previously recognized autoimmune disease. Diabetes insipidus is also often reported. A sellar mass is found in 80% of cases. The diagnosis is confirmed by histology, due to the absence of a specific serological test. The e...

  14. CD4+ type II NKT cells mediate ICOS and programmed death-1-dependent regulation of type 1 diabetes

    DEFF Research Database (Denmark)

    Kadri, Nadir; Korpos, Eva; Gupta, Shashank;

    2012-01-01

    exhibited a memory phenotype including high ICOS expression, increased cytokine production, and limited display of NK cell markers, compared with double-negative 24aß NKT cells. Blocking of ICOS or the programmed death-1/programmed death ligand 1 pathway was shown to abolish the regulation that occurred......Type 1 diabetes (T1D) is a chronic autoimmune disease that results from T cell-mediated destruction of pancreatic ß cells. CD1d-restricted NKT lymphocytes have the ability to regulate immunity, including autoimmunity. We previously demonstrated that CD1d-restricted type II NKT cells, which carry...... diverse TCRs, prevented T1D in the NOD mouse model for the human disease. In this study, we show that CD4(+) 24aß type II NKT cells, but not CD4/CD8 double-negative NKT cells, were sufficient to downregulate diabetogenic CD4(+) BDC2.5 NOD T cells in adoptive transfer experiments. CD4(+) 24aß NKT cells...

  15. Update in Endocrine Autoimmunity

    OpenAIRE

    Anderson, Mark S.

    2008-01-01

    Context: The endocrine system is a common target in pathogenic autoimmune responses, and there has been recent progress in our understanding, diagnosis, and treatment of autoimmune endocrine diseases.

  16. Autoimmune pancreatitis

    DEFF Research Database (Denmark)

    Detlefsen, Sönke; Drewes, Asbjørn M

    2009-01-01

    bile duct. Obstructive jaundice is a common symptom at presentation, and pancreatic cancer represents an important clinical differential diagnosis. In late stages of the disease, the normal pancreatic parenchyma is often replaced by large amounts of fibrosis. Histologically, there seem to be two...... AIP responds to steroid treatment, also a trial with steroids, can help to differentiate AIP from pancreatic cancer. OUTLOOK AND DISCUSSION: This review presents the pathological, radiologic and laboratory findings of AIP. Moreover, the treatment and pathogenesis are discussed.......BACKGROUND: Autoimmune pancreatitis (AIP) is a relatively newly recognized type of pancreatitis that is characterized by diffuse or focal swelling of the pancreas due to lymphoplasmacytic infiltration and fibrosis of the pancreatic parenchyma. MATERIAL AND METHODS: A PubMed literature search was...

  17. Testing agents for prevention or reversal of type 1 diabetes in rodents.

    Directory of Open Access Journals (Sweden)

    Christian W Grant

    Full Text Available We report the results of an independent laboratory's tests of novel agents to prevent or reverse type 1 diabetes (T1D in the non-obese diabetic (NOD mouse, BioBreeding diabetes prone (BBDP rat, and multiple autoimmune disease prone (MAD rat models. Methods were developed to better mimic human clinical trials, including: prescreening, randomization, blinding, and improved glycemic care of the animals. Agents were suggested by the research community in an open call for proposals, and selected for testing by an NIDDK appointed independent review panel. Agents selected for testing to prevent diabetes at later stages of progression in a rodent model were a STAT4 antagonist (DT22669, alpha1 anti-trypsin (Aralast NP, celastrol (a natural product with anti-inflammatory properties, and a Macrophage Inflammatory Factor inhibitor (ISO-092. Agents tested for reversal of established T1D in rodent models were: alpha1 anti-trypsin (Aralast NP, tolerogenic peptides (Tregitopes, and a long-acting formulation of GLP-1 (PGC-GLP-1. None of these agents were seen to prevent or reverse type 1 diabetes, while the positive control interventions were effective: anti-CD3 treatment provided disease reversal in the NOD mouse, dexamethasone prevented T1D induction in the MAD rat, and cyclosporin prevented T1D in the BBDP rat. For some tested agents, details of previous formulation, delivery, or dosing, as well as laboratory procedure, availability of reagents and experimental design, could have impacted our ability to confirm prior reports of efficacy in preclinical animal models. In addition, the testing protocols utilized here provided detection of effects in a range commonly used in placebo controlled clinical trials (for example, 50% effect size, and thus may have been underpowered to observe more limited effects. That said, we believe the results compiled here, showing good control and repeatability, confirm the feasibility of screening diverse test agents in an

  18. Celiac disease and autoimmune thyroid disease.

    Science.gov (United States)

    Ch'ng, Chin Lye; Jones, M Keston; Kingham, Jeremy G C

    2007-10-01

    Celiac disease (CD) or gluten sensitive enteropathy is relatively common in western populations with prevalence around 1%. With the recent availability of sensitive and specific serological testing, many patients who are either asymptomatic or have subtle symptoms can be shown to have CD. Patients with CD have modest increases in risks of malignancy and mortality compared to controls. The mortality among CD patients who comply poorly with a gluten-free diet is greater than in compliant patients. The pattern of presentation of CD has altered over the past three decades. Many cases are now detected in adulthood during investigation of problems as diverse as anemia, osteoporosis, autoimmune disorders, unexplained neurological syndromes, infertility and chronic hypertransaminasemia of uncertain cause. Among autoimmune disorders, increased prevalence of CD has been found in patients with autoimmune thyroid disease, type 1 diabetes mellitus, autoimmune liver diseases and inflammatory bowel disease. Prevalence of CD was noted to be 1% to 19% in patients with type 1 diabetes mellitus, 2% to 5% in autoimmune thyroid disorders and 3% to 7% in primary biliary cirrhosis in prospective studies. Conversely, there is also an increased prevalence of immune based disorders among patients with CD. The pathogenesis of co-existent autoimmune thyroid disease and CD is not known, but these conditions share similar HLA haplotypes and are associated with the gene encoding cytotoxic T-lymphocyte-associated antigen-4. Screening high risk patients for CD, such as those with autoimmune diseases, is a reasonable strategy given the increased prevalence. Treatment of CD with a gluten-free diet should reduce the recognized complications of this disease and provide benefits in both general health and perhaps life expectancy. It also improves glycemic control in patients with type 1 diabetes mellitus and enhances the absorption of medications for associated hypothyroidism and osteoporosis. It

  19. Progress of cancer experimental research in NOD/SCID mice%NOD/SCID小鼠平台上的肿瘤实验研究进展

    Institute of Scientific and Technical Information of China (English)

    孙冰; 吴世凯; 宋三泰

    2008-01-01

    非肥胖糖尿病/严重联合免疫缺陷(non-obese diabetes-SCID mice, NOD/SCID)小鼠具有T、B淋巴细胞联合免疫缺陷、NK细胞活性低下、无循环补体、巨噬细胞和抗原提呈细胞功能损害等特性,近年已成为人类肿瘤移植瘤的最佳研究模型.NOD/SCID鼠的人类血液系统肿瘤模型能够研究造血微环境、白血病细胞的分化调控机制和潜在的治疗靶点,并且建立在此平台上的体内药敏实验,可以指导临床化疗方案设计,目前已显示出突出的疗效.乳腺癌等实体瘤原代肿瘤组织的移植瘤模型,也显示出可复制人类肿瘤特点的优势.此外,NOD/SCID鼠可进行肿瘤干细胞的筛选和鉴定,并寻找针对肿瘤干细胞的特异性治疗靶点.目前的研究已展现了NOD/SCID鼠在肿瘤研究领域的广阔前景.

  20. The autoimmune tautology

    OpenAIRE

    Anaya, Juan-Manuel

    2010-01-01

    Although autoimmune diseases exhibit contrasting epidemiological features, pathology, and clinical manifestations, three lines of evidence demonstrate that these diseases share similar immunogenetic mechanisms (that is, autoimmune tautology). First, clinical evidence highlights the co-occurrence of distinct autoimmune diseases within an individual (that is, polyautoimmunity) and within members of a nuclear family (that is, familial autoimmunity). Second, physiopathologic evidence indicates th...

  1. Infections and autoimmune diseases.

    Science.gov (United States)

    Bach, Jean-François

    2005-01-01

    The high percentage of disease-discordant pairs of monozygotic twins demonstrates the central role of environmental factors in the etiology of autoimmune diseases. Efforts were first focussed on the search for triggering factors. The study of animal models has clearly shown that infections may trigger autoimmune diseases, as in the case of Coxsackie B4 virus in type I diabetes and the encephalomyocarditis virus in autoimmune myositis, two models in which viruses are thought to act by increasing immunogenicity of autoantigens secondary to local inflammation. The induction of a Guillain-Barré syndrome in rabbits after immunization with a peptide derived from Campylobacter jejuni is explained by mimicry between C. jejuni antigens and peripheral nerve axonal antigens. Other models involve chemical modification of autoantigens, as in the case of iodine-induced autoimmune thyroiditis. These mechanisms have so far only limited clinical counterparts (rheumatic fever, Guillain-Barré syndrome and drug-induced lupus or myasthenia gravis) but one may assume that unknown viruses may be at the origin of a number of chronic autoimmune diseases, such as type I diabetes and multiple sclerosis) as illustrated by the convergent data incriminating IFN-alpha in the pathophysiology of type I diabetes and systemic lupus erythematosus. Perhaps the difficulties met in identifying the etiologic viruses are due to the long lag time between the initial causal infection and onset of clinical disease. More surprisingly, infections may also protect from autoimmune diseases. Western countries are being confronted with a disturbing increase in the incidence of most immune disorders, including autoimmune and allergic diseases, inflammatory bowel diseases, and some lymphocyte malignancies. Converging epidemiological evidence indicates that this increase is linked to improvement of the socio-economic level of these countries, posing the question of the causal relationship and more precisely the

  2. Selective destruction of mouse islet beta cells by human T lymphocytes in a newly-established humanized type 1 diabetic model

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yong, E-mail: yongzhao@uic.edu [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Guo, Chengshan; Hwang, David; Lin, Brian; Dingeldein, Michael; Mihailescu, Dan; Sam, Susan; Sidhwani, Seema [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Zhang, Yongkang [Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Jain, Sumit [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Skidgel, Randal A. [Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Prabhakar, Bellur S. [Department of Immunology and Microbiology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Mazzone, Theodore [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Holterman, Mark J. [Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612 (United States)

    2010-09-03

    Research highlights: {yields} Establish a human immune-mediated type 1 diabetic model in NOD-scid IL2r{gamma}{sup null} mice. {yields} Using the irradiated diabetic NOD mouse spleen mononuclear cells as trigger. {yields} The islet {beta} cells were selectively destroyed by infiltrated human T cells. {yields} The model can facilitate translational research to find a cure for type 1 diabetes. -- Abstract: Type 1 diabetes (T1D) is caused by a T cell-mediated autoimmune response that leads to the loss of insulin-producing {beta} cells. The optimal preclinical testing of promising therapies would be aided by a humanized immune-mediated T1D model. We develop this model in NOD-scid IL2r{gamma}{sup null} mice. The selective destruction of pancreatic islet {beta} cells was mediated by human T lymphocytes after an initial trigger was supplied by the injection of irradiated spleen mononuclear cells (SMC) from diabetic nonobese diabetic (NOD) mice. This resulted in severe insulitis, a marked loss of total {beta}-cell mass, and other related phenotypes of T1D. The migration of human T cells to pancreatic islets was controlled by the {beta} cell-produced highly conserved chemokine stromal cell-derived factor 1 (SDF-1) and its receptor C-X-C chemokine receptor (CXCR) 4, as demonstrated by in vivo blocking experiments using antibody to CXCR4. The specificity of humanized T cell-mediated immune responses against islet {beta} cells was generated by the local inflammatory microenvironment in pancreatic islets including human CD4{sup +} T cell infiltration and clonal expansion, and the mouse islet {beta}-cell-derived CD1d-mediated human iNKT activation. The selective destruction of mouse islet {beta} cells by a human T cell-mediated immune response in this humanized T1D model can mimic those observed in T1D patients. This model can provide a valuable tool for translational research into T1D.

  3.  An autoimmune polyglandular syndrome complicated with celiac disease and autoimmune hepatitis.

    Science.gov (United States)

    Dieli-Crimi, Romina; Núñez, Concepción; Estrada, Lourdes; López-Palacios, Natalia

    2016-01-01

     Autoimmune polyglandular syndrome (APS) is a combination of different autoimmune diseases. The close relationship between immune-mediated disorders makes it mandatory to perform serological screening periodically in order to avoid delayed diagnosis of additional autoimmune diseases. We studied a patient with type 1 diabetes (T1D) who later developed an autoimmune thyroid disease (ATD) and was referred to our hospital with a serious condition of his clinical status. The patient was suffering from an advance stage of celiac disease (CD), the delay in its diagnosis and in the establishment of a gluten-free dietled the patient to a severe proteincalorie malnutrition. Later, the patient developed an autoimmune hepatitis (AIH). We consider that clinical deterioration in patients with APS should alert physicians about the possible presence of other immune-mediated diseases. Periodic screening for autoantibodies would help to prevent delayed diagnosis and would improve patient's quality of life. PMID:27236159

  4. Nod2 mediates susceptibility to Yersinia pseudotuberculosis in mice.

    Directory of Open Access Journals (Sweden)

    Ulrich Meinzer

    Full Text Available Nucleotide oligomerisation domain 2 (NOD2 is a component of the innate immunity known to be involved in the homeostasis of Peyer patches (PPs in mice. However, little is known about its role during gut infection in vivo. Yersinia pseudotuberculosis is an enteropathogen causing gastroenteritis, adenolymphitis and septicaemia which is able to invade its host through PPs. We investigated the role of Nod2 during Y. pseudotuberculosis infection. Death was delayed in Nod2 deleted and Crohn's disease associated Nod2 mutated mice orogastrically inoculated with Y. pseudotuberculosis. In PPs, the local immune response was characterized by a higher KC level and a more intense infiltration by neutrophils and macrophages. The apoptotic and bacterial cell counts were decreased. Finally, Nod2 deleted mice had a lower systemic bacterial dissemination and less damage of the haematopoeitic organs. This resistance phenotype was lost in case of intraperitoneal infection. We concluded that Nod2 contributes to the susceptibility to Y. pseudotuberculosis in mice.

  5. Proposed guidelines for the management of nodding syndrome

    OpenAIRE

    Idro, R.; Musubire, K A; Byamah Mutamba, B; Namusoke, H; Muron, J; Abbo, C; Oriyabuzu, R; Ssekyewa, J; Okot, C; Mwaka, D; Ssebadduka, P; I. Makumbi; Opar, B; Aceng, JR; Mbonye, AK

    2013-01-01

    Nodding Syndrome is a poorly understood neurologic disorder of unknown aetiology that affects children and adolescents in Africa. Recent studies have suggested that the head nods are due to atonic seizures and Nodding Syndrome may be classified as probably symptomatic generalised epilepsy. As part of the Ugandan Ministry of Health clinical management response, a multidisciplinary team developed a manual to guide the training of health workers with knowledge and skills to manage the patients. ...

  6. TLR4, NOD1 and NOD2 mediate immune recognition of putative newly identified periodontal pathogens.

    Science.gov (United States)

    Marchesan, J; Jiao, Y Z; Schaff, R A; Hao, J; Morelli, T; Kinney, J S; Gerow, E; Sheridan, R; Rodrigues, V; Paster, B J; Inohara, N; Giannobile, W V

    2016-06-01

    Periodontitis is a polymicrobial inflammatory disease that results from the interaction between the oral microbiota and the host immunity. Although the innate immune response is important for disease initiation and progression, the innate immune receptors that recognize both classical and putative periodontal pathogens that elicit an immune response have not been elucidated. By using the Human Oral Microbe Identification Microarray (HOMIM), we identified multiple predominant oral bacterial species in human plaque biofilm that strongly associate with severe periodontitis. Ten of the identified species were evaluated in greater depth, six being classical pathogens and four putative novel pathogens. Using human peripheral blood monocytes (HPBM) and murine bone-marrow-derived macrophages (BMDM) from wild-type (WT) and Toll-like receptor (TLR)-specific and MyD88 knockouts (KOs), we demonstrated that heat-killed Campylobacter concisus, Campylobacter rectus, Selenomonas infelix, Porphyromonas endodontalis, Porphyromonas gingivalis, and Tannerella forsythia mediate high immunostimulatory activity. Campylobacter concisus, C. rectus, and S. infelix exhibited robust TLR4 stimulatory activity. Studies using mesothelial cells from WT and NOD1-specific KOs and NOD2-expressing human embryonic kidney cells demonstrated that Eubacterium saphenum, Eubacterium nodatum and Filifactor alocis exhibit robust NOD1 stimulatory activity, and that Porphyromonas endodontalis and Parvimonas micra have the highest NOD2 stimulatory activity. These studies allowed us to provide important evidence on newly identified putative pathogens in periodontal disease pathogenesis showing that these bacteria exhibit different immunostimulatory activity via TLR4, NOD1, and NOD2 (Clinicaltrials.gov NCT01154855). PMID:26177212

  7. Autism and Autoimmune Disease: A Family Study

    Science.gov (United States)

    Money, John; And Others

    1971-01-01

    Described in a family in which the youngest boy has early infantile autism, Addison's disease, and moniliasis and two older boys have autoimmune disease with hypoparathyroidism, Addison's disease, moniliasis, and either alopecia totalis or diabetes mellitus, while the oldest boy and parents are symptom free. (KW)

  8. NOD1 and NOD2 receptors in mrigal (Cirrhinus mrigala): Inductive expression and downstream signalling in ligand stimulation and bacterial infections

    Indian Academy of Sciences (India)

    Banikalyan Swain; Madhubanti Basu; Mrinal Samanta

    2013-09-01

    Nucleotide binding and oligomerization domain (NOD)1 and NOD2 are important cytoplasmic pattern recognition receptors (PRRs) and key members of the NOD-like receptor (NLR) family. They sense a wide range of bacteria or their products and play a key role in inducing innate immunity. This report describes the role of NOD1 and NOD2 receptors signalling in innate immunity in the Indian major carp, mrigal (Cirrhinus mrigala). Tissue-specific expression analysis of NOD1 and NOD2 genes by quantitative real-time PCR (qRT-PCR) revealed their wide distribution in various organs/tissues. In the untreated fish, the highest expression of NOD1 and NOD2 was detected in liver and blood, respectively. Stimulation with NOD1- and NOD2-specific ligands, i.e. iE-DAP and MDP, activated NOD1 and NOD2 receptor signalling in vivo and in vitro resulting in significant ( < 0.05) induction of downstream signalling molecule RICK, and the effector molecules IL-1, IL-8 and IFN- in the treated group as compared to their controls. In response to both Gram-positive and Gram-negative bacterial infections, NOD1 and NOD2 receptors signalling were activated and IL-1, IL-8 and IFN- were induced. These findings highlight the important role of NOD receptors in eliciting innate immune response during the pathogenic invasion to the fish.

  9. Questions and Answers on Autoimmunity and Autoimmune Diseases

    Science.gov (United States)

    ... dermatomyositis . What are some of the treatments for autoimmune diseases? Of first importance in treating any autoimmune disease ... being researched. What is the family connection in autoimmune diseases? The ability to develop an autoimmune disease is ...

  10. Central tolerance spares the private high-avidity CD4(+) T-cell repertoire specific for an islet antigen in NOD mice.

    Science.gov (United States)

    Serre, Laurent; Fazilleau, Nicolas; Guerder, Sylvie

    2015-07-01

    Although central tolerance induces the deletion of most autoreactive T cells, some autoreactive T cells escape thymic censorship. Whether potentially harmful autoreactive T cells present distinct TCRαβ features remains unclear. Here, we analyzed the TCRαβ repertoire of CD4(+) T cells specific for the S100β protein, an islet antigen associated with type 1 diabetes. We found that diabetes-resistant NOD mice deficient for thymus specific serine protease (TSSP), a protease that impairs class II antigen presentation by thymic stromal cells, were hyporesponsive to the immunodominant S100β1-15 epitope, as compared to wild-type NOD mice, due to intrathymic negative selection. In both TSSP-deficient and wild-type NOD mice, the TCRαβ repertoire of S100β-specific CD4(+) T cells though diverse showed a specific bias for dominant TCRα rearrangements with limited CDR3α diversity. These dominant TCRα chains were public since they were found in all mice. They were of intermediate- to low-avidity. In contrast, high-avidity T cells expressed unique TCRs specific to each individual (private TCRs) and were only found in wild-type NOD mice. Hence, in NOD mice, the autoreactive CD4(+) T-cell compartment has two major components, a dominant and public low-avidity TCRα repertoire and a private high-avidity CD4(+) T-cell repertoire; the latter is deleted by re-enforced negative selection. PMID:25884569

  11. Structural models of zebrafish (Danio rerio NOD1 and NOD2 NACHT domains suggest differential ATP binding orientations: insights from computational modeling, docking and molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Jitendra Maharana

    Full Text Available Nucleotide-binding oligomerization domain-containing protein 1 (NOD1 and NOD2 are cytosolic pattern recognition receptors playing pivotal roles in innate immune signaling. NOD1 and NOD2 recognize bacterial peptidoglycan derivatives iE-DAP and MDP, respectively and undergoes conformational alternation and ATP-dependent self-oligomerization of NACHT domain followed by downstream signaling. Lack of structural adequacy of NACHT domain confines our understanding about the NOD-mediated signaling mechanism. Here, we predicted the structure of NACHT domain of both NOD1 and NOD2 from model organism zebrafish (Danio rerio using computational methods. Our study highlighted the differential ATP binding modes in NOD1 and NOD2. In NOD1, γ-phosphate of ATP faced toward the central nucleotide binding cavity like NLRC4, whereas in NOD2 the cavity was occupied by adenine moiety. The conserved 'Lysine' at Walker A formed hydrogen bonds (H-bonds and Aspartic acid (Walker B formed electrostatic interaction with ATP. At Sensor 1, Arg328 of NOD1 exhibited an H-bond with ATP, whereas corresponding Arg404 of NOD2 did not. 'Proline' of GxP motif (Pro386 of NOD1 and Pro464 of NOD2 interacted with adenine moiety and His511 at Sensor 2 of NOD1 interacted with γ-phosphate group of ATP. In contrast, His579 of NOD2 interacted with the adenine moiety having a relatively inverted orientation. Our findings are well supplemented with the molecular interaction of ATP with NLRC4, and consistent with mutagenesis data reported for human, which indicates evolutionary shared NOD signaling mechanism. Together, this study provides novel insights into ATP binding mechanism, and highlights the differential ATP binding modes in zebrafish NOD1 and NOD2.

  12. Solar Radiation and Vitamin D: Mitigating Environmental Factors in Autoimmune Disease

    OpenAIRE

    Schwalfenberg, Gerry K.

    2012-01-01

    This paper looks at the environmental role of vitamin D and solar radiation as risk reduction factors in autoimmune disease. Five diseases are considered: multiple sclerosis, type 1 diabetes, rheumatoid arthritis, autoimmune disease of the thyroid, and inflammatory bowel disease. Clinical relevant studies and factors that may indicate evidence that autoimmune disease is a vitamin D-sensitive disease are presented. Studies that have resulted in prevention or amelioration of some autoimmune dis...

  13. Autoimmune Inner Ear Disease

    Science.gov (United States)

    ... Find an ENT Doctor Near You Autoimmune Inner Ear Disease Autoimmune Inner Ear Disease Patient Health Information ... with a hearing loss. How Does the Healthy Ear Work? The ear has three main parts: the ...

  14. Autoimmune Autonomic Ganglionopathy

    Science.gov (United States)

    ... Accessed 9/2/2015. Autoimmune Autonomic Ganglionopathy Summary. Dysautonomia International . http://www.dysautonomiainternational.org/page.php?ID= ... page Basic Information In Depth Information Basic Information Dysautonomia International offers an information page on Autoimmune autonomic ...

  15. Chronic Myelogenous Leukemia Cells Contribute to the Stromal Myofibroblasts in Leukemic NOD/SCID Mouse In Vivo

    Directory of Open Access Journals (Sweden)

    Ryosuke Shirasaki

    2012-01-01

    Full Text Available We recently reported that chronic myelogenous leukemia (CML cells converted into myofibroblasts to create a microenvironment for proliferation of CML cells in vitro. To analyze a biological contribution of CML-derived myofibroblasts in vivo, we observed the characters of leukemic nonobese diabetes/severe combined immunodeficiency (NOD/SCID mouse. Bone marrow nonadherent mononuclear cells as well as human CD45-positive cells obtained from CML patients were injected to the irradiated NOD/SCID mice. When the chimeric BCR-ABL transcript was demonstrated in blood, human CML cells were detected in NOD/SCID murine bone marrow. And CML-derived myofibroblasts composed with the bone marrow-stroma, which produced significant amounts of human vascular endothelial growth factor A. When the parental CML cells were cultured with myofibroblasts separated from CML cell-engrafted NOD/SCID murine bone marrow, CML cells proliferated significantly. These observations indicate that CML cells make an adequate microenvironment for their own proliferation in vivo.

  16. Diabetes

    DEFF Research Database (Denmark)

    Damm, Peter; Mathiesen, Elisabeth R

    2015-01-01

    For >30 years, insulin has been the drug of choice for the medical treatment of gestational diabetes mellitus. However, the use of oral hypoglycaemic agents has increased during the past 1–2 decades, so a recent comparison of treatment with glibenclamide, metformin or insulin in women with gestat......For >30 years, insulin has been the drug of choice for the medical treatment of gestational diabetes mellitus. However, the use of oral hypoglycaemic agents has increased during the past 1–2 decades, so a recent comparison of treatment with glibenclamide, metformin or insulin in women...... with gestational diabetes mellitus is highly relevant....

  17. Cloning, expression, purification, crystallization and preliminary X-ray analysis of NodS N-methyltransferase from Bradyrhizobium japonicum WM9

    International Nuclear Information System (INIS)

    The NodS N-methyltransferase, an enzyme participating in the biosynthesis of the bacterial nodulation (Nod) factor necessary to establish symbiotic nitrogen fixation with a legume plant host, has been crystallized in the apo form as well as in complex with SAH. SAH is a byproduct of SAM degradation during the SAM-dependent methylation reaction. The Nod factor (NF) is a rhizobial signal molecule that is involved in recognition of a legume host and the formation of root and stem nodules. Some unique enzymes are involved in the biosynthesis of NF, which is a variously but specifically substituted lipochitooligosaccharide. One of these enzymes is NodS, an N-methyltransferase that methylates end-deacetylated chitooligosaccharide substrates. In the methylation reaction, NodS uses S-adenosyl-l-methionine (SAM) as a methyl donor. To date, no structural information is available about NodS from any rhizobium. X-ray crystallographic studies of the NodS protein from Bradyrhizobium japonicum WM9, which infects the legumes lupin and serradella, have been undertaken. The nodS gene was cloned and the recombinant protein was expressed in Escherichia coli cells using natural amino acids and as an SeMet derivative. NodS without ligands was crystallized in the presence of PEG 3350 and MgCl2. The protein was also crystallized in complex with S-adenosyl-l-homocysteine (SAH) in the presence of PEG 8000 and MgCl2. SAH is produced from SAM as a byproduct of the methylation reaction. The crystals of apo NodS are tetragonal and diffracted X-rays to 2.42 Å resolution. The NodS–SAH complex crystallizes in an orthorhombic space group and the crystals diffracted X-rays to 1.85 Å resolution

  18. Diabetes

    Science.gov (United States)

    ... nurse educator. Getting better control over your blood sugar, cholesterol, and blood pressure levels helps reduce the risk of kidney disease, eye disease, nervous system disease, heart attack, and stroke. To prevent diabetes ...

  19. Regulatory T-cells and autoimmunity.

    LENUS (Irish Health Repository)

    Ni Choileain, Niamh

    2012-02-03

    Approximately 20% of the population is affected by autoimmune or inflammatory diseases mediated by an abnormal immune response. A characteristic feature of autoimmune disease is the selective targeting of a single cell type, organ or tissue by certain populations of autoreactive T-cells. Examples of such diseases include rheumatoid arthritis, insulin-dependent diabetes mellitus, and systemic lupus erythematosus (SLE), all of which are characterized by chronic inflammation, tissue destruction and target organ malfunction. Although strong evidence links most autoimmune diseases to specific genes, considerable controversy prevails regarding the role of regulatory T-cell populations in the disease process. These cells are now also believed to play a key role in mediating transplantation tolerance and inhibiting the induction of tumor immunity. Though the concept of therapeutic immune regulation aimed at treating autoimmune pathology has been validated in many animal models, the development of strategies for the treatment of human autoimmune disorders remains in its infancy. The main obstacles to this include the conflicting findings of different model systems, as well as the contrasting functions of regulatory T-cells and cytokines involved in the development of such disorders. This review examines the role of regulatory T-cells in the pathogenesis of autoimmunity and describes the therapeutic potential of these cells for the prevention of immune-mediated pathologies in the future. Although much remains to be learned about such pathologies, a clearer understanding of the mechanisms by which regulatory T-cells function will undoubtedly lead to exciting new possibilities for immunotherapeutics.

  20. Predominant Occupation of the Class I MHC Molecule H-2Kwm7 with a Single Self-peptide Suggests a Mechanism for its Diabetes-protective Effect

    Energy Technology Data Exchange (ETDEWEB)

    Brims, D.; Qian, J; Jarchum, I; Mikesh, L; Palmieri, E; Ramagopal, U; Malashkevich, V; Chaparro, R; Lund, T; et. al.

    2010-01-01

    Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing pancreatic {beta} cells. In both humans and the non-obese diabetic (NOD) mouse model of T1D, class II MHC alleles are the primary determinant of disease susceptibility. However, class I MHC genes also influence risk. These findings are consistent with the requirement for both CD{sup 4+} and CD{sup 8+} T cells in the pathogenesis of T1D. Although a large body of work has permitted the identification of multiple mechanisms to explain the diabetes-protective effect of particular class II MHC alleles, studies examining the protective influence of class I alleles are lacking. Here, we explored this question by performing biochemical and structural analyses of the murine class I MHC molecule H-2K{sup wm7}, which exerts a diabetes-protective effect in NOD mice. We have found that H-2K{sup wm7} molecules are predominantly occupied by the single self-peptide VNDIFERI, derived from the ubiquitous protein histone H2B. This unexpected finding suggests that the inability of H-2K{sup wm7} to support T1D development could be due, at least in part, to the failure of peptides from critical {beta}-cell antigens to adequately compete for binding and be presented to T cells. Predominant presentation of a single peptide would also be expected to influence T-cell selection, potentially leading to a reduced ability to select a diabetogenic CD{sup 8+} T-cell repertoire. The report that one of the predominant peptides bound by T1D-protective HLA-A*31 is histone derived suggests the potential translation of our findings to human diabetes-protective class I MHC molecules.

  1. Antiaging Gene Klotho Attenuates Pancreatic β-Cell Apoptosis in Type 1 Diabetes.

    Science.gov (United States)

    Lin, Yi; Sun, Zhongjie

    2015-12-01

    Apoptosis is the major cause of death of insulin-producing β-cells in type 1 diabetes mellitus (T1DM). Klotho is a recently discovered antiaging gene. We found that the Klotho gene is expressed in pancreatic β-cells. Interestingly, halplodeficiency of Klotho (KL(+/-)) exacerbated streptozotocin (STZ)-induced diabetes (a model of T1DM), including hyperglycemia, glucose intolerance, diminished islet insulin storage, and increased apoptotic β-cells. Conversely, in vivo β-cell-specific expression of mouse Klotho gene (mKL) attenuated β-cell apoptosis and prevented STZ-induced diabetes. mKL promoted cell adhesion to collagen IV, increased FAK and Akt phosphorylation, and inhibited caspase 3 cleavage in cultured MIN6 β-cells. mKL abolished STZ- and TNFα-induced inhibition of FAK and Akt phosphorylation, caspase 3 cleavage, and β-cell apoptosis. These promoting effects of Klotho can be abolished by blocking integrin β1. Therefore, these cell-based studies indicated that Klotho protected β-cells by inhibiting β-cell apoptosis through activation of the integrin β1-FAK/Akt pathway, leading to inhibition of caspase 3 cleavage. In an autoimmune T1DM model (NOD), we showed that in vivo β-cell-specific expression of mKL improved glucose tolerance, attenuated β-cell apoptosis, enhanced insulin storage in β-cells, and increased plasma insulin levels. The beneficial effect of Klotho gene delivery is likely due to attenuation of T-cell infiltration in pancreatic islets in NOD mice. Overall, our results demonstrate for the first time that Klotho protected β-cells in T1DM via attenuating apoptosis. PMID:26340932

  2. Quantitative analysis of protein and gene expression in salivary glands of Sjogren's-like disease NOD mice treated by bone marrow soup.

    Directory of Open Access Journals (Sweden)

    Kaori Misuno

    Full Text Available BACKGROUND: Bone marrow cell extract (termed as BM Soup has been demonstrated to repair irradiated salivary glands (SGs and restore saliva secretion in our previous study. In the present study, we aim to investigate if the function of damaged SGs in non-obese diabetic (NOD mice can be restored by BM Soup treatment and the molecular alterations associated with the treatment. METHODS: Whole BM cells were lysed and soluble intracellular contents ("BM Soup" were injected I.V. into NOD mice. Tandem mass tagging with 2-D liquid chromatography-mass spectrometry was used to quantify proteins in the submandibular glands (SMGs between untreated and BM Soup-treated mice. Quantitative PCR was used to identify genes with altered expression in the treated mice. RESULTS BM SOUP: restored salivary flow rates to normal levels and significantly reduced the focus scores of SMGs in NOD mice. More than 1800 proteins in SMG cells were quantified by the proteomic approach. Many SMG proteins involved in inflammation and apoptosis were found to be down-regulated whereas those involved in salivary gland biology and development/regeneration were up-regulated in the BM Soup-treated mice. qPCR analysis also revealed expression changes of growth factors and cytokines in the SMGs of the treated NOD mice. CONCLUSION: BM Soup treatment is effective to restore the function of damaged SGs in NOD mice. Through gene/protein expression analysis, we have found that BM Soup treatment might effectuate via inhibiting apoptosis, focal adhesion and inflammation whereas promoting development, regeneration and differentiation of the SG cells in NOD mice. These findings provide important insights on the potential mechanisms underlying the BM Soup treatment for functional restoration of damaged SGs in NOD mice. Additional studies are needed to further confirm the identified target genes and their related signaling pathways that are responsible for the BM Soup treatment.

  3. The expression of the beta cell-derived autoimmune ligand for the killer receptor nkp46 is attenuated in type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Chamutal Gur

    Full Text Available NK cells rapidly kill tumor cells, virus infected cells and even self cells. This is mediated via killer receptors, among which NKp46 (NCR1 in mice is prominent. We have recently demonstrated that in type 1 diabetes (T1D NK cells accumulate in the diseased pancreas and that they manifest a hyporesponsive phenotype. In addition, we found that NKp46 recognizes an unknown ligand expressed by beta cells derived from humans and mice and that blocking of NKp46 activity prevented diabetes development. Here we investigated the properties of the unknown NKp46 ligand. We show that the NKp46 ligand is mainly located in insulin granules and that it is constitutively secreted. Following glucose stimulation the NKp46 ligand translocates to the cell membrane and its secretion decreases. We further demonstrate by using several modalities that the unknown NKp46 ligand is not insulin. Finally, we studied the expression of the NKp46 ligand in type 2 diabetes (T2D using 3 different in vivo models and 2 species; mice and gerbils. We demonstrate that the expression of the NKp46 ligand is decreased in all models of T2D studied, suggesting that NKp46 is not involved in T2D.

  4. Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

    International Nuclear Information System (INIS)

    Toll-like receptor 4 (TLR4) activation has been proposed to be important for islet cell inflammation and eventually β cell loss in the course of type 1 diabetes (T1D) development. However, according to the “hygiene hypothesis”, bacterial endotoxin lipopolysaccharide (LPS), an agonist on TLR4, inhibits T1D progression. Here we investigated possible mechanisms for the protective effect of LPS on T1D development in non-obese diabetic (NOD) mice. We found that LPS administration to NOD mice during the prediabetic state neither prevented nor reversed insulitis, but delayed the onset and decreased the incidence of diabetes, and that a multiple-injection protocol is more effective than a single LPS intervention. Further, LPS administration suppressed spleen T lymphocyte proliferation, increased the generation of CD4+CD25+Foxp3+ regulatory T cells (Tregs), reduced the synthesis of strong Th1 proinflammatory cytokines, and downregulated TLR4 and its downstream MyD88-dependent signaling pathway. Most importantly, multiple injections of LPS induced a potential tolerogenic dendritic cell (DC) subset with low TLR4 expression without influencing the DC phenotype. Explanting DCs from repeated LPS-treated NOD mice into NOD/SCID diabetic mice conferred sustained protective effects against the progression of diabetes in the recipients. Overall, these results suggest that multiple mechanisms are involved in the protective effects of LPS against the development of diabetes in NOD diabetic mice. These include Treg induction, down-regulation of TLR4 and its downstream MyD88-dependent signaling pathway, and the emergence of a potential tolerogenic DC subset. - Highlights: • Administration of lipopolysaccharide (LPS) prevented type 1 diabetes in NOD mice. • Downregulating TLR4 level and MyD88-dependent pathway contributed to protection of LPS. • LPS administration also hampered DC maturation and promoted Treg differentiation

  5. Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jun [Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan (China); Cao, Hui [Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Wang, Hongjie [Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, FL (United States); Yin, Guoxiao; Du, Jiao; Xia, Fei; Lu, Jingli [Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Xiang, Ming, E-mail: xiangming@mails.tjmu.edu.cn [Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China)

    2015-06-15

    Toll-like receptor 4 (TLR4) activation has been proposed to be important for islet cell inflammation and eventually β cell loss in the course of type 1 diabetes (T1D) development. However, according to the “hygiene hypothesis”, bacterial endotoxin lipopolysaccharide (LPS), an agonist on TLR4, inhibits T1D progression. Here we investigated possible mechanisms for the protective effect of LPS on T1D development in non-obese diabetic (NOD) mice. We found that LPS administration to NOD mice during the prediabetic state neither prevented nor reversed insulitis, but delayed the onset and decreased the incidence of diabetes, and that a multiple-injection protocol is more effective than a single LPS intervention. Further, LPS administration suppressed spleen T lymphocyte proliferation, increased the generation of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells (Tregs), reduced the synthesis of strong Th1 proinflammatory cytokines, and downregulated TLR4 and its downstream MyD88-dependent signaling pathway. Most importantly, multiple injections of LPS induced a potential tolerogenic dendritic cell (DC) subset with low TLR4 expression without influencing the DC phenotype. Explanting DCs from repeated LPS-treated NOD mice into NOD/SCID diabetic mice conferred sustained protective effects against the progression of diabetes in the recipients. Overall, these results suggest that multiple mechanisms are involved in the protective effects of LPS against the development of diabetes in NOD diabetic mice. These include Treg induction, down-regulation of TLR4 and its downstream MyD88-dependent signaling pathway, and the emergence of a potential tolerogenic DC subset. - Highlights: • Administration of lipopolysaccharide (LPS) prevented type 1 diabetes in NOD mice. • Downregulating TLR4 level and MyD88-dependent pathway contributed to protection of LPS. • LPS administration also hampered DC maturation and promoted Treg differentiation.

  6. Sirolimus for Autoimmune Disease of Blood Cells

    Science.gov (United States)

    2016-04-22

    Autoimmune Pancytopenia; Autoimmune Lymphoproliferative Syndrome (ALPS); Evans Syndrome; Idiopathic Thrombocytopenic Purpura; Anemia, Hemolytic, Autoimmune; Autoimmune Neutropenia; Lupus Erythematosus, Systemic; Inflammatory Bowel Disease; Rheumatoid Arthritis

  7. Gluten-free diet prevents diabetes in NOD mice

    Czech Academy of Sciences Publication Activity Database

    Funda, David; Kaas, A.; Bock, T.; Tlaskalová, Helena; Buschard, K.

    1999-01-01

    Roč. 15, - (1999), s. 323-327. ISSN 1520-7552 R&D Projects: GA ČR GA306/98/0433; GA ČR GA311/97/0784; GA MZd NI5051; GA AV ČR IAA7020716; GA AV ČR IAA7020808 Institutional research plan: CEZ:A53/98:Z5-020-9ii Subject RIV: EC - Immunology Impact factor: 2.417, year: 1999

  8. Phenotyping of Nod1/2 double deficient mice and characterization of Nod1/2 in systemic inflammation and associated renal disease

    Directory of Open Access Journals (Sweden)

    Ingrid Stroo

    2012-10-01

    It is indispensable to thoroughly characterize each animal model in order to distinguish between primary and secondary effects of genetic changes. The present study analyzed Nod1 and Nod2 double deficient (Nod1/2 DKO mice under physiological and inflammatory conditions. Nod1 and Nod2 are members of the Nucleotide-binding domain and Leucine-rich repeat containing Receptor (NLR family. Several inflammatory disorders, such as Crohn's disease and asthma, are linked to genetic changes in either Nod1 or Nod2. These associations suggest that Nod1 and Nod2 play important roles in regulating the immune system. Three-month-old wildtype (Wt and Nod1/2 DKO mice were sacrificed, body and organ weight were determined, and blood was drawn. Except for lower liver weight in Nod1/2 DKO mice, no differences were found in body/organ weight between both strains. Leukocyte count and composition was comparable. No significant changes in analyzed plasma biochemical markers were found. Additionally, intestinal and vascular permeability was determined. Nod1/2 DKO mice show increased susceptibility for intestinal permeability while vascular permeability was not affected. Next we induced septic shock and organ damage by administering LPS+PGN intraperitoneally to Wt and Nod1/2 DKO mice and sacrificed animals after 2 and 24 hours. The systemic inflammatory and metabolic response was comparable between both strains. However, renal response was different as indicated by partly preserved kidney function and tubular epithelial cell damage in Nod1/2 DKO at 24 hours. Remarkably, renal inflammatory mediators Tnfα, KC and Il-10 were significantly increased in Nod1/2 DKO compared with Wt mice at 2 hours. Systematic analysis of Nod1/2 DKO mice revealed a possible role of Nod1/2 in the development of renal disease during systemic inflammation.

  9. Environmental Basis of Autoimmunity.

    Science.gov (United States)

    Floreani, Annarosa; Leung, Patrick S C; Gershwin, M Eric

    2016-06-01

    The three common themes that underlie the induction and perpetuation of autoimmunity are genetic predisposition, environmental factors, and immune regulation. Environmental factors have gained much attention for their role in triggering autoimmunity, with increasing evidence of their influence as demonstrated by epidemiological studies, laboratory research, and animal studies. Environmental factors known to trigger and perpetuate autoimmunity include infections, gut microbiota, as well as physical and environmental agents. To address these issues, we will review major potential mechanisms that underlie autoimmunity including molecular mimicry, epitope spreading, bystander activation, polyclonal activation of B and T cells, infections, and autoinflammatory activation of innate immunity. The association of the gut microbiota on autoimmunity will be particularly highlighted by their interaction with pharmaceutical agents that may lead to organ-specific autoimmunity. Nonetheless, and we will emphasize this point, the precise mechanism of environmental influence on disease pathogenesis remains elusive. PMID:25998909

  10. NOD-like receptors in lung diseases

    Directory of Open Access Journals (Sweden)

    Catherine eChaput

    2013-11-01

    Full Text Available The lung is a particularly vulnerable organ at the interface of the body and the exterior environment. It is constantly exposed to microbes and particles by inhalation. The innate immune system needs to react promptly and adequately to potential dangers posed by these microbes and particles, while at the same time avoiding extensive tissue damage. NOD-like receptors (NLRs represent a group of key sensors for microbes and damage in the lung. As such they are important players in various infectious as well as acute and chronic sterile inflammatory diseases, such as pneumonia, chronic obstructive lung disease (COPD, acute lung injury/ARDS, pneumoconiosis and asthma. Activation of most known NLRs leads to the production and release of pro-inflammatory cytokines, and/or to the induction of cell death. We will review NLR functions in the lung during infection and sterile inflammation.

  11. Induction of CD4+CD25+Foxp3+regulatory T cell response by glatiramer acetate in type 1 diabetes

    Institute of Scientific and Technical Information of China (English)

    Guoliang Cui; Yuebo Zhang; Zhenwei Gong; Jingwu Z Zhang; Ying Qin Zang

    2009-01-01

    Glatiramer acetate (GA) is an immunomodulatory peptide drug used to treat multiple sclerosis. Its treatment ef-fect has been expanded to other autoimmune conditions such as uveoretinitis, inflammatory bowel disease, graft re-jection and hepatic fibrosis. Here, we report that GA was effective in altering the clinical course of diabetes in cyclo-phosphamide (CY)-potentiated non-obese diabetic (CY-NOD) mice. Treatment with GA significantly reduced the dia-betic rate in the mice and ameliorated insulitis, which coincided with increased CD4+CD25+Foxp3+T cell response in treated mice. GA treatment led to increased expression of transcription factor Foxp3 and elevated production of interleukin-4 (IL-4) both in vivo and in vitro. It was evident that the effect of GA on up-regulation of Foxp3 was me-diated partially through IL-4. IL-4 was found to maintain Foxp3 expression and regulatory function of CD4+CD25+ regulatory T cells (Tregs). This study provides new evidence that GA has treatment potential for type 1 diabetes through the induction of Tregs and that increased IL-4 production is partially responsible for the enhanced Treg's function in GA treatment.

  12. Bistability in autoimmune diseases

    DEFF Research Database (Denmark)

    Rapin, Nicolas; Mosekilde, Erik; Lund, Ole

    2011-01-01

    Autoimmune diseases damage host tissue, which, in turn, may trigger a stronger immune response. Systems characterized by such positive feedback loops can display co-existing stable steady states. In a mathematical model of autoimmune disease, one steady state may correspond to the healthy state and...... another to an autoimmune steady state characterized by widespread tissue damage and immune activation. We show how a triggering event may move the system from the healthy to the autoimmune state and how transient immunosuppressive treatment can move the system back to the healthy state....

  13. Solar Radiation and Vitamin D: Mitigating Environmental Factors in Autoimmune Disease

    Directory of Open Access Journals (Sweden)

    Gerry K. Schwalfenberg

    2012-01-01

    Full Text Available This paper looks at the environmental role of vitamin D and solar radiation as risk reduction factors in autoimmune disease. Five diseases are considered: multiple sclerosis, type 1 diabetes, rheumatoid arthritis, autoimmune disease of the thyroid, and inflammatory bowel disease. Clinical relevant studies and factors that may indicate evidence that autoimmune disease is a vitamin D-sensitive disease are presented. Studies that have resulted in prevention or amelioration of some autoimmune disease are discussed. An example of the utility of supplementing vitamin D in an unusual autoimmune disease, idiopathic thrombocytic purpura, is presented.

  14. Limiting Behavior of Weighted Sums of NOD Random Variables

    Institute of Scientific and Technical Information of China (English)

    De Hua QIU; Ping Yan CHEN

    2011-01-01

    The strong laws of large numbers and laws of the single logarithm for weighted sums of NOD random variables are established.The results presented generalize the corresponding results of Chen and Gan [5]in independent sequence case.

  15. Autoimmune diseases in women with Turner's syndrome

    DEFF Research Database (Denmark)

    Jørgensen, Kristian T; Rostgaard, Klaus; Bache, Iben;

    2010-01-01

    Danish women with Turner's syndrome followed up for 12,461 person-years between 1980 and 2004. Standardized incidence ratios (SIRs) of first hospitalization for autoimmune disease and 95% confidence intervals (95% CIs) were used as measures of relative risk. RESULTS: The overall risk of autoimmune...... disease among women with Turner's syndrome was twice that among Danish women in general (SIR 2.1 [95% CI 1.6-2.7]). For autoimmune diseases with a female predominance, the SIR among women with Turner's syndrome was 1.7 (95% CI 1.2-2.4), whereas the SIR for autoimmune diseases with a male predominance...... among these women was 3.9 (95% CI 2.5-5.8). Associations were strongest for Hashimoto thyroiditis (SIR 14.6 [95% CI 6.7-27.1]), a strongly female-predominant condition, and type 1 diabetes mellitus (SIR 4.1 [95% CI 2.5-6.3]). CONCLUSION: Women with Turner's syndrome are at excess risk of autoimmune...

  16. American Autoimmune Related Diseases Association

    Science.gov (United States)

    ... Its 25th Anniversary With #25FOR25 Campaign During National Autoimmune Disease Awareness Month AARDA officially kicks of National Autoimmune ... will benefit AARDA. Click here to read more. Autoimmune Disease Awareness Month AARDA and the NCAPG held two ...

  17. Type I autoimmune hepatitis, inverted psoriasis with psoriatic arthropathy and type 2 diabetes mellitus as complications of a chronic B virus hepatitis treated with interferon - Case report

    Directory of Open Access Journals (Sweden)

    George Săraci

    2012-06-01

    Full Text Available We present the case of a 31 year old male patient, admitted in the 3rd Medical Clinic Cluj-Napoca for asthenia, fatigue, effort hepatalgia,pain located in the legs and small joints of the hands. Patient has been diagnosed a year ago with chronic B viral hepatitis and receivedPeginterferon alpha 2a treatment. After performing clinical and paraclinical exams we established that patient suffers from type I autoimmunehepatitis, inverted psoriasis with psoriatic arthropathy, recent onset of type II diabetes mellitus. These conditions are likely to appear consecutivelyto Interferon therapy. The markers for B virus hepatitis (Ag-HBs, IgM-HBc, AgHBe, ADN-HBV were negative. The evolution was favorableafter therapy with immunosuppressants, corticoids, oral antidiabetics and antisecretors.

  18. Heme Oxygenase-1 Induction Prevents Autoimmune Diabetes in Association With Pancreatic Recruitment of M2-Like Macrophages, Mesenchymal Cells, and Fibrocytes.

    Science.gov (United States)

    Husseini, Mahmoud; Wang, Gen-Sheng; Patrick, Christopher; Crookshank, Jennifer A; MacFarlane, Amanda J; Noel, J Ariana; Strom, Alexander; Scott, Fraser W

    2015-11-01

    Immunoregulatory and regenerative processes are activated in the pancreas during the development of type 1 diabetes (T1D) but are insufficient to prevent the disease. We hypothesized that the induction of cytoprotective heme oxygenase-1 (HO-1) by cobalt protophoryrin (CoPP) would prevent T1D by promoting anti-inflammatory and pro-repair processes. Diabetes-prone BioBreeding rats received ip CoPP or saline twice per week for 3 weeks, starting at 30 days and were monitored for T1D. Immunohistochemistry, confocal microscopy, quantitative RT-PCR, and microarrays were used to evaluate postinjection pancreatic changes at 51 days, when islet inflammation is first visible. T1D was prevented in CoPP-treated rats (29% vs 73%). Pancreatic Hmox1 was up-regulated along with islet-associated CD68(+)HO-1(+) cells, which were also observed in a striking peri-lobular interstitial infiltrate. Most interstitial cells expressed the mesenchymal marker vimentin and the hematopoietic marker CD34. Spindle-shaped, CD34(+)vimentin(+) cells coexpressed collagen V, characteristic of fibrocytes. M2 macrophage factors Krüppel-like factor 4, CD163, and CD206 were expressed by interstitial cells, consistent with pancreatic upregulation of several M2-associated genes. CoPP upregulated islet-regenerating REG genes and increased neogenic REG3β(+) and insulin(+) clusters. Thus, short-term induction of HO-1 promoted a protective M2-like milieu in the pancreas and recruited mesenchymal cells, M2 macrophages, and fibrocytes that imparted immunoregulatory and pro-repair effects, preventing T1D. PMID:26252059

  19. Transient B-cell depletion with anti-CD20 in combination with proinsulin DNA vaccine or oral insulin: immunologic effects and efficacy in NOD mice.

    Directory of Open Access Journals (Sweden)

    Ghanashyam Sarikonda

    Full Text Available A recent type 1 diabetes (T1D clinical trial of rituximab (a B cell-depleting anti-CD20 antibody achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin with anti-CD3 antibody (a T cell-directed immunomodulator offers better protection than either entity alone, indicating that novel combination therapies that include a T1D-related autoantigen are possible. To accelerate the identification and development of novel combination therapies that can be advanced into the clinic, we have evaluated the combination of a mouse anti-CD20 antibody with either oral insulin or a proinsulin-expressing DNA vaccine. Anti-CD20 alone, given once or on 4 consecutive days, produced transient B cell depletion but did not prevent or reverse T1D in the NOD mouse. Oral insulin alone (twice weekly for 6 weeks was also ineffective, while proinsulin DNA (weekly for up to 12 weeks showed a trend toward modest efficacy. Combination of anti-CD20 with oral insulin was ineffective in reversing diabetes in NOD mice whose glycemia was controlled with SC insulin pellets; these experiments were performed in three independent labs. Combination of anti-CD20 with proinsulin DNA was also ineffective in diabetes reversal, but did show modest efficacy in diabetes prevention (p = 0.04. In the prevention studies, anti-CD20 plus proinsulin resulted in modest increases in Tregs in pancreatic lymph nodes and elevated levels of proinsulin-specific CD4+ T-cells that produced IL-4. Thus, combination therapy with anti-CD20 and either oral insulin or proinsulin does not protect hyperglycemic NOD mice, but the combination with proinsulin offers limited efficacy in T1D prevention, potentially by augmentation of proinsulin-specific IL-4 production.

  20. Glutathione S-transferases and malondialdehyde in the liver of NOD mice on short-term treatment with plant mixture extract P-9801091.

    Science.gov (United States)

    Petlevski, R; Hadzija, M; Slijepcević, M; Juretić, D; Petrik, J

    2003-04-01

    Changes in the concentration of glutathione S-transferases (GSTs) and malondialdehyde (MDA) were assessed in the liver of normal and diabetic NOD mice with and without treatment with the plant extract P-9801091. The plant extract P-9801091 is an antihyperglycaemic preparation containing Myrtilli folium (Vaccinium myrtillus L.), Taraxaci radix (Taraxacum of fi cinale Web.), Cichorii radix (Cichorium intybus L.), Juniperi fructus (Juniperus communis L.), Centaurii herba (Centaurium umbellatum Gilib.), Phaseoli pericarpium (Phaseolus vulgaris L.), Millefoliiherba (Achillea millefolium L.), Mori folium (Morus nigra L.), Valerianae radix (Valeriana of ficinalis L.) and Urticae herba et radix (Urtica dioica L). Hyperglycaemia in diabetes mellitus is responsible for the development of oxidative stress (via glucose auto-oxidation and protein glycation), which is characterized by increased lipid peroxide production (MDA is a lipid peroxidation end product) and/or decreased antioxidative defence (GST in the liver is predominantly an alpha enzyme, which has antioxidative activity). The catalytic concentration of GSTs in the liver was significantly reduced in diabetic NOD mice compared with normal NOD mice (p < 0.01), while the concentration of MDA showed a rising tendency (not significant). The results showed that statistically significant changes in antioxidative defence occurred in the experimental model of short-term diabetes mellitus. A 7-day treatment with P-9801091 plant extract at a dose of 20 mg/kg body mass led to a significant increase in the catalytic concentration of GSTs in the liver of diabetic NOD mice (p < 0.01) and a decrease in MDA concentration (not significant), which could be explained by its antihyperglycaemic effect. PMID:12722130

  1. THE AUTOIMMUNE ECOLOGY.

    Directory of Open Access Journals (Sweden)

    Juan-Manuel eAnaya

    2016-04-01

    Full Text Available Autoimmune diseases (ADs represent a heterogeneous group of disorders that affect specific target organs or multiple organ systems. These conditions share common immunopathogenic mechanisms (i.e., the autoimmune tautology, which explain the clinical similarities they have among them as well as their familial clustering (i.e., coaggregation. As part of the autoimmune tautology, the influence of environmental exposure on the risk of developing ADs is paramount (i.e., the autoimmune ecology. In fact, environment, more than genetics, shapes immune system. Autoimmune ecology is akin to exposome, that is all the exposures - internal and external - across the lifespan, interacting with hereditary factors (both genetics and epigenetics to favor or protect against autoimmunity and its outcomes. Herein we provide an overview of the autoimmune ecology, focusing on the immune response to environmental agents in general, and microbiota, cigarette smoking, alcohol and coffee consumption, socioeconomic status, gender and sex hormones, vitamin D, organic solvents and vaccines in particular. Inclusion of the autoimmune ecology in disease etiology and health will improve the way personalized medicine is currently conceived and applied.

  2. Activation of NOD receptors by Neisseria gonorrhoeae modulates the innate immune response.

    Science.gov (United States)

    Mavrogiorgos, Nikolaos; Mekasha, Samrawit; Yang, Yibin; Kelliher, Michelle A; Ingalls, Robin R

    2014-05-01

    NOD1 and NOD2 are members of the NOD-like receptor family of cytosolic pattern recognition receptors that recognize specific fragments of the bacterial cell wall component peptidoglycan. Neisseria species are unique amongst Gram-negative bacteria in that they turn over large amounts of peptidoglycan during growth. We examined the ability of NOD1 and NOD2 to recognize Neisseria gonorrhoeae, and determined the role of NOD-dependent signaling in regulating the immune response to gonococcal infection. Gonococci, as well as conditioned medium from mid-logarithmic phase grown bacteria, were capable of activating both human NOD1 and NOD2, as well as mouse NOD2, leading to the activation of the transcription factor NF-κB and polyubiquitination of the adaptor receptor-interacting serine-threonine kinase 2. We identified a number of cytokines and chemokines that were differentially expressed in wild type versus NOD2-deficient macrophages in response to gonococcal infection. Moreover, NOD2 signaling up-regulated complement pathway components and cytosolic nucleic acid sensors, suggesting a broad impact of NOD activation on innate immunity. Thus, NOD1 and NOD2 are important intracellular regulators of the immune response to infection with N. gonorrhoeae. Given the intracellular lifestyle of this pathogen, we believe these cytosolic receptors may provide a key innate immune defense mechanism for the host during gonococcal infection. PMID:23884094

  3. The Non-Immune RIP-kb Mouse is a Useful Host for Islet Transplantation, as the Diabetes is Spontaneous, Mild and Predictable

    OpenAIRE

    Sutherland, Robyn M; Mountford, Joanne N.; Allison, Janette; Harrison, Leonard C.; Lew, Andrew M.

    2002-01-01

    Chemically-induced diabetic mice and spontaneously diabetic NOD mice have been valuable as recipients for experimental islet transplantation. However, their maintenance often requires parenteral insulin. Diabetogenic chemicals can be cytotoxic to the host’s immune system and to other organs some of which are often used as the transplant site. Procurement of diabetic cohorts in the NOD mouse is problematic due to variability in the age of disease onset. We show that RIP-Kb mice, which spontane...

  4. Association of Single Nucleotide Polymorphisms in Cytotoxic T-Lymphocyte Antigen 4 and Susceptibility to Autoimmune Type 1 Diabetes in Tunisians▿

    Science.gov (United States)

    Benmansour, Jihen; Stayoussef, Mouna; Al-Jenaidi, Fayza A.; Rajab, Mansoor H.; Rayana, Chiheb B.; Said, Hichem B.; Mahjoub, Touhami; Almawi, Wassim Y.

    2010-01-01

    In addition to HLA and insulin genes, the costimulatory molecule CTLA-4 gene is a confirmed type 1 diabetes (T1D) susceptibility gene. Previous studies investigated the association of CTLA-4 genetic variants with the risk of T1D, but with inconclusive findings. Here, we tested the contributions of common CTLA-4 gene variants to T1D susceptibility in Tunisian patients and control subjects. The study subjects comprised 228 T1D patients (47.8% females) and 193 unrelated healthy controls (45.6% females). Genotyping for CTLA-4 CT60A/G (rs3087243), +49A/G (rs231775), and −318C/T (rs5742909) was performed by PCR-restriction fragment length polymorphism (RFLP) analysis. The minor-allele frequencies (MAF) for the three CTLA-4 variants were significantly higher in T1D patients, and significantly higher frequencies of homozygous +49G/G and homozygous CT60G/G genotypes were seen in patients, which was confirmed by univariate regression analysis (taking the homozygous wild type as a reference). Of the eight possible three-locus CTLA-4 haplotypes (+49A/G, −318C/T, and CT60A/G) identified, multivariate regression analysis confirmed the positive association of ACG (odds ratio [OR], 1.93; 95% confidence interval [CI], 1.26 to 2.94), GCG (OR, 2.40; 95% CI, 1.11 to 5.21), and GTA (OR, 4.67; 95% CI, 1.52 to 14.39) haplotypes with T1D, after confounding variables were adjusted for. Our results indicate that CTLA-4 gene variants are associated with increased T1D susceptibility in Tunisian patients, further supporting a central role for altered T-cell costimulation in T1D pathogenesis. PMID:20610662

  5. Association of single nucleotide polymorphisms in cytotoxic T-lymphocyte antigen 4 and susceptibility to autoimmune type 1 diabetes in Tunisians.

    Science.gov (United States)

    Benmansour, Jihen; Stayoussef, Mouna; Al-Jenaidi, Fayza A; Rajab, Mansoor H; Rayana, Chiheb B; Said, Hichem B; Mahjoub, Touhami; Almawi, Wassim Y

    2010-09-01

    In addition to HLA and insulin genes, the costimulatory molecule CTLA-4 gene is a confirmed type 1 diabetes (T1D) susceptibility gene. Previous studies investigated the association of CTLA-4 genetic variants with the risk of T1D, but with inconclusive findings. Here, we tested the contributions of common CTLA-4 gene variants to T1D susceptibility in Tunisian patients and control subjects. The study subjects comprised 228 T1D patients (47.8% females) and 193 unrelated healthy controls (45.6% females). Genotyping for CTLA-4 CT60A/G (rs3087243), +49A/G (rs231775), and -318C/T (rs5742909) was performed by PCR-restriction fragment length polymorphism (RFLP) analysis. The minor-allele frequencies (MAF) for the three CTLA-4 variants were significantly higher in T1D patients, and significantly higher frequencies of homozygous +49G/G and homozygous CT60G/G genotypes were seen in patients, which was confirmed by univariate regression analysis (taking the homozygous wild type as a reference). Of the eight possible three-locus CTLA-4 haplotypes (+49A/G, -318C/T, and CT60A/G) identified, multivariate regression analysis confirmed the positive association of ACG (odds ratio [OR], 1.93; 95% confidence interval [CI], 1.26 to 2.94), GCG (OR, 2.40; 95% CI, 1.11 to 5.21), and GTA (OR, 4.67; 95% CI, 1.52 to 14.39) haplotypes with T1D, after confounding variables were adjusted for. Our results indicate that CTLA-4 gene variants are associated with increased T1D susceptibility in Tunisian patients, further supporting a central role for altered T-cell costimulation in T1D pathogenesis. PMID:20610662

  6. Autoimmunity and the Gut

    Directory of Open Access Journals (Sweden)

    Andrew W. Campbell

    2014-01-01

    Full Text Available Autoimmune diseases have increased dramatically worldwide since World War II. This is coincidental with the increased production and use of chemicals both in industrial countries and agriculture, as well as the ease of travel from region to region and continent to continent, making the transfer of a pathogen or pathogens from one part of the world to another much easier than ever before. In this review, triggers of autoimmunity are examined, principally environmental. The number of possible environmental triggers is vast and includes chemicals, bacteria, viruses, and molds. Examples of these triggers are given and include the mechanism of action and method by which they bring about autoimmunity.

  7. Autoimmunity in visual loss.

    Science.gov (United States)

    Petzold, Axel; Wong, Sui; Plant, Gordon T

    2016-01-01

    There are a number of autoimmune disorders which can affect visual function. There are a very large number of mechanisms in the visual pathway which could potentially be the targets of autoimmune attack. In practice it is the retina and the anterior visual pathway (optic nerve and chiasm) that are recognised as being affected in autoimmune disorders. Multiple Sclerosis is one of the commonest causes of visual loss in young adults because of the frequency of attacks of optic neuritis in that condition, however the basis of the inflammation in Multiple Sclerosis and the confirmation of autoimmunity is lacking. The immune process is known to be highly unusual in that it is not systemic and confined to the CNS compartment. Previously an enigmatic partner to Multiple Sclerosis, Neuromyelitis Optica is now established to be autoimmune and two antibodies - to Aquaporin4 and to Myelin Oligodendrocyte Glycoprotein - have been implicated in the pathogenesis. The term Chronic Relapsing Inflammatory Optic Neuropathy is applied to those cases of optic neuritis which require long term immunosuppression and hence are presumed to be autoimmune but where no autoimmune pathogenesis has been confirmed. Optic neuritis occurring post-infection and post vaccination and conditions such as Systemic Lupus Erythematosus and various vasculitides may cause direct autoimmune attack to visual structures or indirect damage through occlusive vasculopathy. Chronic granulomatous disorders such as Sarcoidosis affect vision commonly by a variety of mechanisms, whether and how these are placed in the autoimmune panoply is unknown. As far as the retina is concerned Cancer Associated Retinopathy and Melanoma Associated Retinopathy are well characterised clinically but a candidate autoantibody (recoverin) is only described in the former disorder. Other, usually monophasic, focal retinal inflammatory disorders (Idiopathic Big Blind Spot Syndrome, Acute Zonal Occult Outer Retinopathy and Acute Macular

  8. Regulation of nod factor sulphation genes in Rhizobium tropici CIAT899.

    Science.gov (United States)

    Manyani, H; Sousa, C; Soria Díaz, M E; Gil-Serrano, A; Megías, M

    2001-06-01

    Rhizobium tropici CIAT899 is a tropical symbiont able to nodulate various legumes such as Leucaena, Phaseolus, and Macroptilium. Broad host range of this species is related to its Nod factors wide spectrum. R. tropici contains Nod factors sulphation nod genes, nodHPQ genes, which control nodulation efficiency in Leucaena. To study nodHPQ regulation, we carried out different interposon insertions in its upstream region. One of these generated interruptions, nodI mutant produced nonsulphated Nod factors suggesting a possible dependence of these genes on nodI upstream region. Moreover, analysis results of lacZ transcriptional fusions with these genes in symbiotic plasmid showed dependence of these genes on NodD protein. In order to determine nodHPQ organization, we studied the effect of interposon insertion upstream of each lacZ transcriptional fusion, and the data obtained was used to indicate that nodHPQ belong to the nodABCSUIJ operon. However, comparison between nodP::lacZ beta-galactosidase activity in the symbiotic plasmid and in the pHM500 plasmid (containing nodHPQ genes) suggested constitutive expression in free living, and flavonoid inducible expression in symbiotic conditions. Constitutive nodHPQ expression may play a role in bacterial house-keeping metabolism. On the other hand, the transference of R. tropici nodHPQ genes to other rhizobia that do not present sulphated substitutions demonstrated that NodH protein sulphotransference is specific to C6 at the reducing end. PMID:11467733

  9. Autoimmune Pancreatitis: A Succinct Overview

    OpenAIRE

    Juan Putra; Xiaoying Liu

    2015-01-01

    Autoimmune pancreatitis is a rare type of chronic pancreatitis with characteristic clinical, radiologic, and histopathologic findings. Diagnosis of autoimmune pancreatitis is often challenging due to its low incidence and nonspecific clinical and radiologic findings. Patients with autoimmune pancreatitis and pancreatic cancer share similar clinical presentations, including obstructive jaundice, abdominal pain and weight loss. Due to these overlapping features, autoimmune pancreatitis patients...

  10. Comparative genomic analysis of buffalo (Bubalus bubalis NOD1 and NOD2 receptors and their functional role in in-vitro cellular immune response.

    Directory of Open Access Journals (Sweden)

    Biswajit Brahma

    Full Text Available Nucleotide binding and oligomerization domain (NOD-like receptors (NLRs are innate immune receptors that recognize bacterial cell wall components and initiate host immune response. Structure and function of NLRs have been well studied in human and mice, but little information exists on genetic composition and role of these receptors in innate immune system of water buffalo--a species known for its exceptional disease resistance. Here, a comparative study on the functional domains of NOD1 and NOD2 was performed across different species. The NOD mediated in-vitro cellular responses were studied in buffalo peripheral blood mononuclear cells, resident macrophages, mammary epithelial, and fibroblast cells. Buffalo NOD1 (buNOD1 and buNOD2 showed conserved domain architectures as found in other mammals. The domains of buNOD1 and buNOD2 showed analogy in secondary and tertiary conformations. Constitutive expressions of NODs were ubiquitous in different tissues. Following treatment with NOD agonists, peripheral lymphocytes showed an IFN-γ response along-with production of pro-inflammatory cytokines. Alveolar macrophages and mammary epithelial cells showed NOD mediated in-vitro immune response through NF-κB dependent pathway. Fibroblasts showed pro-inflammatory cytokine response following agonist treatment. Our study demonstrates that both immune and non-immune cells could generate NOD-mediated responses to pathogens though the type and magnitude of response depend on the cell types. The structural basis of ligand recognition by buffalo NODs and knowledge of immune response by different cell types could be useful for development of non-infective innate immune modulators and next generation anti-inflammatory compounds.

  11. Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice.

    Science.gov (United States)

    Roggli, Elodie; Gattesco, Sonia; Caille, Dorothée; Briet, Claire; Boitard, Christian; Meda, Paolo; Regazzi, Romano

    2012-07-01

    During the initial phases of type 1 diabetes, pancreatic islets are invaded by immune cells, exposing β-cells to proinflammatory cytokines. This unfavorable environment results in gene expression modifications leading to loss of β-cell functions. To study the contribution of microRNAs (miRNAs) in this process, we used microarray analysis to search for changes in miRNA expression in prediabetic NOD mice islets. We found that the levels of miR-29a/b/c increased in islets of NOD mice during the phases preceding diabetes manifestation and in isolated mouse and human islets exposed to proinflammatory cytokines. Overexpression of miR-29a/b/c in MIN6 and dissociated islet cells led to impairment in glucose-induced insulin secretion. Defective insulin release was associated with diminished expression of the transcription factor Onecut2, and a consequent rise of granuphilin, an inhibitor of β-cell exocytosis. Overexpression of miR-29a/b/c also promoted apoptosis by decreasing the level of the antiapoptotic protein Mcl1. Indeed, a decoy molecule selectively masking the miR-29 binding site on Mcl1 mRNA protected insulin-secreting cells from apoptosis triggered by miR-29 or cytokines. Taken together, our findings suggest that changes in the level of miR-29 family members contribute to cytokine-mediated β-cell dysfunction occurring during the initial phases of type 1 diabetes. PMID:22537941

  12. Antibodies to Thyroid Peroxidase Arise Spontaneously with Age in NOD.H-2h4 Mice and Appear after Thyroglobulin Antibodies

    OpenAIRE

    Chen, Chun-Rong; Hamidi, Sepehr; Braley-Mullen, Helen; Nagayama, Yuji; Bresee, Catherine; Aliesky, Holly A.; Rapoport, Basil; McLachlan, Sandra M.

    2010-01-01

    Hashimoto’s thyroiditis, a common autoimmune disease, is associated with autoantibodies to thyroglobulin (Tg) and thyroid peroxidase (TPO). TPO, unlike abundant and easily purified Tg, is rarely investigated as an autoantigen in animals. We asked whether antibodies (Abs) develop to both TPO and Tg in thyroiditis that is induced (C57BL/6 and DBA/1 mice) or arises spontaneously (NOD.H-2h4 mice). Screening for TPOAbs was performed by flow cytometry using mouse TPO-expressing eukaryotic cells. Se...

  13. Analysis of antigen specific T cells in diabetes - Lessons from pre-clinical studies and early clinical trials.

    Science.gov (United States)

    Krishnamurthy, Balasubramanian; Selck, Claudia; Chee, Jonathan; Jhala, Guarang; Kay, Thomas W H

    2016-07-01

    Antigen-specific immune tolerance promises to provide safe and effective therapies to prevent type 1 diabetes (T1D). Antigen-specific therapy requires two components: well-defined, clinically relevant autoantigens; and safe approaches to inducing tolerance in T cells specific for these antigens. Proinsulin is a critical autoantigen in both NOD mice, based on knockout mouse studies and induction of immune tolerance to proinsulin preventing disease whereas most antigens cannot, and also in human T1D based on proinsulin-specific T cells being found in the islets of affected individuals and the early appearance of insulin autoantibodies. Effective antigen-specific therapies that prevent T1D in humans have not yet been developed although doubt remains about the best molecular form of the antigen, the dose and the route of administration. Preclinical studies suggest that antigen specific therapy is most useful when administered before onset of autoimmunity but this time-window has not been tested in humans until the recent "pre-point" study. There may be a 'window of opportunity' during the neonatal period when 'vaccine' like administration of proinsulin for a short period may be sufficient to prevent diabetes. After the onset of autoimmunity, naive antigen-specific T cells have differentiated into antigen-experienced memory cells and the immune responses have spread to multiple antigens. Induction of tolerance at this stage becomes more difficult although recent studies have suggested generation of antigen-specific TR1 cells can inhibit memory T cells. Preclinical studies are required to identify additional 'help' that is required to induce tolerance to memory T cells and develop protocols for effective therapy in individuals with established autoimmunity. PMID:27083395

  14. A cluster of coregulated genes determines TGF-β–induced regulatory T-cell (Treg) dysfunction in NOD mice

    OpenAIRE

    D'Alise, Anna Morena; Ergun, Ayla; Hill, Jonathan A.; Mathis, Diane; Benoist, Christophe

    2011-01-01

    Foxp3+ regulatory T cells (Tregs) originate in the thymus, but the Treg phenotype can also be induced in peripheral lymphoid organs or in vitro by stimulation of conventional CD4+ T cells with IL-2 and TGF-β. There have been divergent reports on the suppressive capacity of these TGF-Treg cells. We find that TGF-Tregs derived from diabetes-prone NOD mice, although expressing normal Foxp3 levels, are uniquely defective in suppressive activity, whereas TGF-Tregs from control strains (B6g7) or ex...

  15. Autoimmune liver diseases

    Institute of Scientific and Technical Information of China (English)

    Pietro Invernizzi; Ian R Mackay

    2008-01-01

    The liver was one of the earliest recognized sites among autoimmune diseases yet autoimmune hepatitis,primary biliary cirrhosis,primary sclerosing cholangitis,and their overlap forms,are still problematic in diagnosis and causation.The contributions herein comprise 'pairs of articles' on clinical characteristics,and concepts of etiopathogenesis,for each of the above diseases,together with childhood autoimmune liver disease,overlaps,interpretations of diagnostic serology,and liver transplantation.This issue is timely,since we are witnessing an ever increasing applicability of immunology to a wide variety of chronic diseases,hepatic and non-hepatic,in both developed and developing countries.The 11 invited expert review articles capture the changing features over recent years of the autoimmune liver diseases,the underlying immunomolecular mechanisms of development,the potent albeit still unexplained genetic influences,the expanding repertoire of immunoserological diagnostic markers,and the increasingly effective therapeutic possibilities.

  16. Silica, Silicosis, and Autoimmunity.

    Science.gov (United States)

    Pollard, Kenneth Michael

    2016-01-01

    Inhalation of dust containing crystalline silica is associated with a number of acute and chronic diseases including systemic autoimmune diseases. Evidence for the link with autoimmune disease comes from epidemiological studies linking occupational exposure to crystalline silica dust with the systemic autoimmune diseases systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Although little is known regarding the mechanism by which silica exposure leads to systemic autoimmune disease, there is a voluminous literature on silica exposure and silicosis that may help identify immune processes that precede development of autoimmunity. The pathophysiology of silicosis consists of deposition of silica particles in the alveoli of the lung. Ingestion of these particles by macrophages initiates an inflammatory response, which stimulates fibroblasts to proliferate and produce collagen. Silica particles are encased by collagen leading to fibrosis and the nodular lesions characteristic of the disease. The steps in the development of silicosis, including acute and chronic inflammation and fibrosis, have different molecular and cellular requirements, suggesting that silica-induced inflammation and fibrosis may be mechanistically separate. Significantly, it is unclear whether silica-induced inflammation and fibrosis contribute similarly to the development of autoimmunity. Nonetheless, the findings from human and animal model studies are consistent with an autoimmune pathogenesis that begins with activation of the innate immune system leading to proinflammatory cytokine production, pulmonary inflammation leading to activation of adaptive immunity, breaking of tolerance, and autoantibodies and tissue damage. The variable frequency of these immunological features following silica exposure suggests substantial genetic involvement and gene/environment interaction in silica-induced autoimmunity. However, numerous questions remain unanswered. PMID:27014276

  17. Silica, Silicosis and Autoimmunity.

    Directory of Open Access Journals (Sweden)

    Kenneth Michael Pollard

    2016-03-01

    Full Text Available Inhalation of dust containing crystalline silica is associated with a number of acute and chronic diseases including systemic autoimmune diseases. Evidence for the link with autoimmune disease comes from epidemiological studies linking occupational exposure to crystalline silica dust with the systemic autoimmune diseases SLE, SSc and RA. Although little is known regarding the mechanism by which silica exposure leads to systemic autoimmune disease, there is a voluminous literature on silica exposure and silicosis that may help identify immune processes that precede development of autoimmunity. The pathophysiology of silicosis consists of deposition of silica particles in the alveoli of the lung. Ingestion of these particles by macrophages initiates an inflammatory response which stimulates fibroblasts to proliferate and produce collagen. Silica particles are encased by collagen leading to fibrosis and the nodular lesions characteristic of the disease. The steps in the development of silicosis, including acute and chronic inflammation and fibrosis, have different molecular and cellular requirements suggesting that silica-induced inflammation and fibrosis may be mechanistically separate. Significantly, it is unclear whether silica-induced inflammation and fibrosis contribute similarly to the development of autoimmunity. Nonetheless, the findings from human and animal model studies are consistent with an autoimmune pathogenesis that begins with activation of the innate immune system leading to proinflammatory cytokine production, pulmonary inflammation leading to activation of adaptive immunity, breaking of tolerance, autoantibodies and tissue damage. The variable frequency of these immunological features following silica exposure suggests substantial genetic involvement and gene/environment interaction in silica-induced autoimmunity. However numerous questions remain unanswered.

  18. Update on Diabetes Mellitus

    OpenAIRE

    Murray Korc

    2004-01-01

    Diabetes mellitus is a complex multi-system disorder that may be classified as autoimmune mediated type 1 diabetes, or as insulin resistance associated type 2 diabetes. In type 1 diabetes, there is selective loss of the beta cells within the endocrine islets, as a consequence of T-cell and cytokine mediated destruction of these cells, perhaps in conjunction with destruction of the peri-islet Schwann cells. In type 2 diabetes, the etiology of the resistance ranges from post-receptor defects in...

  19. Differential Modulation of Nods Signaling Pathways by Fatty Acids in Human Colonic Epithelial HCT116 cells

    Science.gov (United States)

    Nucleotide-binding oligomerization domain containing proteins (Nods) are intracellular pattern recognition receptors (PRRs) recognizing conserved moieties of bacterial peptidoglycan through their leucine-rich repeats (LRR) domain. The agonists for Nods activate proinflammtory signaling pathways incl...

  20. Diabetes classification: grey zones, sound and smoke: Action LADA 1

    DEFF Research Database (Denmark)

    Leslie, R D G; Kolb, H; Schloot, N C;

    2008-01-01

    those who are initially insulin dependent. Ketosis-prone diabetes (KPD) and latent autoimmune diabetes in adults (LADA) are each exclusive forms of diabetes which are, at least initially, clinically distinct from type 2 diabetes and type 1 diabetes, and each have a different natural history from these...

  1. Follicular Helper T Cells in Autoimmunity.

    Science.gov (United States)

    Scherm, Martin G; Ott, Verena B; Daniel, Carolin

    2016-08-01

    The development of multiple disease-relevant autoantibodies is a hallmark of autoimmune diseases. In autoimmune type 1 diabetes (T1D), a variable time frame of autoimmunity precedes the clinically overt disease. The relevance of T follicular helper (TFH) cells for the immune system is increasingly recognized. Their pivotal contribution to antibody production by providing help to germinal center (GC) B cells facilitates the development of a long-lived humoral immunity. Their complex differentiation process, involving various stages and factors like B cell lymphoma 6 (Bcl6), is strictly controlled, as anomalous regulation of TFH cells is connected with immunopathologies. While the adverse effects of a TFH cell-related insufficient humoral immunity are obvious, the role of increased TFH frequencies in autoimmune diseases like T1D is currently highlighted. High levels of autoantigen trigger an excessive induction of TFH cells, consequently resulting in the production of autoantibodies. Therefore, TFH cells might provide promising approaches for novel therapeutic strategies. PMID:27324759

  2. NOD2 mutations and colorectal cancer - Where do we stand?

    Science.gov (United States)

    Branquinho, Diogo; Freire, Paulo; Sofia, Carlos

    2016-04-27

    Due to the overwhelming burden of colorectal cancer (CRC), great effort has been placed on identifying genetic mutations that contribute to disease development and progression. One of the most studied polymorphisms that could potentially increase susceptibility to CRC involves the nucleotide-binding and oligomerization-domain containing 2 (NOD2) gene. There is growing evidence that the biological activity of NOD2 is far greater than previously thought and a link with intestinal microbiota and mucosal immunity is increasingly sought after. In fact, microbial composition may be an important contributor not only to inflammatory bowel diseases (IBD) but also to CRC. Recent studies have showed that deficient NOD2 function confers a communicable risk of colitis and CRC. Despite the evidence from experimental models, population-based studies that tried to link certain NOD2 polymorphisms and an increase in CRC risk have been described as conflicting. Significant geographic discrepancies in the frequency of such polymorphisms and different interpretations of the results may have limited the conclusions of those studies. Since being first associated to IBD and CRC, our understanding of the role of this gene has come a long way, and it is tempting to postulate that it may contribute to identify individuals with susceptible genetic background that may benefit from early CRC screening programs or in predicting response to current therapeutic tools. The aim of this review is to clarify the status quo of NOD2 mutations as genetic risk factors to chronic inflammation and ultimately to CRC. The use of NOD2 as a predictor of certain phenotypic characteristics of the disease will be analyzed as well. PMID:27152134

  3. DMPD: Sensing of bacteria: NOD a lonely job. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17161646 Sensing of bacteria: NOD a lonely job. Kufer TA, Sansonetti PJ. Curr Opin ...Microbiol. 2007 Feb;10(1):62-9. Epub 2006 Dec 11. (.png) (.svg) (.html) (.csml) Show Sensing of bacteria: NOD a lonely job.... PubmedID 17161646 Title Sensing of bacteria: NOD a lonely job. Authors Kufer TA, Sansonetti

  4. DMPD: Role of Nods in bacterial infection. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17379560 Role of Nods in bacterial infection. Bourhis LL, Werts C. Microbes Infect.... 2007 Apr;9(5):629-36. Epub 2007 Jan 27. (.png) (.svg) (.html) (.csml) Show Role of Nods in bacterial infection.... PubmedID 17379560 Title Role of Nods in bacterial infection. Authors Bourhis LL, Werts C. Publication M

  5. Plant recognition of Bradyrhizobium japonicum nod factors. Final report, September 15, 1992--March 14, 1997

    Energy Technology Data Exchange (ETDEWEB)

    Stacey, G.

    1998-01-01

    This grant had three objectives: (1) isolate and identify the unique nod factor metabolites made by different wild-type B. japonicum strains; (2) investigate the biological activity of these unique nod factors, especially as it relates to host range; and (3) initiate studies to define the mechanism of plant recognition of the nod factors. This report summarizes the results of this research.

  6. DMPD: NOD-like receptors (NLRs): bona fide intracellular microbial sensors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18585455 NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Shaw...tml) (.csml) Show NOD-like receptors (NLRs): bona fide intracellular microbial sensors. PubmedID 18585455 Ti...tle NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Authors

  7. DNA methylation perspectives in the pathogenesis of autoimmune diseases.

    Science.gov (United States)

    Sun, Bao; Hu, Lei; Luo, Zhi-Ying; Chen, Xiao-Ping; Zhou, Hong-Hao; Zhang, Wei

    2016-03-01

    DNA methylation is now widely recognized as being critical to maintain the function of immune cells. Recent studies suggest that aberrant DNA methylation levels not only can result in immune cells autoreactivity in vitro, but also are related to autoimmunity in vivo. Environmental factors and genetic polymorphisms cause abnormal methylation, which affects the expression of certain immune-related genes, being becoming hot spot of explaining the mechanism of autoimmune diseases. This paper reviews the importance of abnormal methylation during the development of common autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and type 1 diabetes, aiming at a better understanding of the pathogenesis of autoimmune diseases and providing new ideas for the treatment of these diseases. PMID:26821302

  8. Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans.

    Science.gov (United States)

    Vatanen, Tommi; Kostic, Aleksandar D; d'Hennezel, Eva; Siljander, Heli; Franzosa, Eric A; Yassour, Moran; Kolde, Raivo; Vlamakis, Hera; Arthur, Timothy D; Hämäläinen, Anu-Maaria; Peet, Aleksandr; Tillmann, Vallo; Uibo, Raivo; Mokurov, Sergei; Dorshakova, Natalya; Ilonen, Jorma; Virtanen, Suvi M; Szabo, Susanne J; Porter, Jeffrey A; Lähdesmäki, Harri; Huttenhower, Curtis; Gevers, Dirk; Cullen, Thomas W; Knip, Mikael; Xavier, Ramnik J

    2016-05-01

    According to the hygiene hypothesis, the increasing incidence of autoimmune diseases in western countries may be explained by changes in early microbial exposure, leading to altered immune maturation. We followed gut microbiome development from birth until age three in 222 infants in Northern Europe, where early-onset autoimmune diseases are common in Finland and Estonia but are less prevalent in Russia. We found that Bacteroides species are lowly abundant in Russians but dominate in Finnish and Estonian infants. Therefore, their lipopolysaccharide (LPS) exposures arose primarily from Bacteroides rather than from Escherichia coli, which is a potent innate immune activator. We show that Bacteroides LPS is structurally distinct from E. coli LPS and inhibits innate immune signaling and endotoxin tolerance; furthermore, unlike LPS from E. coli, B. dorei LPS does not decrease incidence of autoimmune diabetes in non-obese diabetic mice. Early colonization by immunologically silencing microbiota may thus preclude aspects of immune education. PMID:27133167

  9.  Molecular mimicry in the etiology of autoimmune diseases

    Directory of Open Access Journals (Sweden)

    Jolanta Lis

    2012-07-01

    Full Text Available  There are currently more than 80 different autoimmune diseases, affecting approximately 100 million people worldwide. The etiology of most autoimmune diseases is unknown. The highest incidence of these diseases is in the developed countries and they are more common in women than in men. Among the most often listed factors responsible for the onset of autoimmunity are genetic predisposition and the phenomenon known as molecular mimicry. The latter stems from a similarity between microbial antigens and antigens present in the human body (self antigens. It is believed that such homology is responsible for the production of auto-antibodies and in consequence attack of the immune system against host tissues and organs. However, the main molecular factors responsible for these diseases in most cases remain unknown. While pathogenesis of many autoimmune diseases indicates the presence of molecular mimicry, at the same time the similarities between the own and foreign structures do not always result in autoimmunity. Therefore, prediction of such crucial homology responsible for the development of autoimmune disease is extremely difficult. In this paper we present examples of autoimmune diseases such as type 1 diabetes, multiple sclerosis, reactive arthritis and the potential contribution of micro-organisms to the mechanism of molecular mimicry.

  10. Transient B-Cell Depletion with Anti-CD20 in Combination with Proinsulin DNA Vaccine or Oral Insulin: Immunologic Effects and Efficacy in NOD Mice

    OpenAIRE

    Ghanashyam Sarikonda; Sowbarnika Sachithanantham; Yulia Manenkova; Tinalyn Kupfer; Amanda Posgai; Clive Wasserfall; Philip Bernstein; Laura Straub; Pagni, Philippe P.; Darius Schneider; Teresa Rodriguez Calvo; Marilyne Coulombe; Kevan Herold; Gill, Ronald G.; Mark Atkinson

    2013-01-01

    A recent type 1 diabetes (T1D) clinical trial of rituximab (a B cell-depleting anti-CD20 antibody) achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin) with anti-CD3 antibody (a T cell-directed immunomodulator) offers better protection than either entity alone, indicating that novel combination therapies that i...

  11. Autoimmune basal ganglia disorders.

    Science.gov (United States)

    Dale, Russell C; Brilot, Fabienne

    2012-11-01

    The basal ganglia are deep nuclei in the brain that include the caudate, putamen, globus pallidus, and substantia nigra. Pathological processes involving the basal ganglia often result in disorders of movement and behavior. A number of different autoimmune disorders predominantly involve the basal ganglia and can result in movement and psychiatric disorders. The classic basal ganglia autoimmune disorder is Sydenham chorea, a poststreptococcal neuropsychiatric disorder. Resurgence in the interest in Sydenham chorea is the result of the descriptions of other poststreptococcal neuropsychiatric disorders including tics and obsessive-compulsive disorder, broadly termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Encephalitic processes affecting the basal ganglia are also described including the syndromes basal ganglia encephalitis, encephalitis lethargica, and bilateral striatal necrosis. Last, systemic autoimmune disorders such as systemic lupus erythematosus and antiphospholipid syndrome can result in chorea or parkinsonism. Using paradigms learned from other autoantibody associated disorders, the authors discuss the autoantibody hypothesis and the role of systemic inflammation in autoimmune basal ganglia disorders. Identification of these entities is important as the clinician has an increasing therapeutic repertoire to modulate or suppress the aberrant immune system. PMID:22832771

  12. Autoimmunity and Asbestos Exposure

    Directory of Open Access Journals (Sweden)

    Jean C. Pfau

    2014-01-01

    Full Text Available Despite a body of evidence supporting an association between asbestos exposure and autoantibodies indicative of systemic autoimmunity, such as antinuclear antibodies (ANA, a strong epidemiological link has never been made to specific autoimmune diseases. This is in contrast with another silicate dust, crystalline silica, for which there is considerable evidence linking exposure to diseases such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Instead, the asbestos literature is heavily focused on cancer, including mesothelioma and pulmonary carcinoma. Possible contributing factors to the absence of a stronger epidemiological association between asbestos and autoimmune disease include (a a lack of statistical power due to relatively small or diffuse exposure cohorts, (b exposure misclassification, (c latency of clinical disease, (d mild or subclinical entities that remain undetected or masked by other pathologies, or (e effects that are specific to certain fiber types, so that analyses on mixed exposures do not reach statistical significance. This review summarizes epidemiological, animal model, and in vitro data related to asbestos exposures and autoimmunity. These combined data help build toward a better understanding of the fiber-associated factors contributing to immune dysfunction that may raise the risk of autoimmunity and the possible contribution to asbestos-related pulmonary disease.

  13. The pathogen recognition sensor, NOD2, is variably expressed in patients with pulmonary tuberculosis

    Directory of Open Access Journals (Sweden)

    Johnson Margaret A

    2007-08-01

    Full Text Available Abstract Background NOD2, an intracellular pathogen recognition sensor, modulates innate defences to muropeptides derived from various bacterial species, including Mycobacterium tuberculosis (MTB. Experimentally, NOD2 attenuates two key putative mycobactericidal mechanisms. TNF-α synthesis is markedly reduced in MTB-antigen stimulated-mononuclear cells expressing mutant NOD2 proteins. NOD2 agonists also induce resistance to apoptosis, and may thus facilitate the survival of MTB in infected macrophages. To further define a role for NOD2 in disease pathogenesis, we analysed NOD2 transcriptional responses in pulmonary leucocytes and mononuclear cells harvested from patients with pulmonary tuberculosis (PTB. Methods We analysed NOD2 mRNA expression by real-time polymerase chain-reaction in alveolar lavage cells obtained from 15 patients with pulmonary tuberculosis and their matched controls. We compared NOD2 transcriptional responses, in peripheral leucocytes, before and after anti-tuberculous treatment in 10 patients. In vitro, we measured NOD2 mRNA levels in MTB-antigen stimulated-mononuclear cells. Results No significant differences in NOD2 transcriptional responses were detected in patients and controls. In some patients, however, NOD2 expression was markedly increased and correlated with toll-like-receptor 2 and 4 expression. In whole blood, NOD2 mRNA levels increased significantly after completion of anti-tuberculosis treatment. NOD2 expression levels did not change significantly in mononuclear cells stimulated with mycobacterial antigens in vitro. Conclusion There are no characteristic NOD2 transcriptional responses in PTB. Nonetheless, the increased levels of NOD2 expression in some patients with severe tuberculosis, and the increases in expression levels within peripheral leucocytes following treatment merit further studies in selected patient and control populations.

  14. Shock: A possible presenting manifestation of autoimmune polyendocrine syndrome type II

    Directory of Open Access Journals (Sweden)

    Subodh Banzal

    2014-01-01

    Full Text Available Autoimmune polyendocrine syndrome Type II (APS II, also known as polyglandular autoimmune syndrome Type II or Schmidt syndrome, is constellations of multiple endocrine gland insufficiencies. It is a rare, but most common of the immunoendocrinopathy syndrome. It is characterized by the obligatory occurrence of autoimmune Addison′s disease in combination with thyroid autoimmune diseases and/or Type I diabetes, hypogonadism, hypophysitis, myasthenia gravis, vitiligo, alopecia, pernicious anemia, and celiac disease. Here, we report a case of 38-year-old female patient presented with shock, further diagnosed to have APS II.

  15. Autoimmunity in 2015.

    Science.gov (United States)

    Selmi, Carlo

    2016-08-01

    Compared to the clear trend observed in previous years, the number of peer-reviewed articles published during 2015 and retrieved using the "autoimmunity" key word declined by 4 %, while remaining 5 % of immunology articles. On the other hand, a more detailed analysis of the published articles in leading immunology and autoimmunity journals revealed exciting scenarios, with fascinating lines of evidence being supported by convincing data and likely followed by rapid translational or clinical developments. As examples, the study of the microbiome, the development of new serum or other tissue biomarkers, and a more solid understanding of disease pathogenesis and tolerance breakdown mechanisms have been central issues in the past year. Furthermore and similar to the oncology field, progress in the understanding of single autoimmune condition is becoming most specific with psoriatic and rheumatoid arthritis being ideal paradigms with treatment options diverging after decades of common therapies, as illustrated by IL17-targeting approaches. The ultimate result of these advances is towards personalized medicine with an ideal approach being tailored on a single patient, based on a finely tuned definition of the immunogenetics, epigenetics, microbiome, and biomarkers. Finally, experimental reports suggest that cancer-associated immune mechanisms or the role of T and B cell subpopulations should be better understood in autoimmune diseases. While we hailed the 2014 literature in the autoimmunity world as part of an annus mirabilis, we should not be mistaken in the strong stimulus of research in autoimmunity represented by the 2015 articles that will be summarized in this article. PMID:27422713

  16. Head Nodding Seizures and O.Volvulus Infestation

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2008-12-01

    Full Text Available Head nodding (HN syndrome, a new epilepsy disorder in sub-Sahara Africa, is described in 62 patients studied prospectively at the University of Ulm, Germany; Haydom Lutheran Hospital, Tanzania; and other centers in Austria, Tanzania, and Canada.

  17. Coupling of Nod1D and HOTCHANNEL: static case

    International Nuclear Information System (INIS)

    In this work the joining of the programs Nod1D and HOTCHANNEL, developed in the National Polytechnic Institute (IPN) and in the Electrical Research Institute (IIE) respectively is described. The first one allows to study the neutronic of a nuclear reactor and the second one allows to carry out the analysis of hot channel of a Boiling Water Reactor (BWR). Nod1 D is a program that it solves by nodal methods type finite element those diffusion equations in multigroup, and it is the static part of Nod Kin that it solves the diffusion equation in their time dependent part. For another side HOTCHANNEL is based on a mathematical model constituted by four conservation equations (two of mass conservation, one of motion quantity and one of energy), which are solved applying one discretization in implicit finite differences. Both programs have been verified in independent form using diverse test problems. In this work the modifications that were necessary to carry out to both for obtaining a coupled program that it provides the axial distribution of the neutron flux, the power, the burnup and the void fraction, among others parameters as much as neutronic as thermal hydraulics are described. Those are also mentioned limitations, advantages and disadvantages of the final product to which has been designated Nod1 D-HotChn. Diverse results for the Cycle 1 of the Laguna Verde Unit 1 reactor of the Nucleo electric central comparing them with those obtained directly with the CoreMasterPresto code are provided. (Author)

  18. Caring for the Ethical Ideal: Nel Noddings on Moral Education

    Science.gov (United States)

    Bergman, Roger

    2004-01-01

    Nel Noddings is arguably one of the premier philosophers of moral education in the English-speaking world today. Although she is outside the mainstream theory, research, and practice traditions of cognitive-developmentalism (the Kohlberg legacy) and of character education (which is in public ascendancy), her body of work is unrivalled for…

  19. Effect of dietary gluten on dendritic cells and innate immune subsets in BALB/c and NOD mice

    DEFF Research Database (Denmark)

    Larsen, Jesper; Weile, Christian; Antvorskov, Julie Christine;

    2015-01-01

    (GF) diet. The direct in vivo effect of gluten on innate cells, and particularly dendritic cells (DC) is not sufficiently clarified. Therefore, we wished to investigate the innate cell populations of spontaneous diabetic NOD mice and healthy BALB/c mice kept on a GF or a standard (STD) gluten...... a GF diet increased the percentage of macrophages in BALB/c spleen and of CD11c+ DCs in BALB/c and NOD spleen. Strictly gluten-free (SGF) diet increased the percentage of CD103+ DCs in BALB/c mice and decreased percentages of CD11b+ DCs in mesenteric and pancreatic lymph nodes in BALB/c mice. SGF......The innate immune system is known to play an important role in oral tolerance to dietary antigens. This is important in development of celiac disease (CD) but may also be important in type 1 diabetes (T1D), and could potentially explain the reduced incidence of T1D in mice receiving a gluten-free...

  20. Increased prevalence of autoimmunity in Turner syndrome

    DEFF Research Database (Denmark)

    Mortensen, K H; Cleemann, L; Hjerrild, B E;

    2009-01-01

    Individuals with Turner syndrome (TS) are prone to develop autoimmune conditions such as coeliac disease (CD), thyroiditis and type 1 diabetes (T1DM). The objective of the present study was to examine TS of various karyotypes for autoantibodies and corresponding diseases. This was investigated in a......, but two were classified as having T2DM. One patient had adrenocortical autoantibodies but not adrenal failure. Autoantibodies against intrinsic factor were absent. Anti-GAD-65 was increased in isochromosomal karyotypes (3/23 versus 1/84, P = 0.008) with no other association found between...... clinical symptoms emerge....

  1. Genetics of autoimmune diseases: a multistep process.

    OpenAIRE

    Johannesson, Martina; Hultqvist, Malin; Holmdahl, Rikard

    2006-01-01

    It has so far been difficult to identify genes behind polygenic autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), and type I diabetes (T1D). With proper animal models, some of the complexity behind these diseases can be reduced. The use of linkage analysis and positional cloning of genes in animal models for RA resulted in the identification of one of the genes regulating severity of arthritis in rats and mice, the Ncf1 gene. The Ncf1 gene encodes for the Ncf1 pr...

  2. [Autoimmune hemolytic anemia in children].

    Science.gov (United States)

    Becheur, M; Bouslama, B; Slama, H; Toumi, N E H

    2015-01-01

    Autoimmune hemolytic anemia is a rare condition in children which differs from the adult form. It is defined by immune-mediated destruction of red blood cells caused by autoantibodies. Characteristics of the autoantibodies are responsible for the various clinical entities. Classifications of autoimmune hemolytic anemia include warm autoimmune hemolytic anemia, cold autoimmune hemolytic anemia, and paroxysmal cold hemoglobinuria. For each classification, this review discusses the epidemiology, etiology, clinical presentation, laboratory evaluation, and treatment options. PMID:26575109

  3. Coupling of Nod1D and HOTCHANNEL: static case; Acoplamiento de Nod1D y HOTCHANNEL: caso estatico

    Energy Technology Data Exchange (ETDEWEB)

    Gomez T, A.M. [IPN-ESFM, 07738 Mexico D.F. (Mexico); Ovando C, R. [IIE-Gcia. de Energia Nuclear, Cuernavaca, Morelos (Mexico)]. e-mail: rovando@iie.org.mx

    2003-07-01

    In this work the joining of the programs Nod1D and HOTCHANNEL, developed in the National Polytechnic Institute (IPN) and in the Electrical Research Institute (IIE) respectively is described. The first one allows to study the neutronic of a nuclear reactor and the second one allows to carry out the analysis of hot channel of a Boiling Water Reactor (BWR). Nod1 D is a program that it solves by nodal methods type finite element those diffusion equations in multigroup, and it is the static part of Nod Kin that it solves the diffusion equation in their time dependent part. For another side HOTCHANNEL is based on a mathematical model constituted by four conservation equations (two of mass conservation, one of motion quantity and one of energy), which are solved applying one discretization in implicit finite differences. Both programs have been verified in independent form using diverse test problems. In this work the modifications that were necessary to carry out to both for obtaining a coupled program that it provides the axial distribution of the neutron flux, the power, the burnup and the void fraction, among others parameters as much as neutronic as thermal hydraulics are described. Those are also mentioned limitations, advantages and disadvantages of the final product to which has been designated Nod1 D-HotChn. Diverse results for the Cycle 1 of the Laguna Verde Unit 1 reactor of the Nucleo electric central comparing them with those obtained directly with the CoreMasterPresto code are provided. (Author)

  4. Autoimmunity in Addison's disease.

    Science.gov (United States)

    Martín Martorell, P; Roep, B O; Smit, J W A; Martorell, P M

    2002-08-01

    Addison's disease has a low incidence and is most frequently the result of an autoimmune disease in developed countries. Addison's disease can present as an isolated entity or in combination with other autoimmune diseases: Addison's disease can be part of the distinct polyglandular autoimmune syndromes APS I and II. Autoantibodies in patients with isolated Addison's disease are directed against the enzymes involved in steroid synthesis, P45oc21, P45oscc and P45oc17. Addison's disease, both isolated and in the context of APS II, has been associated with the haplotype HLA-A1, -B8 and DR3. The value of the increased expression of these molecules on adrenocortical cells could point towards an infectious pathogenesis. Given the prevalence, up to 80 %, of autoantibodies in Addison's disease as well as the high predictive value for developing the disease when antibodies are present (41% in three years), we advise screening high-risk populations, such as patients with other autoimmune endocrinopathies or their relatives for the presence of these antibodies. The adrenocortical function of patients positive for antibodies should be followed yearly. PMID:12430572

  5. Autoimmunity and Turner's syndrome.

    Science.gov (United States)

    Lleo, Ana; Moroni, Luca; Caliari, Lisa; Invernizzi, Pietro

    2012-05-01

    Turner Syndrome (TS) is a common genetic disorder, affecting female individuals, resulting from the partial or complete absence of one sex chromosome, and occurring in approximately 50 per 100,000 liveborn girls. TS is associated with reduced adult height and with gonadal dysgenesis, leading to insufficient circulating levels of female sex steroids and to infertility. Morbidity and mortality are increased in TS but average intellectual performance is within the normal range. TS is closely associated to the presence of autoantibodies and autoimmune diseases (AID), especially autoimmune thyroiditis and inflammatory bowel disease. Despite the fact that the strong association between TS and AID is well known and has been widely studied, the underlying immunopathogenic mechanism remains partially unexplained. Recent studies have displayed how TS patients do not show an excess of immunogenic risk markers. This is evocative for a higher responsibility of X-chromosome abnormalities in the development of AID, and particularly of X-genes involved in immune response. For instance, the long arm of the X chromosome hosts a MHC-locus, so the loss of that region may lead to a deficiency in immune regulation. Currently no firm guidelines for diagnosis exist. In conclusion, TS is a condition associated with a number of autoimmune manifestations. Individuals with TS need life-long medical attention. As a consequence of these findings, early diagnosis and regular screening for potential associated autoimmune conditions are essential in the medical follow-up of TS patients. PMID:22154619

  6. Autoimmune paediatric liver disease

    Directory of Open Access Journals (Sweden)

    Giorgina Mieli-Vergani, Diego Vergani

    2008-06-01

    Full Text Available Liver disorders with a likely autoimmune pathogenesis in childhood include autoimmune hepatitis (AIH, autoimmune sclerosing cholangitis (ASC, and de novo AIH after liver transplantation. AIH is divided into two subtypes according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA, type 1 or liver kidney microsomal antibody (LKM1, type 2. There is a female predominance in both. LKM1 positive patients tend to present more acutely, at a younger age, and commonly have partial IgA deficiency, while duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment, and long-term prognosis are similar in both groups. The most common type of paediatric sclerosing cholangitis is ASC. The clinical, biochemical, immunological, and histological presentation of ASC is often indistinguishable from that of AIH type 1. In both, there are high IgG, non-organ specific autoantibodies, and interface hepatitis. Diagnosis is made by cholangiography. Children with ASC respond to immunosuppression satisfactorily and similarly to AIH in respect to remission and relapse rates, times to normalization of biochemical parameters, and decreased inflammatory activity on follow up liver biopsies. However, the cholangiopathy can progress. There may be evolution from AIH to ASC over the years, despite treatment. De novo AIH after liver transplantation affects patients not transplanted for autoimmune disorders and is strikingly reminiscent of classical AIH, including elevated titres of serum antibodies, hypergammaglobulinaemia, and histological findings of interface hepatitis, bridging fibrosis, and collapse. Like classical AIH, it responds to treatment with prednisolone and azathioprine. De novo AIH post liver transplantation may derive from interference by calcineurin inhibitors with the intrathymic physiological mechanisms of T-cell maturation and selection. Whether

  7. Autoimmune paediatric liver disease

    Institute of Scientific and Technical Information of China (English)

    Giorgina Mieli-Vergani; Diego Vergani

    2008-01-01

    Liver disorders with a likely autoimmune pathogenesis in childhood include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC),and de novo AIH after liver transplantation.AIH is divided into two subtypes according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA,type 1) or liver kidney microsomal antibody (LKM1,type 2).There is a female predominance in both.LKM1 positive patients tend to present more acutely,at a younger age,and commonly have partial IgA deficiency,while duration of symptoms before diagnosis,clinical signs,family history of autoimmunity, presence of associated autoimmune disorders,response to treatment,and long-term prognosis are similar in both groups. The most common type of paediatric sclerosing cholangitis is ASC.The clinical,biochemical, immunological,and histological presentation of ASC is often indistinguishable from that of AIH type 1.In both,there are high IgG,non-organ specific autoantibodies,and interface hepatitis.Diagnosis is made by cholangiography.Children with ASC respond to immunosuppression satisfactorily and similarly to AIH in respect to remission and relapse rates,times to normalization of biochemical parameters, and decreased inflammatory activity on follow up liver biopsies. However,the cholangiopathy can progress.There may be evolution from AIH to ASC over the years,despite treatment.De novo AIH after liver transplantation affects patients not transplanted for autoimmune disorders and is strikingly reminiscent of classical AIH,including elevated titres of serum antibodies, hypergammaglobulinaemia,and histological findings of interface hepatitis,bridging fibrosis,and collapse.Like classical AIH,it responds to treatment with prednisolone and azathioprine.De novo AIH post liver transplantation may derive from interference by calcineurin inhibitors with the intrathymic physiological mechanisms of T-cell maturation and selection.Whether this condition is a distinct entity or a form of

  8. Pancreatic islet-specific T-cell clones from nonobese diabetic mice.

    OpenAIRE

    Haskins, K; Portas, M; Bergman, B.; Lafferty, K; Bradley, B

    1989-01-01

    We have produced a panel of islet-specific T-cell clones from nonobese diabetic (NOD) mice. These clones proliferate and make interleukin 2 in an antigen-specific manner in response to NOD antigen-presenting cells and islet cells. Most of the clones respond to islet-cell antigen from different mouse strains but only in the presence of antigen-presenting cells bearing the class II major histocompatibility complex of the NOD mouse. In vivo, the clones mediate the destruction of islet, but not p...

  9. 成人隐匿性自身免疫性糖尿病早期血浆SERPING1的变化及意义%Clinical Significance of Plasma Protease C1 Inhibitor in Latent Autoimmune Diabetes in Adults

    Institute of Scientific and Technical Information of China (English)

    秦雯; 张佳俐; 夏宁

    2014-01-01

    Objective To examine plasma levels of protease C1 inhibitor (SERPING1) in adult patients with latent autoimmune diabetes (LADA), and their clinical significance thereof. Methods The levels of SERPING1 were detected and compared between LADA, type 1 diabetes (T1DM), type 2 diabetes (T2DM) and healthy control groups. The correlation between plasma levels of SERPING1 and other clinical indicators such as age, disease course, glycosylated hemoglobin (HbA1c), fasting blood glucose (FPG), 2 h postprandial plasma glucose (2 hPG), fasting c-peptide (FCP) and 2 h postprandi-al C peptide (2 hCP) was analyzed. Multi-factor regression analysis and receiver operating characteristic (ROC) were used to evaluate the predictive effect of SERPING1 in LADA at the early stage. Results The level of SERPING1 was significantly higher in LADA group than that of T2DM group and control group (P < 0.05). There was a negative correlation between SERPING1 and FCP, and a positive correlation between SERPING1 and HbA1c, FPG and 2 hPG (P<0.05). There were no significant correlation between SERPING1 and age, disease course and 2 hCP. FCP was analyzed by regression equation (P<0.05), and which was the main influence factor of the plasma level of SERPING1. The area under the ROC curve (AUC) of SERPING1 was 0.613 (P<0.05), 95%CI 0.514-0.712. The optimal cut-point of SERPING1 for early prediction of LADA was 289.71 mg/L, and the sensitivity and specificity were 69%and 48%respectively. Conclusion SERPING1 combined with other indicators will be useful for identifying LADA from T2DM at the early stage.%目的:检测成人隐匿性自身免疫性糖尿病(LADA)患者早期血浆中C1酯酶抑制物(SERPING1)的水平,探讨其临床意义。方法检测LADA组患者SERPING1水平,并与1型糖尿病(T1DM)组、2型糖尿病(T2DM)组和正常对照组进行比较。对SERPING1与年龄、病程、糖化血红蛋白(HbA1c)、空腹血糖(FPG)、餐后2 h血糖(2 hPG

  10. Cytokines and Cytokine Profiles in Human Autoimmune Diseases and Animal Models of Autoimmunity

    Directory of Open Access Journals (Sweden)

    Manfred Kunz

    2009-01-01

    Full Text Available The precise pathomechanisms of human autoimmune diseases are still poorly understood. However, a deepened understanding of these is urgently needed to improve disease prevention and early detection and guide more specific treatment approaches. In recent years, many new genes and signalling pathways involved in autoimmunity with often overlapping patterns between different disease entities have been detected. Major contributions were made by experiments using DNA microarray technology, which has been used for the analysis of gene expression patterns in chronic inflammatory and autoimmune diseases, among which were rheumatoid arthritis, systemic lupus erythematosus, psoriasis, systemic sclerosis, multiple sclerosis, and type-1 diabetes. In systemic lupus erythematosus, a so-called interferon signature has been identified. In psoriasis, researchers found a particular immune signalling cluster. Moreover the identification of a new subset of inflammatory T cells, so-called Th17 T cells, secreting interleukin (IL-17 as one of their major cytokines and the identification of the IL-23/IL-17 axis of inflammation regulation, have significantly improved our understanding of autoimmune diseases. Since a plethora of new treatment approaches using antibodies or small molecule inhibitors specifically targeting cytokines, cellular receptors, or signalling mechanisms has emerged in recent years, more individualized treatment for affected patients may be within reach in the future.

  11. A case of polyglandular autoimmune syndrome type III complicated with autoimmune hepatitis.

    Science.gov (United States)

    Oki, Kenji; Yamane, Kiminori; Koide, Junko; Mandai, Koichi; Nakanishi, Shuhei; Fujikawa, Rumi; Kohno, Nobuoki

    2006-10-01

    A 58-year-old woman complaining of finger tremor was referred to our hospital. The diagnosis of Graves' disease was made based on increased free triiodothyronine (18.88 pg/ml) and free thyroxine (7.47 ng/dl), low TSH (TSH receptor binding antibody activity (70.9%). Serum level of AST (62 U/l) and ALT (93 U/l) were increased and liver biopsy revealed linkage of adjacent portal areas by lymphoplasmacytic infiltrates and fibrosis with piecemeal necrosis. Although antinuclear antibody was negative, these findings indicated that she had autoimmune hepatitis (AIH) according to the criteria of the International Autoimmune Hepatitis Scoring System. Slowly progressive type 1 diabetes mellitus (DM) was confirmed by a diabetic response pattern due to 75 g-oral glucose tolerance test, and seropositivity towards anti-glutamic acid decarboxylase (725 U/ml) and islet cell (80 JDF Units) antibodies. This case exhibited an extremely rare combination of three different autoimmune diseases, including Graves' disease, slowly progressive type 1 DM and AIH, and had no known sensitive human leukocyte antigen (HLA) typing or haplotype for these disorders. Although it is common for patients with Graves' disease to exhibit abnormal liver function, it is important to make an accurate diagnosis of AIH because of this life-threatening disorder. PMID:16946565

  12. Autoimmune polyglandular syndrome, type 2 associated with myasthenia gravis

    Directory of Open Access Journals (Sweden)

    Pejin Radoslav

    2012-01-01

    Full Text Available Introduction. Autoimmune polyglandular syndrome type 2 is defined as adrenal insufficiency associated with autoimmune primary hypothyroidism and/or with autoimmune type 1 diabetes mellitus, but very rare with myasthenia gravis. Case report. We presented a case of an autoimmune polyglandular syndrome, type 2 associated with myasthenia gravis. A 49-year-old female with symptoms of muscle weakness and low serum levels of cortisol and aldosterone was already diagnosed with primary adrenal insufficiency. Primary hypothyroidism was identified with low values of free thyroxine 4 (FT4 and raised values of thyroidstumulating hormone (TSH. The immune system as a cause of hypothyroidism was confirmed by the presence of thyroid antibodies to peroxidase and TSH receptors. Myasthenia gravis was diagnosed on the basis of a typical clinical feature, positive diagnostic tests and an increased titre of antibodies against the acetylcholine receptors. It was not possible to confirm the immune nature of adrenal insufficiency by the presence of antibodies to 21- hydroxylase. The normal morphological finding of the adrenal glands was an indirect confirmation of the condition as well as the absence of other diseases that might have led to adrenal insufficiency and low levels of both serum cortisol and aldosterone. Hormone replacement therapy, anticholinergic therapy and corticosteroid therapy for myasthenia gravis improved the patient’s general state of health and muscle weakness. Conclusion. This case report indicates a need to examine each patient with an autoimmune disease carefully as this condition may be associated with another autoimmune diseases.

  13. PREVELANCE OF ANTI-TPO ANTIBODY IN TYPE-1 DIABETES AND THYROID DYSFUNCTION IN TPO ANTIBODY POSITIVE DIABET ICS

    OpenAIRE

    Ganesan; Josephine Latha

    2012-01-01

    ABSTRACT: BACKGROUND: The appearance of TPO-Abs precedes thyroid dysfunction and increases in autoimmune diseases like type1diabetes. Thyroid peroxidase (TPO) antibodies are one of the major secondary antibodies associated wi th autoimmune thyroid disease and can be used as diagnostic marker. The prevalence of thyroid auto antibodies is increased when patients have non-thyroid autoimmune diseases such as type 1 diabetes and pernicious anemia. Thyroid dysfuncti...

  14. Autoimmune polyglandular syndrome type 3 complicated by mineralocorticoid-responsive hyponatremia of the elderly

    Directory of Open Access Journals (Sweden)

    Hidekatsu Yanai

    2010-09-01

    Full Text Available We experienced the first case with autoimmune polyglandular syndrome type 3 (anti-thyroid peroxidase antibody-positive hypothyroidism and anti-glutamic acid decarboxylase antibody-positive diabetes complicated by mineralocorticoid-responsive hyponatremia of the elderly. This case is also a rare slowly progressive insulin-dependent diabetes mellitus (SPIDDM case, for which the patient has been treated for many years with sulfonylurea or glinide. Our observation also demonstrated that glucose metabolism in autoimmune diabetes such as SPIDDM is influenced by appetite, thyroid function and glucocorticoid effect.

  15. Structural and functional insights into CARDs of zebrafish (Danio rerio) NOD1 and NOD2, and their interaction with adaptor protein RIP2.

    Science.gov (United States)

    Maharana, Jitendra; Dehury, Budheswar; Sahoo, Jyoti Ranjan; Jena, Itishree; Bej, Aritra; Panda, Debashis; Sahoo, Bikash Ranjan; Patra, Mahesh Chandra; Pradhan, Sukanta Kumar

    2015-08-01

    Nucleotide-binding and oligomerization domain-containing protein 1 (NOD1) and NOD2 are cytosolic pattern-recognition receptors (PRRs) composed of an N-terminal caspase activation and recruitment domain (CARD), a central NACHT domain and C-terminal leucine-rich repeats (LRRs). They play a vital role in innate immune signaling by activating the NF-κB pathway via recognition of peptidoglycans by LRRs, and ATP-dependent self-oligomerization of NACHT followed by downstream signaling. After oligomerization, CARD/s play a crucial role in activating downstream signaling via the adaptor molecule, RIP2. Due to the inadequacy of experimental 3D structures of CARD/s of NOD2 and RIP2, and results from differential experimental setups, the RIP2-mediated CARD-CARD interaction has remained as a contradictory statement. We employed a combinatorial approach involving protein modeling, docking, molecular dynamics simulation, and binding free energy calculation to illuminate the molecular mechanism that shows the possible involvement of either the acidic or basic patch of zebrafish NOD1/2-CARD/a and RIP2-CARD in CARD-CARD interaction. Herein, we have hypothesized 'type-I' mode of CARD-CARD interaction in NOD1 and NOD2, where NOD1/2-CARD/a involve their acidic surfaces to interact with RIP2. Asp37 and Glu51 (of NOD1) and Arg477, Arg521 and Arg529 (of RIP2) were identified to be crucial for NOD1-RIP2 interaction. However, in NOD2-RIP2, Asp32 (of NOD2) and Arg477 and Arg521 (of RIP2) were anticipated to be significant for downstream signaling. Furthermore, we found that strong electrostatic contacts and salt bridges are crucial for protein-protein interactions. Altogether, our study has provided novel insights into the RIP2-mediated CARD-CARD interaction in zebrafish NOD1 and NOD2, which will be helpful to understand the molecular basis of the NOD1/2 signaling mechanism. PMID:26079944

  16. Diabetes preventive gluten-free diet decreases the number of caecal bacteria in non-obese diabetic mice

    DEFF Research Database (Denmark)

    Hansen, Axel Kornerup; Ling, Fenjung; Anne, Kaas;

    2006-01-01

    Background A gluten-free diet reduces the incidence of diabetes mellitus in non-obese diabetic (NOD) mice, but the mechanism is not known. The aim of this study was to examine the possible influence of the diet on the caecal bacterial flora, which may affect the intestinal physiology and mediate...... disease prevention. Methods Two groups of NOD mice from the age of 3 weeks were fed either a gluten-free diet or a standard diet. Each diabetic mouse, when diagnosed, along with a non-diabetic mouse from the same diet group and two nondiabetic mice from the alternate diet group were euthanized and sampled...... for classical bacteriological examination. Results Nine out of 19 (47%) standard-fed mice and 1 out of 19 (5%) gluten-free-fed mice developed diabetes (p < 0.01). Mice on the gluten-free diet had significantly fewer aerobically (p < 0.01) and microaerophilically (p < 0.001) cultivated bacteria in...

  17. Update on autoimmune hepatitis

    Institute of Scientific and Technical Information of China (English)

    Andreas Teufel; Peter R Galle; Stephan Kanzler

    2009-01-01

    Autoimmune hepatitis (AIH) is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features, hyperglobulinemia (IgG), and the presence of circulating autoantibodies, as well as a response to immunosuppressant drugs. Current treatment consists of prednisone and azathioprine and in most patients this disease has become very treatable. Over the past 2 years, a couple of new insights into the genetic aspects, clinical course and treatment of AIH have been reported, which will be the focus of this review. In particular, we concentrate on genome-wide microsatellite analysis, a novel mouse model of AIH, the evaluation of a large AIH cohort for overlap syndromes,suggested novel criteria for the diagnosis of AIH, and the latest studies on treatment of AIH with budenoside and mycophenolate mofetil.

  18. MDSC in Autoimmunity

    OpenAIRE

    Cripps, James G.; Gorham, James D.

    2011-01-01

    Myeloid derived suppressor cells (MDSC) were first described nearly two decades ago. Until recently, however, descriptions of MDSC populations were found almost exclusively in animal models of cancer or in cancer patients. Over the last few years, an increasing number of reports have been published describing populations of myeloid cells with MDSC-like properties in murine models of autoimmune disease. In contrast to the proposed deleterious role of MDSC in cancer - where these cells likely i...

  19. [Diagnostics of autoimmune diseases].

    Science.gov (United States)

    Beleznay, Zsuzsanna; Regenass, Stephan

    2008-09-01

    Autoantibodies play a key role in diagnostic laboratories as markers of autoimmune diseases. In addition to their role as markers they mediate diverse effects in vivo. Autoantibodies with protective effect have been described. Natural protective IgM autoantibodies against tumour-antigens of malignant cells or their precursors may contribute to increased survival rates of carcinoma patients. In a mouse model of systemic lupus erythematosus it has been shown that anti-dsDNA IgM autoantibodies protect from glomerular damage. In contrast, a direct pathogenic role of autoantibodies has been well established e.g. in myasthenia gravis or in Goodpasture syndrome. Similarly autoantibodies against SSA Ro52 are detrimental in neonatal lupus erythematosus with congenital heart block. Moreover, putatively protective autoantibodies may become pathogenic during the course of the disease such as the onconeuronal autoantibodies whose pathogenicity depends on their compartmentalisation. In patients with paraneoplastic syndromes tumour cells express proteins that are also naturally present in the brain. Anti-tumour autoantibodies which temporarily suppress tumour growth can provoke an autoimmune attack on neurons once having crossed the blood-brain barrier and cause specific neurological symptoms. Only a restricted number of autoantibodies are useful follow-up markers for the effectiveness of treatment in autoimmune diseases. Certain autoantibodies hold prognostic value and appear years or even decades before the diagnosis of disease such as the antimitochondrial antibodies in primary biliary cirrhosis or anti-citrullinated protein (CCP)-antibodies in rheumatoid arthritis. It is crucial to know whether the autoantibodies in question recognise linear or conformational epitopes in order to choose the appropriate detection methods. Indirect immunofluorescence microscopy remains a very useful tool for confirmation of results of commercially available immunoassays and for detection of

  20. Functions of NOD-Like Receptors in Human Diseases

    OpenAIRE

    Zhong, Yifei; Kinio, Anna; Saleh, Maya

    2013-01-01

    Nucleotide-binding and oligomerization domain NOD-like receptors (NLRs) are highly conserved cytosolic pattern recognition receptors that perform critical functions in surveying the intracellular environment for the presence of infection, noxious substances, and metabolic perturbations. Sensing of these danger signals by NLRs leads to their oligomerization into large macromolecular scaffolds and the rapid deployment of effector signaling cascades to restore homeostasis. While some NLRs operat...

  1. Autoimmune Progesterone Anaphylaxis

    Directory of Open Access Journals (Sweden)

    Mohammad Hassan Bemanian

    2007-06-01

    Full Text Available Progesterone induced dermatitis is a rare disorder. It typically occurs in females due to anautoimmune phenomenon to endogenous progesterone production, but can also be caused byexogenous intake of a synthetic progestin. Here in, we present a case of autoimmune progesterone anaphylaxis (AIPA observed in an adolescent female.The patient is an 18-year-old Caucasian female with no significant past medical history and noprior exogenous hormone use, who presented to her primary care physician complaining of cyclic skin eruptions with dyspnea, cough and respiratory distress. She noted that her symptoms occurred monthly, just prior to her menses. An intradermal skin test using 0.1 cml of progesterone was performed. The patient developed a 15mm wheal after 15 minutes, confirming the diagnosis of AIPA.The patient was started on a continuous regimen of an oral conjugated estrogen (0.625mg. The skin eruptions and respiratory symptoms have not returned since the initiation of this therapy.Autoimmune progesterone dermatitis manifests via the occurrence of cyclic skin eruptions.Women with the disorder commonly present with dermatologic lesions in the luteal phase of themenstrual cycle, if there are any other organ involvement in addition to skin (e.g. lung, GI thereaction should be called as autoimmune progesterone anaphylaxis. Diagnosis of AIPA is confirmed by performing a skin allergen test using progesterone.

  2. Autoimmune polyglandular syndrome type 3 with anorexia.

    Science.gov (United States)

    Kahara, Toshio; Wakakuri, Hitomi; Takatsuji, Juri; Motoo, Iori; Shima, Kosuke R; Ishikura, Kazuhide; Usuda, Rika; Noda, Yatsugi

    2012-01-01

    A 71-year-old man with diabetes mellitus visited our hospital with complaints of anorexia and weight loss (12 kg/3 months). He had megaloblastic anemia, cobalamin level was low, and autoantibody to intrinsic factor was positive. He was treated with intramuscular cyanocobalamin, and he was able to consume meals. GAD autoantibody and ICA were positive, and he was diagnosed with slowly progressive type 1 diabetes mellitus (SPIDDM). Thyroid autoantibodies were positive. According to these findings, he was diagnosed with autoimmune polyglandular syndrome type 3 with SPIDDM, pernicious anemia, and Hashimoto's thyroiditis. Extended periods of cobalamin deficiency can cause serious complications such as ataxia and dementia, and these complications may not be reversible if replacement therapy with cobalamin is delayed. Although type 1 diabetes mellitus with coexisting pernicious anemia is very rare in Japan, physicians should consider the possibility of pernicious anemia when patients with diabetes mellitus have cryptogenic anorexia with the finding of significant macrocytosis (MCV > 100 fL). PMID:23304573

  3. Fetal Hox11 expression patterns predict defective target organs: a novel link between developmental biology and autoimmunity

    OpenAIRE

    Lonyai, Anna; Kodama, Shohta; Burger, Douglas; Faustman, Denise L.

    2008-01-01

    Developmental biology has long been ignored in the etiology and diverse manifestations of autoimmune diseases. Yet a role for development is suggested by intriguing overlaps in particular organs targeted in autoimmune diseases, in this case type 1 diabetes and Sjogren’s syndrome. Patients with type 1 diabetes have high rates of co-occurring Sjogren’s syndrome, and both conditions are associated with hearing loss and tongue abnormalities. All of these co-occurrences are found in organs tracing...

  4. Autoimmune thyroid disease and other non-endocrine autoimmune diseases

    OpenAIRE

    Todorović-Đilas Ljiljana; Ičin Tijana; Novaković-Paro Jovanka; Bajkin Ivana

    2011-01-01

    Introduction, Autoimmune diseases are chronic conditions initiated by the loss of immunological tolerance to self-antigens. They constitute heterogeneous group of disorders, in which multiple alterations in the immune system result in a spectrum of syndromes that either target specific organs or affect the body systematically. Recent epidemiological studies have shown a possible shift of one autoimmune disease to another or the fact that more than one autoimmune disease may coexist in a...

  5. Inflammatory Bowel Disease: Autoimmune or Immune-mediated Pathogenesis?

    Directory of Open Access Journals (Sweden)

    Zhonghui Wen

    2004-01-01

    Full Text Available The pathogenesis of Crohn's disease (CD and ulcerative colitis (UC, the two main forms of inflammatory bowel disease (IBD, is still unclear, but both autoimmune and immune-mediated phenomena are involved. Autoimmune phenomena include the presence of serum and mucosal autoantibodies against intestinal epithelial cells in either form of IBD, and against human tropomyosin fraction five selectively in UC. In addition, perinuclear antineutrophil cytoplasmic antibodies (pANCA are common in UC, whereas antibodies against Saccharomyces cerevisiae (ASCA are frequently found in CD. Immune-mediate phenomena include a variety of abnormalities of humoral and cell-mediated immunity, and a generalized enhanced reactivity against intestinal bacterial antigens in both CD and UC. It is currently believed that loss of tolerance against the indigenous enteric flora is the central event in IBD pathogenesis. Various complementary factors probably contribute to the loss of tolerance to commensal bacteria in IBD. They include defects in regulatory T-cell function, excessive stimulation of mucosal dendritic cells, infections or variants of proteins critically involved in bacterial antigen recognition, such as the products of CD-associated NOD2/CARD15 mutations.

  6. The Ubiquitin Ligase XIAP Recruits LUBAC for NOD2 Signaling in Inflammation and Innate Immunity

    DEFF Research Database (Denmark)

    Damgaard, Rune Busk; Nachbur, Ueli; Yabal, Monica;

    2012-01-01

    -linked lymphoproliferative syndrome type-2 (XLP-2). Here, we demonstrate that the RING domain of XIAP is essential for NOD2 signaling and that XIAP contributes to exacerbation of inflammation-induced hepatitis in experimental mice. We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly...... signaling. We conclude that XIAP and LUBAC constitute essential ubiquitin ligases in NOD2-mediated inflammatory signaling and propose that deregulation of NOD2 signaling contributes to XLP-2 pathogenesis....

  7. Mycobacterial heat shock protein 65 and experimental autoimmune uveitis

    Institute of Scientific and Technical Information of China (English)

    杨俊杰

    2010-01-01

    @@ Uveitis, common cause of human visual disability and blindness, is an inflammatory eye disease of unknown etiology. Human autoimmune uveiti, which characterizes inflammation of different tissues of the eyes, is diverse and complex. Approximately 50% of patients with uveitis were found to occur in families in which clustering of other underlying systemic autoimmune diseases has been observed (multiplex families) such as diabetes, sarcoidosis, rheumatoid arthritis (RA), Behcet disease, multiple sclerosis (MS), and others [1-3]. Animal models of experimental autoimmune uveitis (EAU), which represent different forms of clinical uveitis, have been widely used for studying the immunopathological mechanisms of uveitis to develop preventive or therapeutic strategies because of the difficulties in obtaining tissues from a patient's inflamed eye for experiments [4].

  8. A Retrospective Longitudinal Cohort Study of Antihypertensive Drug Use and New-Onset Diabetes in Taiwanese Patients

    Directory of Open Access Journals (Sweden)

    Ching-Ya Huang

    2013-01-01

    Full Text Available Antihypertensive drugs have been linked to new-onset diabetes (NOD; however, data on the effect of these drugs on the development of NOD in hypertensive patients has not been well determined in a clinical setting. The aim was to investigate the association between antihypertensive drugs and NOD in Taiwan. We conducted a retrospective study of hypertensive Taiwanese patients receiving antihypertensive drugs treatment between January 2006 and December 2011. Clinical information and laboratory parameters were collected by reviewing the medical records. We estimated the odds ratios (ORs of NOD associated with antihypertensive drug use; nondiabetic subjects served as the reference group. A total of 120 NOD cases were identified in 1001 hypertensive patients during the study period. The risk of NOD after adjusting sex, age, baseline characteristics, and lipid profiles was higher among users of thiazide diuretics (OR, 1.65; 95% confidence interval (CI, 1.12–2.45 and nondihydropyridine (non-DHP calcium channel blockers (CCBs (OR, 1.96; 95% CI, 1.01–3.75 than among nonusers. Other antihypertensive drug classes were not associated with risk of NOD. Our results show that patients with hypertension who take thiazide diuretics and non-DHP CCBs are at higher risk of developing NOD than those who take other classes of antihypertensive drugs in Taiwan.

  9. Evidence for the involvement of NOD2 in regulating colonic epithelial cell growth and survival

    Institute of Scientific and Technical Information of China (English)

    Sheena M Cruickshank; Louise Wakenshaw; John Cardone; Peter D Howdle; Peter J Murray; Simon R Carding

    2008-01-01

    AIM: To investigate the function of NOD2 in colonic epithelial cells (CEC).METHODS: A combination of in vivo and in vitro analyses of epithelial cell turnover in the presence and absence of a functional NOD2 protein and, in response to enteric Salmonella typhimurium infection, were used. shRNA interference was also used to investigate the consequences of knocking down NOD2 gene expression on the growth and survival of colorectal carcinoma cell lines.RESULTS: In the colonic mucosa the highest levels of NOD2 expression were in proliferating crypt epithelial cells. Muramyl dipeptide (MDP), that is recognized by NOD2, promoted CEC growth in vitro. By contrast, the growth of NOD2-deficient CECs was impaired. In vivo CEC proliferation was also reduced and apoptosis increased in Nod2-/- mice, which were also evident following enteric Salmonella infection. Furthermore, neutralization of NOD2 mRNA expression in human colonic carcinoma cells by shRNA interference resulted in decreased survival due to increased levels of apoptosis.CONCLUSION: These findings are consistent with the involvement of NOD2 protein in promoting CEC growth and survival. Defects in proliferation by CECs in cases of CD may contribute to the underlying pathology of disrupted intestinal homeostasis and excessive inflammation.

  10. Autoimmune Thyroid Diseases in Children

    OpenAIRE

    Francesca Crea; Carla Bizzarri; Marco Cappa

    2011-01-01

    The two major autoimmune thyroid diseases (ATDs) include Graves' disease (GD) and autoimmune thyroiditis (AT); both of which are characterized by infiltration of the thyroid by T and B cells reactive to thyroid antigens, by the production of thyroid autoantibodies and by abnormal thyroid function (hyperthyroidism in GD and hypothyroidism in AT). While the exact etiology of thyroid autoimmunity is not known, it is believed to develop when a combination of genetic susceptibility and environment...

  11. New insights into disease-specific absence of complement factor H related protein C in mouse models of spontaneous autoimmune diseases.

    Science.gov (United States)

    Mehta, Gaurav; Ferreira, Viviana P; Skerka, Christine; Zipfel, Peter F; Banda, Nirmal K

    2014-11-01

    Complement factor H (CFH) protein is an inhibitor of the alternative pathway of complement (AP) both in the fluid phase and on the surface of host cells. Mouse and human complement factor H-related (CFHR) proteins also belong to the fH family of plasma glycoproteins. The main goal of the current study was to compare the presence of mRNA for two mCFHR proteins in spontaneously developing autoimmune diseases in mice such as dense deposit disease (DDD), diabetes mellitus (DM), basal laminar deposits (BLD), collagen antibody-induced arthrits (CAIA) and systemic lupus erythematosus (SLE). Here we report for the first time that the CFHR-C mRNA was universally absent in the liver from three strains of lupus-prone mice and in a diabetic-prone mouse strain. The mRNA levels (pg/ng) for CFH and CFHR-B in MRL-lpr/lpr, at 9 wks and 23 wks were 707.2±44.4, 54.5±5.75 and 729±252.9, 74.04±22.76, respectively. The mRNA levels for CFH and CFHR-B in NZB/NZW mice, at 9 wks and 54 wks were 579.9±23.8, 58.8±1.41 and 890.3±135.2, 63.30±9.2, respectively. CFHR-C protein was absent in the circulation of MRL-lpr/lpr and NZB/NZW mice before and after the development of lupus. Similarly, mRNA and protein for CFHR-C was universally absent in liver and other organs and in the circulation of NOD mice before and after the development of DM. In contrast, the mRNAs for CFH, CFHR-B and CFHR-C were universally present in the liver from mice with and without DDD, BLD and CAIA. The levels of mRNA for CFHR-B in mice with and without BLD were ∼4 times higher than the mice with lupus. The complete absence of mRNA for CFHR-C in lupus and diabetic-prone strains indicates that polymorphic variation within the mouse CFHR family exists and raises the possibility that such variation contributes to lupus and diabetic phenotypes. PMID:25033230

  12. Implication of NOD1 and NOD2 for the differentiation of multipotent mesenchymal stem cells derived from human umbilical cord blood.

    Directory of Open Access Journals (Sweden)

    Hyung-Sik Kim

    Full Text Available Toll-like receptors (TLRs and Nod-like receptors (NLRs are known to trigger an innate immune response against microbial infection. Although studies suggest that activation of TLRs modulate the function of mesenchymal stem cells (MSCs, little is known about the role of NLRs on the MSC function. In this study, we investigated whether NOD1 and NOD2 regulate the functions of human umbilical cord blood-derived MSCs (hUCB-MSCs. The genes of TLR2, TLR4, NOD1, and NOD2 were expressed in hUCB-MSCs. Stimulation with each agonist (Pam(3CSK(4 for TLR2, LPS for TLR4, Tri-DAP for NOD1, and MDP for NOD2 led to IL-8 production in hUCB-MSC, suggesting the expressed receptors are functional in hUCB-MSC. CCK-8 assay revealed that none of agonist influenced proliferation of hUCB-MSCs. We next examined whether TLR and NLR agonists affect osteogenic-, adipogenic-, and chondrogenic differentiation of hUCB-MSCs. Pam(3CSK(4 and Tri-DAP strongly enhanced osteogenic differentiation and ERK phosphorylation in hUCB-MSCs, and LPS and MDP also slightly did. Treatment of U0126 (MEK1/2 inhibitor restored osteogenic differentiation enhanced by Pam(3CSK(4. Tri-DAP and MDP inhibited adipogenic differentiation of hUCB-MSCs, but Pam(3CSK(4 and LPS did not. On chondrogenic differentiation, all TLR and NLR agonists could promote chondrogenesis of hUCB-MSCs with difference in the ability. Our findings suggest that NOD1 and NOD2 as well as TLRs are involved in regulating the differentiation of MSCs.

  13. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases

    OpenAIRE

    Lenz, Tobias L.; Deutsch, Aaron J.; Han, Buhm; Hu, Xinli; Okada, Yukinori; Eyre, Stephen; Knapp, Michael; Zhernakova, Alexandra; Huizinga, Tom W. J.; Abecasis, Gonçalo; Becker, Jessica; Boeckxstaens, Guy; Chen, Wei-Min; Franke, Andre; Gladman, Dafna D

    2015-01-01

    Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases...

  14. Autoimmune diseases in Adult Life after Childhood Cancer in Scandinavia (ALiCCS)

    DEFF Research Database (Denmark)

    Holmqvist, Anna Sällfors; Olsen, Jørgen H.; Mellemkjaer, Lene;

    2015-01-01

    all autoimmune diseases combined, corresponding to an AER of 67 per 100 000 person-years. The SHRRs were significantly increased for autoimmune haemolytic anaemia (16.3), Addison's disease (13.9), polyarteritis nodosa (5.8), chronic rheumatic heart disease (4.5), localised scleroderma (3......OBJECTIVES: The pattern of autoimmune diseases in childhood cancer survivors has not been investigated previously. We estimated the risk for an autoimmune disease after childhood cancer in a large, population-based setting with outcome measures from comprehensive, nationwide health registries.......6), idiopathic thrombocytopenic purpura (3.4), Hashimoto's thyroiditis (3.1), pernicious anaemia (2.7), sarcoidosis (2.2), Sjögren's syndrome (2.0) and insulin-dependent diabetes mellitus (1.6). The SHRRs for any autoimmune disease were significantly increased after leukaemia (SHRR 1.6), Hodgkin's lymphoma (1...

  15. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers

    DEFF Research Database (Denmark)

    Eaton, William W.; Byrne, Majella; Ewald, Henrik;

    2006-01-01

    ,704 persons in Denmark diagnosed with schizophrenia from 1981 to 1998 and their parents along with a sample of matched comparison subjects and their parents. The data linkage required that the autoimmune disease occur before the diagnosis of schizophrenia. RESULTS: A history of any autoimmune disease was......OBJECTIVE: Individuals with schizophrenia and their relatives tend to have either higher or lower than expected prevalences of autoimmune disorders, especially rheumatoid arthritis, celiac disease, autoimmune thyroid diseases, and type 1 diabetes. The purpose of the study was to estimate the...... association of schizophrenia with these disorders as well as a range of other autoimmune diseases in a single large epidemiologic study. METHOD: The Danish Psychiatric Register, the National Patient Register, and a register with socioeconomic information were linked to form a data file that included all 7...

  16. Autoimmune diseases and myelodysplastic syndromes.

    Science.gov (United States)

    Komrokji, Rami S; Kulasekararaj, Austin; Al Ali, Najla H; Kordasti, Shahram; Bart-Smith, Emily; Craig, Benjamin M; Padron, Eric; Zhang, Ling; Lancet, Jeffrey E; Pinilla-Ibarz, Javier; List, Alan F; Mufti, Ghulam J; Epling-Burnette, Pearlie K

    2016-05-01

    Immune dysregulation and altered T-cell hemostasis play important roles in the pathogenesis of myelodysplastic syndromes (MDS). Recent studies suggest an increased risk of MDS among patients with autoimmune diseases. Here, we investigated the prevalence of autoimmune diseases among MDS patients, comparing characteristics and outcomes in those with and without autoimmune diseases. From our study group of 1408 MDS patients, 391 (28%) had autoimmune disease, with hypothyroidism being the most common type, accounting for 44% (n = 171) of patients (12% among all MDS patients analyzed). Other autoimmune diseases with ≥5% prevalence included idiopathic thrombocytopenic purpura in 12% (n = 46), rheumatoid arthritis in 10% (n = 41), and psoriasis in 7% (n = 28) of patients. Autoimmune diseases were more common in female MDS patients, those with RA or RCMD WHO subtype, and those who were less dependent on red blood cell transfusion. Median overall survival (OS) was 60 months (95% CI, 50-70) for patients with autoimmune diseases versus 45 months (95% CI, 40-49) for those without (log-rank test, P = 0.006). By multivariate analysis adjusting for revised IPSS and age >60 years, autoimmune diseases were a statistically significant independent factor for OS (HR 0.78; 95% CI, 0.66-0.92; P = 0.004). The rate of acute myeloid leukemia (AML) transformation was 23% (n = 89) in MDS patients with autoimmune disease versus 30% (n = 301) in those without (P = 0.011). Patient groups did not differ in response to azacitidine or lenalidomide treatment. Autoimmune diseases are prevalent among MDS patients. MDS patients with autoimmune diseases have better OS and less AML transformation. Am. J. Hematol. 91:E280-E283, 2016. © 2016 Wiley Periodicals, Inc. PMID:26875020

  17. Coeliac disease in endocrine diseases of autoimmune origin.

    Science.gov (United States)

    Miśkiewicz, Piotr; Kępczyńska-Nyk, Anna; Bednarczuk, Tomasz

    2012-01-01

    Abstract Coeliac disease (CD, sometimes called gluten-sensitive enteropathy or nontropical sprue) is an inflammatory disorder of the small intestine of autoimmune origin. It occurs in genetically predisposed people and is induced by a gluten protein, which is a component of wheat. The prevalence of histologically confirmed CD is estimated in screening studies of adults in the United States and Europe to be between 0.2% and 1.0%. The results of previous studies have indicated that the prevalence of CD is increased in patients with other autoimmune disorders such as: autoimmune thyroid diseases, type 1 diabetes mellitus, and Addison's disease. A coincidence of the above diseases constitutes autoimmune polyglandular syndrome (APS). The high prevalence of CD in APS is probably due to the common genetic predisposition to the coexistent autoimmune diseases. The majority of adult patients have the atypical or silent type of the disease. This is the main reason why CD so often goes undiagnosed or the diagnosis is delayed. CD, if undiagnosed and untreated, is associated with many medical disorders including haematological (anaemia), metabolical (osteopenia/osteoporosis), obstetric-gynaecological (infertility, spontaneous abortions, late puberty, early menopause), neurological (migraine, ataxia, epilepsy) as well as with an increased risk of malignancy, especially: enteropathy-associated T-cell lymphoma, small intestine adenocarcinoma, and oesophageal and oropharyngeal carcinomas. Early introduction of a gluten-free diet and lifelong adherence to this treatment decreases the risk of these complications. PMID:22744631

  18. MHC class II polymorphisms, autoreactive T-cells and autoimmunity

    Directory of Open Access Journals (Sweden)

    Sue eTsai

    2013-10-01

    Full Text Available Major histocompatibility complex (MHC genes, also known as human leukocyte antigen genes (HLA in humans, are the prevailing contributors of genetic susceptibility to autoimmune diseases such as Type 1 Diabetes (T1D, Multiple Sclerosis (MS, and Rheumatoid arthritis (RA, among others (Todd and Wicker, 2001;MacKay et al., 2002;Hafler et al., 2007. Although the pathways through which MHC molecules afford autoimmune risk or resistance remain to be fully mapped out, it is generally accepted that they do so by shaping the central and peripheral T cell repertoires of the host towards autoimmune proclivity or resistance, respectively. Disease-predisposing MHC alleles would both spare autoreactive thymocytes from central tolerance and bias their development towards a pathogenic phenotype. Protective MHC alleles, on the other hand, would promote central deletion of autoreactive thymocytes and skew their development towards non-pathogenic phenotypes. This interpretation of the data is at odds with two other observations: that in MHC-heterozygous individuals, resistance is dominant over susceptibility; and that it is difficult to understand how deletion of one or a few clonal autoreactive T cell types would suffice to curb autoimmune responses driven by hundreds if not thousands of autoreactive T cell specificities. This review provides an update on current advances in our understanding of the mechanisms underlying MHC class II-associated autoimmune disease susceptibility and/or resistance and attempts to reconcile these seemingly opposing concepts.

  19. NOD2 is highly expressed in Behçet disease with pulmonary manifestations

    Directory of Open Access Journals (Sweden)

    Hamzaoui Kamel

    2012-02-01

    Full Text Available Abstract Background Excessive Th1 cells and TLRs functions are involved in the pathogenesis of Behcet's disease (BD in response to bacterial antigens. NOD2, an intracellular pathogen recognition sensor, modulates innate defence to muropeptides derived from various bacterial species. To further define a role for NOD2 in BD, we analysed NOD2 transcriptional responses in BAL-MNC from BD patients with pulmonary manifestations. Methods We analysed NOD1, NOD2, T-bet and TLRs mRNA expression with real-time polymerase chain-reaction in BAL cells obtained from 23 BD patients with pulmonary manifestations and their matched controls. Results We found that NOD2 mRNA expression was highly up-regulated in BAL cells from BD and sarcoidosis patients compared to healthy control group (P = 0.001. In BD patients, significant correlation was found between NOD2 and T-bet mRNA expression (r = 0.602; P = 0.0009. In BAL from BD patients, NOD2 and T-bet mRNA expression were significantly correlated with BAL-lymphocytes (r = 0.485, P = 0.010; r = 0684, P = 0.0001 respectively. NOD2 in BD was also correlated with TLR 2(r = 0.444; P = 0.021 and TLR 4 (r = 0.574; P = 0.001 mRNA expression. Conclusion Our results indicate that BAL-MNC from BD patients expressed NOD2 as a result of lung inflammation. TLRs and NOD2 synergize for the induction of proinflammatory cytokines. BAL inflammatory cells showed an increased Th1 situation as indicated by increased T-bet mRNA expression.

  20. Higher susceptibility of NOD/LtSz-scid Il2rg−/− NSG mice to xenotransplanted lung cancer cell lines

    International Nuclear Information System (INIS)

    No lung cancer xenograft model using non-obese diabetic (NOD)-scid Il2rg−/− mice has been reported. The purpose of this study is to select a suitable mouse strain as a xenogenic host for testing tumorigenicity of lung cancer. We directly compared the susceptibility of four immunodeficient mouse strains, c-nu, C.B-17 scid, NOD-scid, and NOD/LtSz-scid Il2rg−/− (NSG) mice, for tumor formation from xenotransplanted lung cancer cell lines. Various numbers (101–105 cells/head) of two lung cancer cell lines, A549 and EBC1, were subcutaneously inoculated and tumor sizes were measured every week up to 12 weeks. When 104 EBC1 cells were inoculated, no tumor formation was observed in BALB/c-nu or C.B-17 scid mice. Tumors developed in two of the five NOD-scid mice (40%) and in all the five NSG mice (100%). When 103 EBC1 cells were injected, no tumors developed in any strain other than NSG mice, while tumorigenesis was achieved in all the five NSG mice (100%, P=0.0079) within 9 weeks. NSG mice similarly showed higher susceptibility to xenotransplantation of A549 cells. Tumor formation was observed only in NSG mice after inoculation of 103 or fewer A549 cells (40% vs 0% in 15 NSG mice compared with others, respectively, P=0.0169). We confirmed that the engrafted tumors originated from inoculated human lung cancer cells by immunohistochemical staining with human cytokeratin and vimentin. NSG mice may be the most suitable strain for testing tumorigenicity of lung cancer, especially if only a few cells are available

  1. Effect of iodide on Fas, Fas-ligand and Bcl-w mRNA expression in thyroid of NOD mice pretreated with methimazole

    Directory of Open Access Journals (Sweden)

    L.H.B. Boechat

    2002-03-01

    Full Text Available Nonobese diabetic (NOD mice and a derived strain, NOD.H.2h4, have been used as a model for experimental spontaneous thyroiditis and thyroiditis induced by iodide excess after a goiter-inducing period. Some authors have proposed that iodide, given after methimazole or propylthiouracil, is capable of inducing apoptosis in thyroid cells and that anti-thyroid drugs can modulate the expression of apoptosis components such as Fas and its ligand (Fas-L. Here we evaluated the effect of potassium iodide (20 µg/animal for 4 days, ip given to NOD mice at the 10th week of life after exposure to methimazole (1 mg/ml in drinking water from the 4th to the 10th week of life. Fas, Fas-L and Bcl-w expression were analyzed semiquantitatively by RT-PCR immediately after potassium iodide administration (group MI44D or at week 32 (MI32S. Control groups were added at 10 (C10 and 32 weeks (C32, as well as a group that received only methimazole (CM10. An increase in the expression of Fas-L and Bcl-w (P<0.01, ANOVA was observed in animals of group MI44D, while Fas was expressed at higher levels (P = 0.02 in group C32 (72.89 ± 47.09 arbitrary units when compared to group C10 (10.8 ± 8.55 arbitrary units. Thus, the analysis of Fas-L and Bcl-w expression in the MI44D group and Fas in group C32 allowed us to detect two different patterns of expression of these apoptosis components in thyroid tissue of NOD mice.

  2. Hepatitis C virus infection in a child with autoimmune polyendocrine syndrome type 2: a case report

    OpenAIRE

    Metwalley Kotb; Farghaly Hekma

    2012-01-01

    Abstract Introduction Autoimmune polyendocrine syndrome type 2 is a rare disorder. Its prevalence in western populations has been reported as 1.5 to 4.5/100,000. On the other hand, its prevalence in Egypt is unknown. It is characterized by the association of autoimmune Addison’s disease with thyroid autoimmune diseases and/or type I diabetes mellitus. Hepatitis C virus infection is an important public health issue worldwide. Egypt has the highest prevalence of hepatitis C virus infection of a...

  3. The role of parvovirus B19 in the pathogenesis of autoimmunity and autoimmune disease.

    Science.gov (United States)

    Kerr, Jonathan R

    2016-04-01

    Human parvovirus B19 is a single-stranded DNA virus which preferentially targets the erythroblasts in the bone marrow. B19 infection commonly causes erythema infectiosum, arthralgia, fetal death, transient aplastic crisis in patients with shortened red cell survival, and persistent infection in people who are immunocompromised. Less common clinical manifestations include atypical skin rashes, neurological syndromes, cardiac syndromes, and various cytopenias. B19 infection has also been associated with development of a variety of different autoimmune diseases, including rheumatological, neurological, neuromuscular, cardiovascular, haematological, nephrological and metabolic. Production of a variety of autoantibodies has been demonstrated to occur during B19 infection and these have been shown to be key to the pathogenesis of the particular disease process in a significant number of cases, for example, production of rheumatoid factor in cases of B19-associated rheumatoid arthritis and production of anti-glutamic acid decarboxylase (GAD) in patients with B19-associated type 1 diabetes mellitus. B19 infection has also been associated with the development of multiple autoimmune diseases in 12 individuals. Documented mechanisms in B19-associated autoimmunity include molecular mimicry (IgG antibody to B19 proteins has been shown to cross react with a variety of recognised human autoantigens, including collagen II, keratin, angiotensin II type 1 receptor, myelin basic protein, cardiolipin, and platelet membrane glycoprotein IIb/IIIa), B19-induced apoptosis with presentation of self-antigens to T lymphocytes, and the phospholipase activity of the B19 unique VP1 protein. PMID:26644521

  4. Mast Cell and Autoimmune Diseases

    OpenAIRE

    Yunzhi Xu; Guangjie Chen

    2015-01-01

    Mast cells are important in innate immune system. They have been appreciated as potent contributors to allergic reaction. However, increasing evidence implicates the important role of mast cells in autoimmune disease like rheumatoid arthritis and multiple sclerosis. Here we review the current stage of knowledge about mast cells in autoimmune diseases.

  5. Antinuclear antibodies defining autoimmunity pathways

    OpenAIRE

    Tan, Eng M.

    2014-01-01

    Immunofluorescent imaging has been a powerful technique in helping to identify intracellular nuclear and cytoplasmic molecules which are target antigens of autoantibodies in systemic autoimmune disorders. Patterns of staining can be correlated with molecules engaged in specific cellular functions and distributed in distinct cellular domains. Different autoimmune disorders have different profiles of autoantibodies, and immunodiagnostics has become an important adjunct in differential diagnosis...

  6. Inhibition of Nod2 signaling and target gene expression by curcumin

    Science.gov (United States)

    Nod2 is an intracellular pattern recognition receptor that detects a conserved moiety of bacterial peptidoglycan and subsequently activates proinflammatory signaling pathways. Mutations in Nod2 have been implicated to be linked to inflammatory granulomatous disorders, such as Crohn’s disease and Bla...

  7. Nod2 suppresses Borrelia burgdorferi mediated murine Lyme arthritis and carditis through the induction of tolerance.

    Directory of Open Access Journals (Sweden)

    Tanja Petnicki-Ocwieja

    Full Text Available The internalization of Borrelia burgdorferi, the causative agent of Lyme disease, by phagocytes is essential for an effective activation of the immune response to this pathogen. The intracellular, cytosolic receptor Nod2 has been shown to play varying roles in either enhancing or attenuating inflammation in response to different infectious agents. We examined the role of Nod2 in responses to B. burgdorferi. In vitro stimulation of Nod2 deficient bone marrow derived macrophages (BMDM resulted in decreased induction of multiple cytokines, interferons and interferon regulated genes compared with wild-type cells. However, B. burgdorferi infection of Nod2 deficient mice resulted in increased rather than decreased arthritis and carditis compared to control mice. We explored multiple potential mechanisms for the paradoxical response in in vivo versus in vitro systems and found that prolonged stimulation with a Nod2 ligand, muramyl dipeptide (MDP, resulted in tolerance to stimulation by B. burgdorferi. This tolerance was lost with stimulation of Nod2 deficient cells that cannot respond to MDP. Cytokine patterns in the tolerance model closely paralleled cytokine profiles in infected Nod2 deficient mice. We propose a model where Nod2 has an enhancing role in activating inflammation in early infection, but moderates inflammation after prolonged exposure to the organism through induction of tolerance.

  8. Comparative Genomic Analysis of Buffalo (Bubalus bubalis) NOD1 and NOD2 Receptors and Their Functional Role in In-Vitro Cellular Immune Response

    OpenAIRE

    Brahma, Biswajit; Kumar, Sushil; De, Bidhan Chandra; Mishra, Purusottam; Patra, Mahesh Chandra; Gaur, Deepak; Chopra, Meenu; Gautam, Devika; Mahanty, Sourav; Malik, Hrudananda; Malakar, Dhruba; Datta, Tirtha Kumar; De, Sachinandan

    2015-01-01

    Nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) are innate immune receptors that recognize bacterial cell wall components and initiate host immune response. Structure and function of NLRs have been well studied in human and mice, but little information exists on genetic composition and role of these receptors in innate immune system of water buffalo—a species known for its exceptional disease resistance. Here, a comparative study on the functional domains of NOD1 and...

  9. Symbiotic Activity of Pea (Pisum sativum after Application of Nod Factors under Field Conditions

    Directory of Open Access Journals (Sweden)

    Anna Siczek

    2014-04-01

    Full Text Available Growth and symbiotic activity of legumes are mediated by Nod factors (LCO, lipo-chitooligosaccharides. To assess the effects of application of Nod factors on symbiotic activity and yield of pea, a two-year field experiment was conducted on a Haplic Luvisol developed from loess. Nod factors were isolated from Rhizobium leguminosarum bv. viciae strain GR09. Pea seeds were treated with the Nod factors (10−11 M or water (control before planting. Symbiotic activity was evaluated by measurements of nitrogenase activity (acetylene reduction assay, nodule number and mass, and top growth by shoot mass, leaf area, and seed and protein yield. Nod factors generally improved pea yield and nitrogenase activity in the relatively dry growing season 2012, but not in the wet growing season in 2013 due to different weather conditions.

  10. Genetic risk factors for type 1 diabetes

    DEFF Research Database (Denmark)

    Pociot, Flemming; Lernmark, Åke

    2016-01-01

    the environment is generally needed. The pathogenesis can be divided into three stages: 1, appearance of β-cell autoimmunity, normoglycaemia, and no symptoms; 2, β-cell autoimmunity, dysglycaemia, and no symptoms; and 3, β-cell autoimmunity, dysglycaemia, and symptoms of diabetes. The genetic......Type 1 diabetes is diagnosed at the end of a prodrome of β-cell autoimmunity. The disease is most likely triggered at an early age by autoantibodies primarily directed against insulin or glutamic acid decarboxylase, or both, but rarely against islet antigen-2. After the initial appearance of one of...... these autoantibody biomarkers, a second, third, or fourth autoantibody against either islet antigen-2 or the ZnT8 transporter might also appear. The larger the number of β-cell autoantibody types, the greater the risk of rapid progression to clinical onset of diabetes. This association does not...

  11. Endocrine autoimmunity in Turner syndrome

    Science.gov (United States)

    2013-01-01

    Background Turner syndrome is caused by numeric and structural abnormalities of the X chromosome. An increased frequency of autoimmunity as well as an elevated incidence of autoantibodies was observed in Turner patients. The aim of this study was to conduct a retrospective analysis of the incidence of autoimmunity in 66 Italian patients affected by Turner syndrome. Methods Sixty-six unselected and consecutive Italian Turner patients were recruited. The association between age, karyotype and the presence of clinical/pre-clinical autoimmune disorders and of autoantibodies was examined. Results Out of the 66 Turner patients, 26 had thyroid autoimmune disorders (39.4%), 14 patients had Hashimoto’s thyroiditis with clinical or subclinical hypothyroidism (21.2%) and 12 patients had circulating anti-thyroid antibodies, echographic pattern of diffuse hypoechogenicity and normal thyroid hormone levels (18.2%). None were affected by Graves’ disease. We analyzed the overall incidence of thyroid autoimmunity within the 3 different age groups 0–9.9, 10–19.9 and 20–29.9 years. No statistically significant difference was observed in the incidence of thyroid autoimmunity within the age-groups (χ2-test p > 0.05). Out of the 66 patients, 31 patients had the 45,X karyotype; within this first group 14 out of 31 patients were affected by autoimmune thyroid disease. A second group of 29 patients included 19 patients with mosaicism, 5 patients with deletions and 5 patients with ring chromosome; out of these 29 patients 7 were affected by autoimmune thyroid disease. A third group included 6 patients with X isochromosome; 5 out of 6 were affected by autoimmune thyroid disease. A statistically significant difference in the frequency of thyroid autoimmunity within the different karyotype groups was observed (χ2-test p = 0.0173). When comparing the X isochromosome group with the pooled group of other karyotypes, of note, the frequency of thyroid autoimmunity was

  12. Application of NOD/SCID Mice in Research of Experimental Hematology-Review%NOD/SCID小鼠在实验血液学研究中的应用

    Institute of Scientific and Technical Information of China (English)

    于文俊; 杨文华; 史哲新; 杨向东; 王慧娟

    2008-01-01

    NOD/SCID(非肥胖糖尿病/重症联合免疫缺陷)小鼠是在SCID(重症联合免疫缺陷)小鼠的基础上与非肥胖性糖尿病小鼠(NOD/Lt)品系回交的免疫缺陷鼠.NOD/SCID小鼠既有先天免疫缺陷,又有T和B淋巴细胞缺乏,各种肿瘤细胞可以植入,且较少发生排斥反应及移植物抗宿主病(GVHD),所以NOD/SCID小鼠逐渐成为血液学实验研究的有用工具.本文从NOD/SCID小鼠的生物学特性及其在建立人类白血病模型、干细胞移植、药物研究及NOD/SCID小鼠应用中存在的不足和改良等方面综合述评.

  13. Cannabinoids and autoimmune diseases: A systematic review.

    Science.gov (United States)

    Katchan, Valeria; David, Paula; Shoenfeld, Yehuda

    2016-06-01

    Cannabinoids have shown to have a variety effects on body systems. Through CB1 and CB2 receptors, amongst other, they exert an effect by modulating neurotransmitter and cytokine release. Current research in the role of cannabinoids in the immune system shows that they possess immunosuppressive properties. They can inhibit proliferation of leucocytes, induce apoptosis of T cells and macrophages and reduce secretion of pro-inflammatory cytokines. In mice models, they are effective in reducing inflammation in arthritis, multiple sclerosis, have a positive effect on neuropathic pain and in type 1 diabetes mellitus. They are effective as treatment for fibromyalgia and have shown to have anti-fibrotic effect in scleroderma. Studies in human models are scarce and not conclusive and more research is required in this field. Cannabinoids can be therefore promising immunosuppressive and anti-fibrotic agents in the therapy of autoimmune disorders. PMID:26876387

  14. SOCS, inflammation and autoimmunity

    Directory of Open Access Journals (Sweden)

    Akihiko eYoshimura

    2012-03-01

    Full Text Available Cytokines play essential roles in innate and adaptive immunity. However, excess cytokines or dysregulation of cytokine signaling can cause a variety of diseases, including allergies, autoimmune diseases, inflammation, and cancer. Most cytokines utilize the so-called Janus kinase-signal transducers and activators of transcription (JAK-STAT pathway. This pathway is negatively regulated by various mechanisms including suppressors of cytokine signaling (SOCS proteins. SOCS proteins bind to JAK or cytokine receptors, thereby suppressing further signaling events. Especially, SOCS1 and SOCS3 are strong inhibitors of JAK, because these two contain kinase inhibitory region (KIR at the N-terminus. Studies using conditional knockout mice have shown that SOCS proteins are key physiological as well as pathological regulators of immune homeostasis. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of helper T cell differentiation and functions.

  15. Adult autoimmune enteropathy

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Recent reports have suggested that autoimmune enteropathy involving the small bowel may occur in adults as well as in children. Apparently, the endoscopic and histological changes are similar to celiac disease before treatment, but these are not altered by any form of dietary restriction, including a gluten-free diet. As in celiac disease, histologic changes in gastric and colonic biopsies have also been recorded. Anti enterocyte antibodies detected with immunofluorescent methods have been reported by a few laboratories, but these antibodies appear not to be specific and may simply represent epiphenomena. A widely available, reproducible and quantitative anti-enterocyte antibody assay is needed that could be applied in small bowel disorders that have the histological appearance of celiac disease, but fail to respond to a gluten-free diet.

  16. Treated of type 1 diabetes mellitus in non-obese diabetic mice by transplantation of allogeneic bone marrow and pancreatic tissue

    International Nuclear Information System (INIS)

    Non-obese diabetic (NOD) mice provide a model for type 1 diabetes mellitus. We previously showed that allogeneic bone marrow transplantation (ABMT) can prevent and treat insulitis and overt diabetes in NOD mice. However, ABMT alone could not be used to treat overt diabetes in NOD mice whose islets had been completely destroyed. To provide insulin-producing cells, pancreatic tissue from newborn mice was grafted under the renal capsules in combination with ABMT. The aims of concomitant ABMT are as follows. (i) It induces immunological tolerance to the donor-type major histocompatibility complex determinants and permits the host to accept subsequent pancreatic allografts from the bone marrow donor. (ii) ABMT replaces abnormal stem cells with normal stem cells. After transplantation of bone marrow plus newborn pancreas, NOD mice showed reduction of the glycosuria and a normal response in the glucose-tolerance test. Immunohistological study revealed the presence of clustered insulin-containing beta cells in the grafted pancreatic transplants. ABMT may become a viable treatment of established type 1 diabetes mellitus in humans

  17. What caused the increase of autoimmune and allergic diseases: A decreased or an increased exposure to luminal microbial components?

    Institute of Scientific and Technical Information of China (English)

    Xiaofa Qin

    2007-01-01

    @@ TO THE EDITOR The dramatic increase of allergic and autoimmune diseases such as asthma, atopic dermatitis (eczema), allergic rhinitis, inflammatory bowel disease (IBD, including both Crohn's disease and ulcerative colitis), multiple sclerosis,and insulin-dependent diabetes mellitus (type Ⅰ diabetes)in the developed countries in the last century[1-3] is a big puzle.

  18. Tests for genetic interactions in type 1 diabetes

    DEFF Research Database (Denmark)

    Morahan, Grant; Mehta, Munish; James, Ian; Chen, Wei-Min; Akolkar, Beena; Erlich, Henry A; Hilner, Joan E; Julier, Cécile; Nerup, Jørn; Nierras, Concepcion; Pociot, Flemming; Todd, John A; Rich, Stephen S

    2011-01-01

    Interactions between genetic and environmental factors lead to immune dysregulation causing type 1 diabetes and other autoimmune disorders. Recently, many common genetic variants have been associated with type 1 diabetes risk, but each has modest individual effects. Familial clustering of type 1...... diabetes has not been explained fully and could arise from many factors, including undetected genetic variation and gene interactions....

  19. Animal Models of Diabetic Neuropathy: Progress Since 1960s

    Directory of Open Access Journals (Sweden)

    Md. Shahidul Islam

    2013-01-01

    Full Text Available Diabetic or peripheral diabetic neuropathy (PDN is one of the major complications among some other diabetic complications such as diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy. The use of animal models in the research of diabetes and diabetic complications is very common when rats and mice are most commonly used for many reasons. A numbers of animal models of diabetic and PDN have been developed in the last several decades such as streptozotocin-induced diabetic rat models, conventional or genetically modified or high-fat diet-fed C57BL/Ks (db/db mice models, streptozotocin-induced C57BL6/J and ddY mice models, Chinese hamster neuropathic model, rhesus monkey PDN model, spontaneously diabetic WBN/Kob rat model, L-fucose-induced neropathic rat model, partial sciatic nerve ligated rat model, nonobese diabetic (NOD mice model, spontaneously induced Ins2 Akita mice model, leptin-deficient (ob/ob mice model, Otsuka Long-Evans Tokushima Fatty (OLETF rat model, surgically-induced neuropathic model, and genetically modified Spontaneously Diabetic Torii (SDT rat model, none of which are without limitations. An animal model of diabetic or PDN should mimic the all major pathogeneses of human diabetic neuropathy. Hence, this review comparatively evaluates the animal models of diabetic and PDN which are developed since 1960s with their advantages and disadvantages to help diabetic research groups in order to more accurately choose an appropriate model to meet their specific research objectives.

  20. Cytosolic proteins NODs involved in the regulation of immune and inflammatory responses%参与免疫及炎症反应调控的胞浆蛋白NODs

    Institute of Scientific and Technical Information of China (English)

    胡巢凤

    2004-01-01

    Nucleotide- binding oligomerization domain (NOD) proteins are members of a growing family of cytosolic factors related to the apoptosis regulator Apaf-1 and a class of plant disease resistance proteins. NOD proteins have been implicated in the induction of NF-κB activity and in the activation of caspases. Biochemical evidence has unraveled the role of NOD1 and NOD2 as intraceUular sensors of bacterial peptidoglycan. Notably, genetic variation in the genes encoding the NOD proteins NOD2, cryopyrin and C Ⅱ TA inhmnans is associated with inflammatory disease or increased susceptibility to bacterial infections. NOD proteins may be involved in the recognition of microorganisms and regulation of inflammatory responses.

  1. The role of melatonin in autoimmune and atopic diseases

    Directory of Open Access Journals (Sweden)

    J.R. Calvo

    2016-04-01

    Full Text Available Melatonin is the main secretory product synthesized and secreted by the pineal gland during the night. Melatonin is a pleitropic molecule with a wide distribution within phylogenetically distant organisms and has a great functional versatility, including the regulation of circadian and seasonal rhythms and antioxidant and anti-inflammatory properties. It also possesses the capacity to modulate immune responses by regulation of the TH1/TH2 balance and cytokine production. Immune system eradicates infecting organisms without serious injury to host tissues, but sometimes these responses are inadequately controlled, giving rise to called hypersensitivity diseases, or inappropriately targeted to host tissues, causing the autoimmune diseases. In clinical medicine, the hypersensitivity diseases include the allergic or atopic diseases and the hallmarks of these diseases are the activation of TH2 cells and the production of IgE antibody. Regarding autoimmunity, at the present time we know that the key events in the development of autoimmunity are a failure or breakdown of the mechanisms normally responsible for maintaining self-tolerance in B lymphocytes, T lymphocytes, or both, the recognition of self-antigens by autoreactive lymphocytes, the activation of these cells to proliferate and differentiate into effector cells, and the tissue injury caused by the effector cells and their products. Melatonin treatment has been investigated in atopic diseases, in several animal models of autoimmune diseases, and has been also evaluated in clinical autoimmune diseases. This review summarizes the role of melatonin in atopic diseases (atopic dermatitis and asthma and in several autoimmune diseases, such as arthritis rheumatoid, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes mellitus, and inflammatory bowel diseases.

  2. [Autoimmune pancreatitis as an element of autoimmune polyglandular syndrome].

    Science.gov (United States)

    Dyrla, Przemysław; Nowak, Tomasz; Gil, Jerzy; Adamiec, Cezary; Bobula, Mariusz; Saracyn, Marek

    2016-05-26

    Autoimmune pancreatitis constantly belongs to diseases which often causes significant diagnostic problem and often runs out with surgical intervention as considered to be a pancreatic cancer. Important although usually underestimated problems are polyglandular syndromes, which may consist of autoimmune pancreatitis (AIP) problem as well. This case report is an example of autoimmune polyglandular syndrome (APS), which was connected with the surgical treatment with biliary bypass anastomosis because of the unresectable lesion in the head of pancreas. The definite remission of the pancreatic lesion finally came after a steroid therapy. Differentiation between neoplastic and inflammatory pancreatic tumors very often remains a serious clinical problem. On grounds of imaging and cytopathology exams it is often difficult to decide about the nature of a lesion. The negative result of cytopathological biopsy examination does not finally settle straightforward diagnosis. Diagnostic problems affect also autoimmune pancreatitis. It is worth to undertake attempts to differentiate pancreatic lesions especially in cases of concomitance with other autoimmune polyglandular syndromes. That is because it is connected with completely different treatment and outcome. We should remember about diagnostic criteria of autoimmune pancreatitis. Appropriate diagnosis for patients with AIP gives them a chance to avoid serious surgical resection and possible complications. PMID:27234865

  3. Healthy first-degree relatives of patients with type 1 dabetes exhibit significant differences in basal gene expression pattern of immunocompetent cells compared to controls: expression pattern as predeterminant of autoimmune diabetes

    Czech Academy of Sciences Publication Activity Database

    Štechová, K.; Kolář, Michal; Blatný, R.; Halbhuber, Z.; Včeláková, J.; Hubáčková, M.; Petruželková, L.; Sumnik, Z.; Obermannová, B.; Pithová, P.; Staviková, V.; Krivjanská, M.; Neuwirth, Aleš; Kalousková, S.; Filipp, Dominik

    2012-01-01

    Roč. 75, č. 2 (2012), s. 210-219. ISSN 0300-9475 R&D Projects: GA MŠk 2B08066 Institutional research plan: CEZ:AV0Z50520514 Keywords : type 1 diabetes * microarray analysis * pathogenesis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.199, year: 2012

  4. The Role of Gluten in Celiac Disease and Type 1 Diabetes

    OpenAIRE

    Gloria Serena; Stephanie Camhi; Craig Sturgeon; Shu Yan; Alessio Fasano

    2015-01-01

    Celiac disease (CD) and type 1 diabetes (T1D) are autoimmune conditions in which dietary gluten has been proven or suggested to play a pathogenic role. In CD; gluten is established as the instigator of autoimmunity; the autoimmune process is halted by removing gluten from the diet; which allows for resolution of celiac autoimmune enteropathy and subsequent normalization of serological markers of the disease. However; an analogous causative agent has not yet been identified for T1D. Neverthele...

  5. New approach for in vivo detection of insulitis in type I diabetes: activated lymphocyte targeting with 123I-labelled interleukin 2

    International Nuclear Information System (INIS)

    Insulitis is considered the histopathological hallmark of type I diabetes. In the non-obese diabetic (NOD) mouse, diabetes has never been observed in the absence of insulitis. The in vivo detection of insulitis could be of relevance for early prediction of diabetes. As approximately 15% of islet-infiltrating lymphocytes express interleukin 2 receptors, the authors have labelled recombinant inter-leukin 2 with 123I and used this radiopharmaceutical to detect insulitis by gamma camera imaging. The authors studied 71 prediabetic NOD and 27 normal Balb/c mice. Labelled α-lactalbumin was used as the control protein. In the first set of experiments the tissue distribution of radiolabelled interleukin 2 in isolated organs from animals sacrificed at different time points was studied. Higher radioactivity was detected in the pancreas of NOD mice injected with labelled interleukin 2, as compared to NOD mice receiving labelled α-lactalbumin. In another set of experiments, gamma camera images have been acquired after injection of 123I-labelled interleukin 2. Radioactivity in the pancreatic region of prediabetic NOD and Balb/c mice showed similar kinetics to those observed by single organ counting, with higher accumulation in the pancreatic region of NOD mice. Finally, a positive correlation was found between the radioactivity in the pancreas and the extent of lymphocytic infiltration. This study demonstrates that 123I-labelled interleukin 2 administered intravenously accumulates specifically in the inflamed pancreas of diabetes-prone NOD mice, suggesting its potential application in human insulin-dependent diabetes mellitus. 34 refs., 6 figs., 1 tab

  6. Role of Nucleotide-Binding Oligomerization Domain-Containing (NOD 2 in Host Defense during Pneumococcal Pneumonia.

    Directory of Open Access Journals (Sweden)

    Tijmen J Hommes

    Full Text Available Streptococcus (S. pneumoniae is the most common causative pathogen in community-acquired pneumonia. Nucleotide-binding oligomerization domain-containing (NOD 2 is a pattern recognition receptor located in the cytosol of myeloid cells that is able to detect peptidoglycan fragments of S. pneumoniae. We here aimed to investigate the role of NOD2 in the host response during pneumococcal pneumonia. Phagocytosis of S. pneumoniae was studied in NOD2 deficient (Nod2-/- and wild-type (Wt alveolar macrophages and neutrophils in vitro. In subsequent in vivo experiments Nod2-/- and Wt mice were inoculated with serotype 2 S. pneumoniae (D39, an isogenic capsule locus deletion mutant (D39Δcps or serotype 3 S. pneumoniae (6303 via the airways, and bacterial growth and dissemination and the lung inflammatory response were evaluated. Nod2-/- alveolar macrophages and blood neutrophils displayed a reduced capacity to internalize pneumococci in vitro. During pneumonia caused by S. pneumoniae D39 Nod2-/- mice were indistinguishable from Wt mice with regard to bacterial loads in lungs and distant organs, lung pathology and neutrophil recruitment. While Nod2-/- and Wt mice also had similar bacterial loads after infection with the more virulent S. pneumoniae 6303 strain, Nod2-/- mice displayed a reduced bacterial clearance of the normally avirulent unencapsulated D39Δcps strain. These results suggest that NOD2 does not contribute to host defense during pneumococcal pneumonia and that the pneumococcal capsule impairs recognition of S. pneumoniae by NOD2.

  7. Immuno-neuro-endocrine networks: A study on the inflammatory state of circulating monocytes and CD4+ T cells in psychiatric and endocrine autoimmune disease

    NARCIS (Netherlands)

    R.C. Drexhage (Roos)

    2011-01-01

    textabstractThis thesis deals with immune aspects of bipolar disorder, schizophrenia, autoimmune thyroid disease and type 1 diabetes mellitus and therefore we give a short introduction to each disease.

  8. Autoimmune Inner Ear Disease (AIED)

    Science.gov (United States)

    ... to order. Mention “VEDA” to receive a 15% discount. Paid Advertisement Disclaimer Information on this website is ... treatment of autoimmune inner ear disease. Although drug companies are not directly studying treatments for inner ear ...

  9. Epigenetic alterations underlying autoimmune diseases.

    Science.gov (United States)

    Aslani, Saeed; Mahmoudi, Mahdi; Karami, Jafar; Jamshidi, Ahmad Reza; Malekshahi, Zahra; Nicknam, Mohammad Hossein

    2016-03-01

    Recent breakthroughs in genetic explorations have extended our understanding through discovery of genetic patterns subjected to autoimmune diseases (AID). Genetics, on the contrary, has not answered all the conundrums to describe a comprehensive explanation of causal mechanisms of disease etiopathology with regard to the function of environment, sex, or aging. The other side of the coin, epigenetics which is defined by gene manifestation modification without DNA sequence alteration, reportedly has come in to provide new insights towards disease apprehension through bridging the genetics and environmental factors. New investigations in genetic and environmental contributing factors for autoimmunity provide new explanation whereby the interactions between genetic elements and epigenetic modifications signed by environmental agents may be responsible for autoimmune disease initiation and perpetuation. It is aimed through this article to review recent progress attempting to reveal how epigenetics associates with the pathogenesis of autoimmune diseases. PMID:26761426

  10. ATPase Cycle of the Nonmotile Kinesin NOD Allows Microtubule End Tracking and Drives Chromosome Movement

    Energy Technology Data Exchange (ETDEWEB)

    Cochran, J.; Sindelar, C; Mulko, N; Collins, K; Kong, S; Hawley, R; Kull, F

    2009-01-01

    Segregation of nonexchange chromosomes during Drosophila melanogaster meiosis requires the proper function of NOD, a nonmotile kinesin-10. We have determined the X-ray crystal structure of the NOD catalytic domain in the ADP- and AMPPNP-bound states. These structures reveal an alternate conformation of the microtubule binding region as well as a nucleotide-sensitive relay of hydrogen bonds at the active site. Additionally, a cryo-electron microscopy reconstruction of the nucleotide-free microtubule-NOD complex shows an atypical binding orientation. Thermodynamic studies show that NOD binds tightly to microtubules in the nucleotide-free state, yet other nucleotide states, including AMPPNP, are weakened. Our pre-steady-state kinetic analysis demonstrates that NOD interaction with microtubules occurs slowly with weak activation of ADP product release. Upon rapid substrate binding, NOD detaches from the microtubule prior to the rate-limiting step of ATP hydrolysis, which is also atypical for a kinesin. We propose a model for NOD's microtubule plus-end tracking that drives chromosome movement.

  11. Inibição da expressão de ciclooxigenase 2 em feridas cutâneas de camundongos NOD submetidos à terapia a laser de baixa intensidade Inhibition of cyclooxygenase 2 expression in NOD mice cutaneous wound by low-level laser therapy

    Directory of Open Access Journals (Sweden)

    Carolina de Lourdes Julião Vieira Rocha

    2012-09-01

    Full Text Available CONTEXTO: A terapia a laser de baixa intensidade (LLLT tem sido relatada como importante moduladora da cicatrização de feridas cutâneas aumentando a proliferação fibroblástica associada ao aumento da expressão da citocina fator transformador de crescimento- β2 (TGF-βB2. OBJETIVO: No presente estudo foram avaliados os efeitos da LLLT sobre a expressão da enzima ciclooxigenase 2 (COX2 no sítio do reparo tecidual utilizando o modelo experimental com camundongos diabéticos não obesos (NOD para estudar a cicatrização de feridas cutâneas. MÉTODOS: Foram utilizados 30 camundongos NOD, destes 14 ficaram diabéticos e foram divididos em dois grupos: o grupo I (n=7 foi submetido a um procedimento cirúrgico de feridas cutâneas e o grupo II (n=7 foi submetido a um procedimento cirúrgico de feridas cutâneas e tratados com LLLT. O grupo II foi submetido à LLLT nos seguintes parâmetros: 15 mW de potência, dose de 3,8 J/cm² e tempo de aplicação de 20 segundos. Após sete dias do ato cirúrgico e após aplicação do laser, os animais foram eutanasiados com sobredose de anestesia e amostras das feridas foram colhidas para posterior análise histopatológica, histomorfométrica e imuno-histoquímica. RESULTADOS: A LLLT promoveu a inibição da expressão da COX2 em feridas cutâneas de camundongos diabéticos. CONCLUSÃO: Em conjunto, os resultados sugeriram que a LLLT é capaz de modular negativamente a expressão da enzima COX2 contribuindo para o controle da resposta inflamatória em feridas cutâneas de camundongos NOD.BACKGROUND: Low-level laser therapy (LLLT has been reported to modulate the healing of wounds by inducing an increase in fibroblast number associated with increased expression of the cytokine transforming growth factor-β2 (TGF-β2. OBJECTIVE: In the present study, the effect of LLLT on expression of COX2 at the site of tissue repair was evaluated, using an experimental model with non obese diabetic mice (NOD to study

  12. Endocrine autoimmunity in Turner syndrome

    OpenAIRE

    Grossi, Armando; Crinò, Antonino; Luciano, Rosa; Lombardo, Antonietta; Cappa, Marco; Fierabracci, Alessandra

    2013-01-01

    Background Turner syndrome is caused by numeric and structural abnormalities of the X chromosome. An increased frequency of autoimmunity as well as an elevated incidence of autoantibodies was observed in Turner patients. The aim of this study was to conduct a retrospective analysis of the incidence of autoimmunity in 66 Italian patients affected by Turner syndrome. Methods Sixty-six unselected and consecutive Italian Turner patients were recruited. The association between age, karyotype and t...

  13. Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection

    DEFF Research Database (Denmark)

    Christensen, Dan Ploug; Gysemans, Conny; Lundh, Morten;

    2014-01-01

    Type 1 diabetes is due to destruction of pancreatic β-cells. Lysine deacetylase inhibitors (KDACi) protect β-cells from inflammatory destruction in vitro and are promising immunomodulators. Here we demonstrate that the clinically well-tolerated KDACi vorinostat and givinostat revert diabetes in the...... nonobese diabetic (NOD) mouse model of type 1 diabetes and counteract inflammatory target cell damage by a mechanism of action consistent with transcription factor-rather than global chromatin-hyperacetylation. Weaning NOD mice received low doses of vorinostat and givinostat in their drinking water until...... 100-120 d of age. Diabetes incidence was reduced by 38% and 45%, respectively, there was a 15% increase in the percentage of islets without infiltration, and pancreatic insulin content increased by 200%. Vorinostat treatment increased the frequency of functional regulatory T-cell subsets and their...

  14. Effect of cholera toxoid-proinsulin conjugate and cholera toxin B subunit admixtures on spontaneous autoimmune diabetes%霍乱毒素B亚单位-胰岛素原融合蛋白抗糖尿病

    Institute of Scientific and Technical Information of China (English)

    高玲; 张大兵; 任宏; 欧阳凤秀; 姜庆五

    2005-01-01

    目的观察雌性非肥胖糖尿病(NOD)小鼠口服胰岛素和霍乱毒素B亚单位-胰岛素原融合蛋白(CTB-proinsulin)+霍乱毒素B亚单位五聚体(CTB五聚体)对糖尿病发生的影响,为社区非肥胖性糖尿病干预提供参考依据.方法40只雌性3~4周龄NOD小鼠随机分为4组:分别给予磷酸缓冲液(PBS)500μl,胰岛素(insulin)1 mg,CTB-proinsulin 100μg+CTG五聚体1μg,CTB-proinsulin 300μg+CTG五聚体3μg.每周灌胃2次至12周龄;从12周龄起,动态监测小鼠尿糖、血糖至26周龄,观察糖尿病的发生,比较不同抗原诱导免疫耐受的作用.结果与PBS组比较,CTB-proinsulin+CTG五聚体与胰岛素均能延缓、减少NOD小鼠糖尿病的发生,26周龄时小鼠糖尿病的累积发病率:PBS组100%,CTB-proinsulin100μg+CTG五聚体1μg组、CTGproinsulin 300μg+CTG五聚体3μg组和胰岛素组分别为40%,40%和50%(P<0.010).各组生存时间分布有差别.结论不同剂量组的CTB-proinsulin+CTG五聚体与胰岛素能够提高NOD鼠生存率,并可达到与胰岛素相同保护作用而所需抗原剂量较小.

  15. Modulation by Melatonin of the Pathogenesis of Inflammatory Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Huey-Kang Sytwu

    2013-05-01

    Full Text Available Melatonin is the major secretory product of the pineal gland during the night and has multiple activities including the regulation of circadian and seasonal rhythms, and antioxidant and anti-inflammatory effects. It also possesses the ability to modulate immune responses by regulation of the T helper 1/2 balance and cytokine production. Autoimmune diseases, which result from the activation of immune cells by autoantigens released from normal tissues, affect around 5% of the population. Activation of autoantigen-specific immune cells leads to subsequent damage of target tissues by these activated cells. Melatonin therapy has been investigated in several animal models of autoimmune disease, where it has a beneficial effect in a number of models excepting rheumatoid arthritis, and has been evaluated in clinical autoimmune diseases including rheumatoid arthritis and ulcerative colitis. This review summarizes and highlights the role and the modulatory effects of melatonin in several inflammatory autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, and inflammatory bowel disease.

  16. Autoimmune sleep disorders.

    Science.gov (United States)

    Silber, Michael H

    2016-01-01

    A number of autoantibodies, some paraneoplastic, are associated with sleep disorders. Morvan syndrome and limbic encephalitis, associated with voltage-gated potassium channel-complex antibodies, principally against CASPR2 and LGI1, can result in profound insomnia and rapid eye movement sleep behavior disorder (RBD). Patients with aquaporin-4 antibodies and neuromyelitis optica may develop narcolepsy in association with other evidence of hypothalamic dysfunction, sometimes as the initial presentation. Central sleep apnea and central neurogenic hypoventilation are found in patients with anti-N-methyl-d-aspartate receptor antibody encephalitis, and obstructive sleep apnea, stridor, and hypoventilation are prominent features of a novel tauopathy associated with IgLON5 antibodies. In addition, paraneoplastic diseases may involve the hypothalamus and cause sleep disorders, particularly narcolepsy and RBD in those with Ma1 and Ma2 antibodies. Patients with antineuronal nuclear autoantibodies type 2 may develop stridor. Several lines of evidence suggest that narcolepsy is an autoimmune disorder. There is a strong relationship with the human leukocyte antigen (HLA) DQB1*06:02 haplotype and polymorphisms in the T-cell receptor alpha locus and purinergic receptor P2Y11 genes. Patients with recent-onset narcolepsy may have high titers of antistreptococcal or other antibodies, although none has yet been shown to be disease-specific but, supporting an immune basis, recent evidence indicates that narcolepsy in children can be precipitated by one type of vaccination against the 2009-2010 H1N1 influenza pandemic. PMID:27112685

  17. Ultraviolet radiation and autoimmune disease: insights from epidemiological research

    International Nuclear Information System (INIS)

    This review examines the epidemiological evidence that suggests ultraviolet radiation (UVR) may play a protective role in three autoimmune diseases: multiple sclerosis, insulin-dependent diabetes mellitus and rheumatoid arthritis. To date, most of the information has accumulated from population studies that have studied the relationship between geography or climate and autoimmune disease prevalence. An interesting gradient of increasing prevalence with increasing latitude has been observed for at least two of the three diseases. This is most evident for multiple sclerosis, but a similar gradient has been shown for insulin-dependent diabetes mellitus in Europe and North America. Seasonal influences on both disease incidence and clinical course and, more recently, analytical studies at the individual level have provided further support for a possible protective role for UVR in some of these diseases but the data are not conclusive. Organ-specific autoimmune diseases involve Th1 cell-mediated immune processes. Recent work in photoimmunology has shown ultraviolet B (UVB) can specifically attenuate these processes through several mechanisms which we discuss. In particular, the possible contribution of an UVR-induced increase in serum vitamin D (1,25(OH)2D3) levels in the beneficial immunomodulation of these diseases is discussed

  18. Exocrine Pancreatic Insufficiency in Diabetes Mellitus: A Complication of Diabetic Neuropathy or a Different Type of Diabetes?

    OpenAIRE

    Hardt, Philip D; Nils Ewald

    2011-01-01

    Pancreatic exocrine insufficiency is a frequently observed phenomenon in type 1 and type 2 diabetes mellitus. Alterations of exocrine pancreatic morphology can also be found frequently in diabetic patients. Several hypotheses try to explain these findings, including lack of insulin as a trophic factor for exocrine tissue, changes in secretion and/or action of other islet hormones, and autoimmunity against common endocrine and exocrine antigens. Another explanation might be that diabetes melli...

  19. Nod-shuffle 3D spectroscopy with PMAS

    Science.gov (United States)

    Roth, Martin M.; Fechner, Thomas; Becker, Thomas; Kelz, Andreas

    2004-09-01

    PMAS is a versatile integral field spectrograph based on the principle of a fiber-coupled lens array type of IFU. The instrument was commissioned at the Calar Alto 3.5m Telescope in May 2001. PMAS is offered as a common user instrument at Calar Alto since 2002. However, it has remained flexible enough to be used as a testbed for new observing techniques. Since the instrument is sensitive in the wavelength range from 0.35 to 1 μm, it is being used to experiment with faint object 3D spectroscopy for a variety of objects in stellar and extragalactic astronomy. Among these experiments, we have implemented a nod-shuffle mode of operation, which is a beam switching technique to achieve a high degree of sky subtraction accuracy. We describe the technical details of the special solution found for PMAS and first results obtained in test observations of faint haloes of planetary nebulae.

  20. Interactions between Nod-like Receptors and Intestinal Bacteria

    Directory of Open Access Journals (Sweden)

    Marcel R de Zoete

    2013-12-01

    Full Text Available Nucleotide oligomerization domain (Nod-like Receptors (NLRs are cytosolic sensors that mediate the activation of Caspase-1 and the subsequent processing and secretion of the pro-inflammatory cytokines IL-1β and IL-18, as well as an inflammatory cell death termed pyroptosis. While a multitude of bacteria have been shown to activate one or more NLRs under in vitro conditions, the exact impact of NLR activation during the course of colonization, both of pathogenic and commensal nature, is less understood. In this review, we will focus on the role of intestinal NLRs during the various stages of infection with common gastrointestinal bacterial pathogens, as well as NLR function in controlling and shaping the microbiota.

  1. Type 1 diabetes pathogenesis - Prevention???

    Directory of Open Access Journals (Sweden)

    C S Muralidhara Krishna

    2015-01-01

    Full Text Available Pathogenesis of type 1 diabetes is multi-faceted, including, autoimmunity, genetics and environment. Autoimmunity directed against pancreatic islet cells results in slowly progressive selective beta-cell destruction ("Primary autoimmune insulitis", culminating over years in clinically manifested insulin-dependent diabetes mellitus (IDDM. Circulating serum autoantibodies directed against the endocrine cells of the islets of Langerhans (Islet cell autoantibodies - ICAb are an important hallmark of this disease. Assays for islet cell autoantibodies have facilitated the investigation and understanding of several facets in the pathogenesis of autoimmune diabetes. Their applications have extended into clinical practice and have opened new avenues for early preclinical prediction and preventive prophylaxis in IDDM/type 1 DM. Recently, surprisingly, differences in insulin content between T1DM islets, as well as, ′patchy′ or ′lobular′ destruction of islets have been described. These unique pathobiological phenomena, suggest that beta cell destruction may not always be inexorable and inevitably complete/total, and thus raise hopes for possible therapeutic interruption of beta cell autoimmunity - destruction and cure of type 1 diabetes. "Recurrent or secondary autoimmune insulitis" refers to the rapid reappearance of islet cell autoantibodies post pancreas transplant, and selective islet beta cell destruction in the grafted pancreas [never forgetting or "anamnestic" beta cell destructive memory], in the absence of any graft pancreas rejection [monozygotic twin to twin transplantation]. The one definite environmental factor is congenital rubella, because of which a subset of children subsequently develop type 1 diabetes. The putative predisposing factors are viruses, gluten and cow′s milk. The putative protective factors include gut flora, helminths, viral infections, and Vitamin D. Prevention of T1DM can include: Primary prevention strategies

  2. A rare presentation of hypopituitarism in hepatic overlap syndrome of autoimmune hepatitis and autoimmune cholangitis

    OpenAIRE

    Gupta V; Singh H.; Talapatra P; Ray S

    2016-01-01

    Autoimmune cholangitis is the antimitochondrial antibody-negative autoimmune hepatopathy with clinical and histological features similar to that of primary biliary cirrhosis. Autoimmune cholangitis has a predominant cholestatic phase. However, transaminasemia might be dominant in certain patients, indicating associated autoimmune hepatitis. Such an autoimmune hepatopathy has been termed as hepatic overlap syndrome. Due to the autoimmune nature of the disease, associated diseases of other orga...

  3. Cloning of nod gene regions from mesquite rhizobia and bradyrhizobia and nucleotide sequence of the nodD gene from mesquite rhizobia.

    Science.gov (United States)

    Thomas, P M; Golly, K F; Virginia, R A; Zyskind, J W

    1995-09-01

    Nitrogen-fixing symbiosis between bacteria and the tree legume mesquite (Prosopis glandulosa) is important for the maintenance of many desert ecosystems. Genes essential for nodulation and for extending the host range to mesquite were isolated from cosmid libraries of Rhizobium (mesquite) sp. strain HW17b and Bradyrhizobium (mesquite) sp. strain HW10h and were shown to be closely linked. All of the cosmid clones of rhizobia that extended the host range of Rhizobium (Parasponia) sp. strain NGR234CS to mesquite also supported nodulation of a Sym- mesquite strain. The cosmid clones of bradyrhizobia that extended the host range of Rhizobium (Parasponia) sp. strain NGR234CS to mesquite were only able to confer nodulation ability in the Sym- mesquite strain if they also contained a nodD-hybridizing region. Subclones containing just the nodD genes of either genus did not extend the host range of Rhizobium (Parasponia) sp. to mesquite, indicating that the nodD gene is insufficient for mesquite nodulation. The nodD gene region is conserved among mesquite-nodulating rhizobia regardless of the soil depth from which they were collected, indicating descent from a common ancestor. In a tree of distance relationships, the NodD amino acid sequence from mesquite rhizobia clusters with homologs from symbionts that can infect both herbaceous and tree legumes, including Rhizobium tropici, Rhizobium leguminosarum bv; phaseoli, Rhizobium loti, and Bradyrhizobium japonicum. PMID:7574650

  4. Pankreaskrankheiten und Diabetes mellitus

    OpenAIRE

    Galonska M; Hartje I; Büchsel R

    2012-01-01

    Pankreatogener Diabetes entsteht nach akuter oder chronischer Pankreatitis, nach Pankreasresektion, bei einem Pankreaskarzinom sowie bei autoimmuner Pankreatitis. Bei der chronischen Pankreatitis haben die Krankheitsdauer, die Ätiologie sowie das Auftreten von Kalzifikationen Bedeutung für das Ausmaß der endokrinen Dysfunktion. Die Ätiologie und das Ausmaß der Operation bestimmen die Ausprägung der endokrinen Dysfunktion nach Pankreasresektion. Etwa 85 % der Patienten mit Autoimmunp...

  5. NOD/SCID孕鼠淋巴细胞表型检测和NK细胞活性分析%Lymphocyte phenotyping and NK cell activity analysis in pregnant NOD/SCID mice

    Institute of Scientific and Technical Information of China (English)

    林羿; 王通; 狄静芳; 曾山; 黄锦桃; 冯铮; 曾耀英

    2005-01-01

    目的观察NOD/SCID小鼠免疫状况和生育力特征,并分析NK细胞亚群对同基因交配组合NOD/SCID×NOD/SCID妊娠结局的影响.方法采用流式细胞术对未孕和孕13.5 d的NOD/SCID小鼠进行淋巴细胞表型分析,并系统地观察和比较NOD/SCID×NOD/SCID和BALB/c×BALB/c小鼠的生育力特征.分别采用多聚次黄苷酸-胞苷酸(polyinosinic-polycytidylic acid,poly I:C)或抗asialoGM1单抗(anti-asialo GM1)刺激或抑制NK细胞活性,并分别观察这些因素对妊娠结局的影响.结果 与对照组NOD/SCID小鼠相比,poly I:C处理组NOD/SCID×NOD/SCID小鼠平均每窝产仔数增多,而注射抗asialo GM1单抗则使胚胎吸收率增高,进而平均每窝产仔数显著减少.结论在NOD/SCID小鼠孕期母-胎界面保持适当水平的NK细胞活性对妊娠结局有利.

  6. Therapeutic manipulation of natural killer (NK) T cells in autoimmunity: are we close to reality?

    Science.gov (United States)

    Simoni, Y; Diana, J; Ghazarian, L; Beaudoin, L; Lehuen, A

    2013-01-01

    T cells reactive to lipids and restricted by major histocompatibility complex (MHC) class I-like molecules represent more than 15% of all lymphocytes in human blood. This heterogeneous population of innate cells includes the invariant natural killer T cells (iNK T), type II NK T cells, CD1a,b,c-restricted T cells and mucosal-associated invariant T (MAIT) cells. These populations are implicated in cancer, infection and autoimmunity. In this review, we focus on the role of these cells in autoimmunity. We summarize data obtained in humans and preclinical models of autoimmune diseases such as primary biliary cirrhosis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, psoriasis and atherosclerosis. We also discuss the promise of NK T cell manipulations: restoration of function, specific activation, depletion and the relevance of these treatments to human autoimmune diseases. PMID:23199318

  7. Targeting Homeostatic T Cell Proliferation to Control Beta-Cell Autoimmunity.

    Science.gov (United States)

    Vignali, Debora; Monti, Paolo

    2016-05-01

    Immunomodulation of the autoreactive T cell response is considered a major strategy to control beta-cell autoimmunity, both in the natural history of type 1 diabetes and in islet transplantation, which can be affected by autoimmunity recurrence. So far, these strategies have had modest results, prompting efforts to define novel cellular and molecular targets to control autoreactive T cell expansion and activation. Novel findings highlighted the important role of the homeostatic cytokine interleukin-7 in inducing proliferation and differentiation of autoreactive T cell clones that causes beta-cell autoimmunity. In this review, we discuss recent evidences and novel findings on the role of IL-7 mediated homeostatic T cell proliferation in the process of beta-cell destruction and evidences of how targeting IL-7 and its receptor could be an innovative and effective strategy to control beta-cell autoimmunity. PMID:26983628

  8. Diabetes in Population Isolates

    DEFF Research Database (Denmark)

    Grarup, Niels; Moltke, Ida; Albrechtsen, Anders;

    2016-01-01

    Type 2 diabetes (T2D) is an increasing health problem worldwide with particularly high occurrence in specific subpopulations and ancestry groups. The high prevalence of T2D is caused both by changes in lifestyle and genetic predisposition. A large number of studies have sought to identify...... on glucose-stimulated plasma glucose, serum insulin levels, and T2D. The variant defines a specific subtype of non-autoimmune diabetes characterized by decreased post-prandial glucose uptake and muscular insulin resistance. These and other recent findings in population isolates illustrate the value...

  9. AUTOIMMUNE EPIDERMAL BLISTERING DISEASES

    Directory of Open Access Journals (Sweden)

    Ana Maria Abreu Velez

    2013-11-01

    Full Text Available Autoimmune bullous skin diseases (ABDs are uncommon, potentially fatal diseases of skin and mucous membranes which are associated with deposits of autoantibodies and complement against distinct molecules of the epidermis and dermal/epidermal basement membrane zone (BMZ. These autoantibodies lead to a loss in skin molecular integrity, which manifests clinically as formation of blisters or erosions. In pemphigus vulgaris, loss of adhesion occurs within the epidermis. The pioneering work of Ernst H. Beutner, Ph.D. and Robert E. Jordon, M.D. confirmed the autoimmune nature of these diseases. Walter F. Lever, M.D. contributed significantly to our understanding of the histopathologic features of these diseases. Walter Lever, M.D. and Ken Hashimoto, M.D. contributed electron microscopic studies of these diseases, especially in pemphigus vulgaris and bullous pemphigoid. In bullous pemphigoid (BP, linear IgA bullous dermatosis, epidermolysis bullosa acquisita (EBA and dermatitis herpetiformis (DH, loss of adhesion takes place within or underneath the BMZ. Classic EBA demonstrates extensive skin fragility; DH is commonly associated with gluten-sensitive enteropathy, and manifests clinically with pruritic papulovesicles on the extensor surfaces of the extremities and the lumbosacral area. The clinical spectrum of bullous pemphigoid includes tense blisters, urticarial plaques, and prurigo-like eczematous lesions. Pemphigoid gestationis mostly occurs during the last trimester of pregnancy, and mucous membrane pemphigoid primarily involves the oral mucosa and conjunctivae and leads to scarring. Linear IgA bullous dermatosis manifests with tense blisters in a „cluster of jewels”-like pattern in childhood (chronic bullous disease of childhood and is more clinically heterogeneous in adulthood. Many of the autoantigens in these disorders are known and have been well characterized. ABDs may be influenced by both genetic and exogenous factors. The diagnoses of

  10. Estrogens and autoimmune diseases.

    Science.gov (United States)

    Cutolo, Maurizio; Capellino, Silvia; Sulli, Alberto; Serioli, Bruno; Secchi, Maria Elena; Villaggio, Barbara; Straub, Rainer H

    2006-11-01

    Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immune-suppressors . Several physiological, pathological, and therapeutic conditions may change the serum estrogen milieu and/or peripheral conversion rate, including the menstrual cycle, pregnancy, postpartum period, menopause, being elderly, chronic stress, altered circadian rhythms, inflammatory cytokines, and use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. In particular, cortisol and melatonin circadian rhythms are altered, at least in rheumatoid arthritis (RA), and partially involve sex hormone circadian synthesis and levels as well. Abnormal regulation of aromatase activity (i.e., increased activity) by inflammatory cytokine production (i.e., TNF-alpha, IL-1, and IL-6) may partially explain the abnormalities of peripheral estrogen synthesis in RA (i.e., increased availability of 17-beta estradiol and possible metabolites in synovial fluids) and in systemic lupus erythematosus, as well as the altered serum sex-hormone levels and ratio (i.e., decreased androgens and DHEAS). In the synovial fluids of RA patients, the increased estrogen concentration is observed in both sexes and is more specifically characterized by the hydroxylated forms, in particular 16alpha-hydroxyestrone, which is a mitogenic and cell proliferative endogenous hormone. Local effects of sex hormones in autoimmune rheumatic diseases seems to consist mainly in modulation of cell proliferation and cytokine production (i.e., TNF-alpha, Il-1, IL-12). In this respect, it is interesting that male patients with RA seem to profit more from anti-TNFalpha strategies than do female patients. PMID:17261796

  11. Expression of Nucleotide-oligomerization Domain (NOD) and Related Genes in Mouse Tissues Infected with Mycobacterium leprae

    Science.gov (United States)

    Kim, Tae Hoon; Chae, Gue-Tae

    2015-01-01

    The nucleotide-oligomerization domain (NOD) is an important molecule involved in host defense against bacterial infection. To study the role of NODs in the host response to Mycobacterium leprae, we measured the mRNA levels of NODs and related genes in infected mouse tissues. The mRNA expression of NOD1, NOD2, caspase-1 and ASC was increased in mouse footpads. Whereas NOD2 expression in macrophages was increased at 2 and 24 h post-infection with M. leprae, there was no expression of NOD1 at these time points. An increase in caspase-1 expression was observed at 2 h and continued at 24 h. However, the expression of ASC was increased only at the early time point. The expression of caspase-1 is regulated by NOD2-dependent pathway in established HEK 293. Our results suggest NOD2, rather than NOD1, may be associated with the host response to M. leprae and that caspase-1 activation is essential for the host response. PMID:26770186

  12. Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling

    DEFF Research Database (Denmark)

    Damgaard, Rune Busk; Fiil, Berthe Katrine; Speckmann, Carsten;

    2013-01-01

    ), an immunodeficiency associated with a potentially fatal deregulation of the immune system, whose aetiology is not well understood. Here, we identify the XIAP baculovirus IAP repeat (BIR)2 domain as a hotspot for missense mutations in XLP2. We demonstrate that XLP2-BIR2 mutations severely impair NOD1....../2-dependent immune signalling in primary cells from XLP2 patients and in reconstituted XIAP-deficient cell lines. XLP2-BIR2 mutations abolish the XIAP-RIPK2 interaction resulting in impaired ubiquitylation of RIPK2 and recruitment of linear ubiquitin chain assembly complex (LUBAC) to the NOD2-complex. We show...... that the RIPK2 binding site in XIAP overlaps with the BIR2 IBM-binding pocket and find that a bivalent Smac mimetic compound (SMC) potently antagonises XIAP function downstream of NOD2 to limit signalling. These findings suggest that impaired immune signalling in response to NOD1/2 stimulation is a...

  13. The effect of NOD2 on the microbiota in Crohn's disease.

    Science.gov (United States)

    Lauro, Mackenzie L; Burch, Jason M; Grimes, Catherine Leimkuhler

    2016-08-01

    Recent advancements toward the treatment of Crohn's disease (CD) indicate great promise for long-term remission. CD patients suffer from a complex host of dysregulated interactions between their innate immune system and microbiome. The most predominant link to the onset of CD is a genetic mutation in the innate immune receptor nucleotide-binding oligomerization domain-containing 2 (NOD2). NOD2 responds to the presence of bacteria and stimulates the immune response. Mutations to NOD2 promote low diversity and dysbiosis in the microbiome, leading to impaired mucosal barrier function. Current treatments suppress the immune response rather than enhancing the function of this critical protein. New progress toward stabilizing NOD2 signaling through its interactions with chaperone proteins holds potential in the development of novel CD therapeutics. PMID:27035071

  14. Autoimmune hepatitis in association with lymphocytic colitis.

    LENUS (Irish Health Repository)

    Cronin, Edmond M

    2012-02-03

    Autoimmune hepatitis is a rare, chronic inflammatory disorder which has been associated with a number of other auto-immune conditions. However, there are no reports in the medical literature of an association with microscopic (lymphocytic) colitis. We report the case of a 53-year-old woman with several autoimmune conditions, including lymphocytic colitis, who presented with an acute hepatitis. On the basis of the clinical features, serology, and histopathology, we diagnosed autoimmune hepatitis. To our knowledge, this is the first report of autoimmune hepatitis in association with lymphocytic colitis, and lends support to the theory of an autoimmune etiology for lymphocytic colitis.

  15. Backchannel Head Nods in Danish First Meeting Encounters with a Humanoid Robot

    DEFF Research Database (Denmark)

    Krogsager, Anders; Segato, Nicolaj; Rehm, Matthias

    2014-01-01

    investigate the use of head nods in communications between a user and a humanoid robot (Nao) that they meet for the first time. Contrary to the virtual agent case, the robot elicited less talking from the user when it was using head nods as a feedback signal. A follow-up experiment revealed that the physical...... embodiment of the robot had a huge impact on the users' behavior in the first encounters....

  16. Backchannel Head Nods in Danish First Meeting Encounters with a Humanoid Robot

    DEFF Research Database (Denmark)

    Krogsager, Anders; Segato, Nicolaj; Rehm, Matthias

    investigate the use of head nods in communications between a user and a humanoid robot (Nao) that they meet for the first time. Contrary to the virtual agent case, the robot elicited less talking from the user when it was using head nods as a feedback signal. A follow-up experiment revealed that the physical...... embodiment of the robot had a huge impact on the users' behavior in the first encounters....

  17. Treating young adults with type 2 diabetes or monogenic diabetes.

    Science.gov (United States)

    Owen, Katharine R

    2016-06-01

    It is increasingly recognised that diabetes in young adults has a wide differential diagnosis. There are many monogenic causes, including monogenic beta-cell dysfunction, mitochondrial diabetes and severe insulin resistance. Type 2 diabetes in the young is becoming more prevalent, particularly after adolescence. It's important to understand the clinical features and diagnostic tools available to classify the different forms of young adult diabetes. Classic type 1 diabetes is characterised by positive β-cell antibodies and absence of endogenous insulin secretion. Young type 2 diabetes is accompanied by metabolic syndrome with obesity, hypertension and dyslipidaemia. Monogenic β-cell dysfunction is characterised by non-autoimmune, C-peptide positive diabetes with a strong family history, while mitochondrial diabetes features deafness and other neurological involvement. Severe insulin resistance involves a young-onset metabolic syndrome often with a disproportionately low BMI. A suspected diagnosis of monogenic diabetes is confirmed with genetic testing, which is widely available in specialist centres across the world. Treatment of young adult diabetes is similarly diverse. Mutations in the transcription factors HNF1A and HNF4A and in the β-cell potassium ATP channel components cause diabetes which responds to low dose and high dose sulfonylurea agents, respectively, while glucokinase mutations require no treatment. Monogenic insulin resistance and young-onset type 2 diabetes are both challenging to treat, but first line management involves insulin sensitisers and aggressive management of cardiovascular risk. Outcomes are poor in young-onset type 2 diabetes compared to both older onset type 2 and type 1 diabetes diagnosed at a similar age. The evidence base for treatments in monogenic and young-onset type 2 diabetes relies on studies of moderate quality at best and largely on extrapolation from work conducted in older type 2 diabetes subjects. Better quality

  18. Type 1 autoimmune pancreatitis

    Directory of Open Access Journals (Sweden)

    Zen Yoh

    2011-12-01

    Full Text Available Abstract Before the concept of autoimmune pancreatitis (AIP was established, this form of pancreatitis had been recognized as lymphoplasmacytic sclerosing pancreatitis or non-alcoholic duct destructive chronic pancreatitis based on unique histological features. With the discovery in 2001 that serum IgG4 concentrations are specifically elevated in AIP patients, this emerging entity has been more widely accepted. Classical cases of AIP are now called type 1 as another distinct subtype (type 2 AIP has been identified. Type 1 AIP, which accounts for 2% of chronic pancreatitis cases, predominantly affects adult males. Patients usually present with obstructive jaundice due to enlargement of the pancreatic head or thickening of the lower bile duct wall. Pancreatic cancer is the leading differential diagnosis for which serological, imaging, and histological examinations need to be considered. Serologically, an elevated level of IgG4 is the most sensitive and specific finding. Imaging features include irregular narrowing of the pancreatic duct, diffuse or focal enlargement of the pancreas, a peri-pancreatic capsule-like rim, and enhancement at the late phase of contrast-enhanced images. Biopsy or surgical specimens show diffuse lymphoplasmacytic infiltration containing many IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. A dramatic response to steroid therapy is another characteristic, and serological or radiological effects are normally identified within the first 2 or 3 weeks. Type 1 AIP is estimated as a pancreatic manifestation of systemic IgG4-related disease based on the fact that synchronous or metachronous lesions can develop in multiple organs (e.g. bile duct, salivary/lacrimal glands, retroperitoneum, artery, lung, and kidney and those lesions are histologically identical irrespective of the organ of origin. Several potential autoantigens have been identified so far. A Th2-dominant immune reaction and the activation of

  19. Autoimmune pancreatitis. An update

    International Nuclear Information System (INIS)

    Autoimmune pancreatitis (AIP) is a rare disease, the pathophysiological understanding of which has been greatly improved over the last years. The most common form, type 1 AIP belongs to the IgG4-related diseases and must be distinguished from type 2 AIP, which is a much rarer entity associated with chronic inflammatory bowel disease. Clinically, there is an overlap with pancreatic cancer. Imaging and further criteria, such as serological and histological parameters are utilized for a differentiation between both entities in order to select the appropriate therapy and to avoid the small but ultimately unnecessary number of pancreatectomies. The diagnostics of AIP are complex, whereby the consensus criteria of the International Association of Pancreatology have become accepted as the parameters for discrimination. These encompass five cardinal criteria and one therapeutic criterion. By applying these criteria AIP can be diagnosed with a sensitivity of 84.9 %, a specificity of 100 % and an accuracy of 93.8 %. The diagnosis of AIP is accomplished by applying several parameters of which two relate to imaging. As for the routine diagnostics of the pancreas these are ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). Important for the differential diagnosis is the exclusion of signs of local and remote tumor spread for which CT and MRI are established. The essential diagnostic parameter of histology necessitates sufficient sample material, which cannot usually be acquired by a fine needle biopsy. CT or MRI are the reference standard methods for identification of the optimal puncture site and imaging-assisted (TruCut) biopsy. In patients presenting with unspecific upper abdominal pain, painless jaundice combined with the suspicion of a pancreatic malignancy in imaging but a mismatch of secondary signs of malignancy, AIP should also be considered as a differential diagnosis. As the diagnosis of AIP only partially relies on imaging radiologists also

  20. SCID与NOD/SCID小鼠部分免疫指标的比较%Comparison of some immune indexes between SCID and NOD/SCID mice

    Institute of Scientific and Technical Information of China (English)

    郝智慧; 孔丽娟; 王成; 王欣丽; 傅谨凤; 李兰芳

    2016-01-01

    目的 测定SCID和NOD/SCID小鼠的免疫器官质量、血常规指标以及部分血液生化指标(immunoglobulin G,IgG),分析比较2个免疫缺陷小鼠在免疫方面的特点.方法 对4~8、12~ 16和20~24周龄SCID与NOD/SCID小鼠眼眶静脉采血,测定血常规指标,剖取胸腺和脾脏进行称质量比较.对4~6、8~ 10、16~18周龄的SCID和NOD/SCID小鼠眼眶静脉采血,测定比较血清IgG含量.结果 a.同周龄SCID与NOD/SCID小鼠胸腺质量差异无显著性.3个年龄段(4~8、12~16和20~24周龄)的NOD/SCID小鼠脾脏显著低于各组SCID小鼠(P<0.05),SCID小鼠脾脏随年龄增加趋势明显;b.NOD/SCID小鼠白细胞数(white blood cell count,WBC)、淋巴细胞绝对值(lymphocytes,LYM#)、红细胞数(red blood cell,RBC)、血红蛋白含量(hemoglobin,HGB)及平均血红蛋白浓度(mean corpuscular hemoglobin concentration,MCHC)显著低于同周龄SCID小鼠(P<0.05),高龄SCID小鼠白细胞水平和淋巴细胞百分比显著高于低龄(4~8周龄)SCID鼠(P<0.05).c.NOD/SCID小鼠血清IgG含量显著低于SCID小鼠(P<0.05).结论 SCID与NOD/SCID小鼠部分免疫指标存在显著性差异.

  1. [Bullous autoimmune disorders in children].

    Science.gov (United States)

    Sárdy, M; Kasperkiewicz, M

    2013-06-01

    We review the pathogenesis, clinical features, diagnosis, differential diagnosis, and therapy of autoimmune bullous skin diseases of childhood, especially of the most common linear IgA dermatosis. In autoimmune bullous diseases, autoantibodies are formed against different adhesion molecules of the skin. These are not only pathophysiologically relevant, but also serve as basis for diagnosis and follow-up of these diseases. In case an autoimmune bullous disease is suspected, histopathology and immunohistopathology (direct immunofluorescence microscopy) as well as serological tests (indirect immunofluorescence microscopy, ELISA, immunoblot) should be performed. Therapy depends on the diagnosis. In IgA-mediated pathogenesis, dapsone can be successfully used. In IgG-mediated diseases, immunosuppression with corticosteroids and steroid-sparing agents should be initiated, although only local therapy is sufficient to control a self-limiting pemphigus neonatorum. In dermatitis herpetiformis, a life-long gluten-free diet is recommended. PMID:23677541

  2. Thyroid dysfunction: an autoimmune aspect.

    Science.gov (United States)

    Khan, Farah Aziz; Al-Jameil, Noura; Khan, Mohammad Fareed; Al-Rashid, May; Tabassum, Hajera

    2015-01-01

    Auto immune thyroid disease (AITD) is the common organ specific autoimmune disorder, Hashimoto thyroiditis (HT) and Grave's disease (GD) are its well-known sequelae. It occurs due to loss of tolerance to autoantigens thyroid peroxidase (TPO), thyroglobulin (Tg), thyroid stimulating hormone receptor (TSH-R) which leads to the infiltration of the gland. T cells in chronic autoimmune thyroiditis (cAIT) induce apoptosis in thyroid follicular cells and cause destruction of the gland. Presences of TPO antibodies are common in HT and GD, while Tg has been reported as an independent predictor of thyroid malignancy. Cytokines are small proteins play an important role in autoimmunity, by stimulating B and T cells. Various cytokines IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-14, TNF-α and IFN-γ are found in thyroid follicular cells which enhance inflammatory response with nitric oxide (NO) and prostaglandins. PMID:26221205

  3. [Infectious agents and autoimmune diseases].

    Science.gov (United States)

    Riebeling-Navarro, C; Madrid-Marina, V; Camarena-Medellín, B E; Peralta-Zaragoza, O; Barrera, R

    1992-01-01

    In this paper the molecular aspects of the relationships between infectious agents and autoimmune diseases, the mechanisms of immune response to infectious agents, and the more recent hypotheses regarding the cause of autoimmune diseases are discussed. The antigens are processed and selected by their immunogenicity, and presented by HLA molecules to the T cell receptor. These events initiate the immune response with the activation and proliferation of T-lymphocytes. Although there are several hypotheses regarding the cause of autoimmune diseases and too many findings against and in favor of them, there is still no conclusive data. All these hypothesis and findings are discussed in the context of the more recent advances. PMID:1615352

  4. Islet endocrine-cell behavior from birth onward in mice with the nonobese diabetic genetic background

    NARCIS (Netherlands)

    Pelegri, C; Rosmalen, J G; Durant, S; Throsby, M; Alvès, V; Coulaud, J; Esling, A; Pléau, J M; Drexhage, H A; Homo-Delarche, F

    2001-01-01

    BACKGROUND: Glucagon-producing alpha cells play a crucial role during the perinatal period. Because of their peri-islet localization near the early dendritic and macrophage cell infiltration, we thought it pertinent to investigate alpha cells in greater depth in nonobese diabetic (NOD) mice, a well-

  5. The Role of MIF in Type 1 and Type 2 Diabetes Mellitus

    OpenAIRE

    Yuriko I. Sánchez-Zamora; Miriam Rodriguez-Sosa

    2014-01-01

    Autoimmunity and chronic low-grade inflammation are hallmarks of diabetes mellitus type one (T1DM) and type two (T2DM), respectively. Both processes are orchestrated by inflammatory cytokines, including the macrophage migration inhibitory factor (MIF). To date, MIF has been implicated in both types of diabetes; therefore, understanding the role of MIF could affect our understanding of the autoimmune or inflammatory responses that influence diabetic pathology. This review highlights our curren...

  6. Coeliac disease with autoimmune haemolytic anaemia.

    OpenAIRE

    Miller, D. G.

    1984-01-01

    Two patients are described who have developed autoimmune haemolytic anaemia in association with their coeliac disease. Autoimmune haemolytic anaemia may represent an extension of immunological disorders linked with coeliac disease, centred on the histocompatibility antigen B8.

  7. Autoimmune thyroid disorders—An update

    OpenAIRE

    Swain, Manorama; Swain, Truptirekha; Mohanty, Binoy Kumar

    2005-01-01

    Background: Autoimmune thyroid disease (AITD), a common organ specific autoimmune disorder is seen mostly in women between 30–50 yrs of age. Thyroid autoimmunity can cause several forms of thyroiditis ranging from hypothyroidism (Hashimoto’s thyroiditis) to hyperthyroidism (Graves’Disease). Prevalence rate of autoimmune mediated hypothyroidism is about 0.8 per 100 and 95% among them are women. Graves’ disease is about one tenth as common as hypothyroidism and tends to occur more in younger in...

  8. Roles for GTP-binding proteins in Vigna unguiculata responding to Nod factors or chitin elicitors

    International Nuclear Information System (INIS)

    μNod factors are lipo-chito-oligosaccharides secreted by Rhizobium to initiate deformation of legume root hairs and other changes such as increases in intracellular calcium in responsive root hairs. We studied the effects of Nod factors and G-protein modulators on root hair deformation and found significant deformation of root hairs after 30 min exposure to the compounds. Since G-proteins have been implicated in the root hair response to Nod factors in vivo, we examined the GTP-binding profiles of root microsomal membrane fractions isolated from the nodulation competent zone of the legume Vigna unguiculata. GTP competitively binds to microsomal membrane fractions labelled with [35S]GTPγS with a high affinity, yielding a two-site displacement curve with displacement constants (Ki) of 0.58 μM and 0.16 μM. Competition with either ATP or GDP revealed a one-site displacement curve with Ki of 4.14 and 11.7 μM respectively. To test if exposure to Nod factors affect the GTP-binding profile, we isolated microsomal membrane fractions from roots pretreated with either NodNGR[S] (from Rhizobium sp. NGR234) or the four-sugar, tetracetylchitotetraose (TACT) backbone of Nod factors. Pretreatment with NodNGR[S] results in an increased affinity for GTP of several hundred-fold. Roots pretreated with TACT also showed a similar but slightly smaller increase in affinity for GTP. To begin identification of possible candidates microsomal proteins were separated by SDS-PAGE and GTP-binding proteins were probed with [35S]GTPγS. Microsomal membrane factions isolated from roots pretreated with NodNGR[S] revealed two proteins (27 kDa and 25 kDa) with a higher affinity for GTPγS. Western blotting of the microsomal membrane preparation with anti-Rac antibodies also showed changes in Rac associated signal in microsomal membranes prepared from either NodNGR[S] or TACT pretreated roots. These results provide further support for a role for small, monomeric G-proteins in the Nod factor signal

  9. The properties of NodD were affected by mere variation in length within its hinge region

    Institute of Scientific and Technical Information of China (English)

    Bihe Hou; Fengqing Li; Xiaoer Yang; Cruofan Hong

    2009-01-01

    In Rhizobium leguminosarum by. viciae, NodD, a member of the LysR-type transcriptional regulators, while auto-regulating, activates transcription of other nod genes in the presence of naringenin. A hinge region of NodD was previously identified in our lab-oratory as a functional region independent of its N-terminal DNA-binding and C-terminal regulatory domain. Further study was carried out to see the possible effect of the length variation in the hinge region on NodD's properties. To our surprise, as many as seven classes of phenotypes were observed. Class Ⅰ is deficient of activating nodA transcription and abolishes auto-regulation; class Ⅱ is able to acti-vate nodA transcription independently of naringenin and abolishes auto-regulation; class Ⅲ retains auto-regulating but partial activating ability; class Ⅳ is able to activate transcription independently of narin-genin and retains auto-regulation; in class Ⅴ, nod A is transcribed constitutively but the transcription level is drastically down-regulated in the presence of narin-genin; in class Ⅵ, nodA is transcribed constitutively with higher induction ratio; in class Ⅶ, nodA is tran-scribed constitutively with lower induction ratio. To learn more about the possible mechanism, circular permutation assays were done, which showed that the length variation of the hinge of NodD caused by mutation led to the change in bend angles of nod pro-moter. This finding should help to get an insight into how transcriptional regulation is mediated by NodD at the molecular level as well as to understand the regulatory system of this important family.

  10. Activation of nucleotide oligomerization domain 2 (NOD2 by human cytomegalovirus initiates innate immune responses and restricts virus replication.

    Directory of Open Access Journals (Sweden)

    Arun Kapoor

    Full Text Available Nucleotide-binding oligomerization domain 2 (NOD2 is an important innate immune sensor of bacterial pathogens. Its induction results in activation of the classic NF-κB pathway and alternative pathways including type I IFN and autophagy. Although the importance of NOD2 in recognizing RNA viruses has recently been identified, its role in sensing DNA viruses has not been studied. We report that infection with human cytomegalovirus (HCMV results in significant induction of NOD2 expression, beginning as early as 2 hours post infection and increasing steadily 24 hours post infection and afterwards. Infection with human herpesvirus 1 and 2 does not induce NOD2 expression. While the HCMV-encoded glycoprotein B is not required for NOD2 induction, a replication competent virion is necessary. Lentivirus-based NOD2 knockdown in human foreskin fibroblasts (HFFs and U373 glioma cells leads to enhanced HCMV replication along with decreased levels of interferon beta (IFN-β and the pro-inflammatory cytokine, IL8. NOD2 induction in HCMV-infected cells activates downstream NF-κB and interferon pathways supported by reduced nuclear localization of NF-κB and pIRF3 in NOD2 knockdown HFFs. Stable overexpression of NOD2 in HFFs restricts HCMV replication in association with increased levels of IFN-β and IL8. Similarly, transient overexpression of NOD2 in U373 cells or its downstream kinase, RIPK2, results in decreased HCMV replication and enhanced cytokine responses. However, overexpression of a mutant NOD2, 3020insC, associated with severe Crohn's disease, results in enhanced HCMV replication and decreased levels of IFN-β in U373 cells. These results show for the first time that NOD2 plays a significant role in HCMV replication and may provide a model for studies of HCMV recognition by the host cell and HCMV colitis in Crohn's disease.

  11. Autoimmune Skin Diseases in the Dog

    OpenAIRE

    Parker, W M

    1981-01-01

    Diagnoses of autoimmune skin diseases require very careful observation of the skin lesions, and selection of an intact vesicle for histopathological examination. If available, immunofluorescent studies can be very useful in confirming the diagnosis of autoimmune skin disease. Seven autoimmune skin diseases are briefly reviewed. Therapy must be aggressive and owner warned of the guarded prognosis.

  12. [New insights in steroid diabetes].

    Science.gov (United States)

    Kurir, Tina Ticinović; Bozić, Josko; Markotić, Anita; Novak, Anela

    2012-10-01

    Glucocorticoids (GC) are the cornerstone in the treatment of numerous chronic autoimmune and inflammatory diseases. GC treatment is accompanied by significant metabolic adverse effects, including insulin resistance, glucose intolerance and diabetes, visceral adiposity, dyslipidemia and skeletal muscle atrophy. GCs are the most common cause of drug-induced diabetes mellitus. However, not everyone treated with glucocorticoids develops diabetes. Predictors of development of diabetes are age, weight, family history of diabetes mellitus, or personal history of gestational diabetes. There is evidence that patients with decreased insulin secretory reserve are much more likely to develop diabetes. Diabetes from topical steroid use is uncommon, but high-dose steroids have been associated with significant hyperglycemia, including development of hyperglycemic hyperosmolar syndrome and even diabetic ketoacidosis in patients with type 1 diabetes mellitus. Several mechanisms contribute to the development of hyperglycemia and steroid-induced diabetes, including decreased peripheral insulin sensitivity, increased hepatic glucose production, and inhibition of pancreatic insulin production and secretion. Physicians treating patients with GCs should be aware of the induction of metabolic disturbances and should not solely rely on fasting measurements. In addition, our review indicates that insulin therapy could be considered when treating patients on GC therapy. PMID:23814973

  13. Nonirradiated NOD/SCID-Human Chimeric Animal Model for Primary Human Multiple Myeloma : A Potential in Vivo Culture System

    OpenAIRE

    Huang, Shang-Yi; Tien, Hwei-Fang; Su, Fang-Hsein; Hsu, Su-Ming

    2004-01-01

    The NOD/SCID human chimeric animal model was generated by implanting of human fetal bones (FBs) into subcutaneous sites of NOD/SCID mice (NOD/SCID-hu+), followed by inoculation of primary bone marrow mononuclear cells (BMNCs) obtained from patients with multiple myeloma (MM) into the FBs. The BMNCs from 30 patients with MM were inoculated, and 28 (93%) of them revealed evidence of tumor growth of myeloma cells (MCs) in the NOD/SCID-hu+ mice. Intriguingly, 17 (61%) of the 28 patients’ BMNCs in...

  14. Multiparametric autoimmune diagnostics: recent advances

    OpenAIRE

    Damoiseaux J

    2016-01-01

    Jan Damoiseaux Central Diagnostic Laboratory, Maastricht University Medical Centre, Maastricht, the Netherlands Abstract: Autoimmune diagnostics in a routine clinical laboratory is constantly challenged by the discovery of new autoantibodies and technical innovations in the immunoassays applied. These challenges are, in particular, combined in the multiparametric immunoassays. Appropriate positioning of multiparametric immunoassays within the laboratory requires integrated knowledge of the c...

  15. Pancreatic Tuberculosis or Autoimmune Pancreatitis

    OpenAIRE

    Ayesha Salahuddin; Muhammad Wasif Saif

    2014-01-01

    Introduction. Isolated pancreatic and peripancreatic tuberculosis is a challenging diagnosis due to its rarity and variable presentation. Pancreatic tuberculosis can mimic pancreatic carcinoma. Similarly, autoimmune pancreatitis can appear as a focal lesion resembling pancreatic malignancy. Endoscopic ultrasound-guided fine needle aspiration provides an effective tool for differentiating between benign and malignant pancreatic lesions. The immune processes involved in immunoglobulin G4 relate...

  16. An autosomal locus causing autoimmune disease: Autoimmune polyglandular disease type I assigned to chromosome 21

    OpenAIRE

    Aaltonen, Johanna; Björses, Petra; Sandkuijl, Lodewijk; Perheentupa, Jaakko; Peltonen, Leena Johanna

    1994-01-01

    textabstractAutoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease characterized by a variable combination of the failure of the endocrine glands. The pathogenesis of this unique autoimmune disease is unknown; unlike many other autoimmune diseases, APECED does not show association to specific HLA haplotypes. Unravelling the APECED locus will identify a novel gene outside the HLA loci influencing the outcome of autoimmune diseases. We have assigned the di...

  17. Congenic Mesenchymal Stem Cell Therapy Reverses Hyperglycemia in Experimental Type 1 Diabetes

    OpenAIRE

    Jurewicz, Mollie; Yang, Sunmi; Augello, Andrea; Jonathan G Godwin; Moore, Robert F.; Azzi, Jamil; Fiorina, Paolo; Atkinson, Mark; Sayegh, Mohamed H.; Abdi, Reza

    2010-01-01

    OBJECTIVE A number of clinical trials are underway to test whether mesenchymal stem cells (MSCs) are effective in treating various diseases, including type 1 diabetes. Although this cell therapy holds great promise, the optimal source of MSCs has yet to be determined with respect to major histocompatibility complex matching. Here, we examine this question by testing the ability of congenic MSCs, obtained from the NOR mouse strain, to reverse recent-onset type 1 diabetes in NOD mice, as well a...

  18. Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice

    OpenAIRE

    Rita E Mirza; Fang, Milie M.; Eileen M Weinheimer-Haus; Ennis, William J.; Koh, Timothy J.

    2014-01-01

    The hypothesis of this study was that sustained activity of the Nod-like receptor protein (NLRP)-3 inflammasome in wounds of diabetic humans and mice contributes to the persistent inflammatory response and impaired healing characteristic of these wounds. Macrophages (Mp) isolated from wounds on diabetic humans and db/db mice exhibited sustained inflammasome activity associated with low level of expression of endogenous inflammasome inhibitors. Soluble factors in the biochemical milieu of thes...

  19. Thyroid autoimmunity in pregnant Nigerians

    Directory of Open Access Journals (Sweden)

    Oluwatosin O Kayode

    2015-01-01

    Full Text Available Context: Thyroid autoimmunity is a recognized disorder in pregnancy and is associated with a number of adverse pregnancy outcomes. Aim: This study set out to determine the relationship between pregnancy and thyroid autoimmunity in Nigerian women. Settings and Design: This was an analytical cross-sectional study carried out in a tertiary hospital in South Western Nigeria with a total study population of 108 pregnant and 52 nonpregnant women. Subjects and Methods: Serum thyroid stimulating hormone, free thyroxine and thyroid peroxidase antibodies (TPO-Ab were quantitatively determined using enzyme linked immuno-assays. Pregnant women were grouped into three categories ( 28 weeks. The relationship between pregnancy and thyroid autoimmunity was determined using Spearman correlation. Analysis of variance was used in comparison of means, Chi-square test used in analyzing proportions while P ≤ 0.05 was considered as significant. Results: The mean age of the pregnant women was 30.4 ± 6.0 years while the mean gestational age of all pregnant women was 20.6 ± 9.6 weeks. The mean TPO-Ab of 11.58 IU/ml in the pregnant was significantly higher than that of the controls of 7.23 IU/ml (P < 0.001. Out of 108 pregnant women, 27 (25% had elevated TPO-Ab as against about 2% of the nonpregnant women levels P < 0.001. The number of pregnant women with elevated TPO-Ab levels decreased from 33.3% in the first group to 25.6% and 15.2% in the second and third groups. Conclusion: Thyroid autoimmunity expressed by the presence of TPO-Ab is high among pregnant Nigerian women and the frequency of autoimmunity appears to decline with advancing gestational age.

  20. The use of stem cells for the treatment of autoimmune diseases

    Directory of Open Access Journals (Sweden)

    S.B. Rosa

    2007-12-01

    Full Text Available Autoimmune diseases constitute a heterogeneous group of conditions commonly treated with anti-inflammatory, immunosuppressant and immunomodulating drugs, with satisfactory results in most cases. Nevertheless, some patients become resistant to conventional therapy. The use of high doses of drugs in such cases results in the need for bone marrow reconstitution, a situation which has stimulated research into the use of hematopoietic stem cells in autoimmune disease therapy. Stem cell transplantation in such diseases aims to destroy the self-reacting immune cells and produce a new functional immune system, as well as substitute cells for tissue damaged in the course of the disease. Significant results, such as the reestablishment of tolerance and a decrease in the recurrence of autoimmune disease, have been reported following stem cell transplantation in patients with autoimmune disease in Brazil and throughout the world. These results suggest that stem cell transplantation has the potential to become an important therapeutic approach to the treatment of various autoimmune diseases including rheumatoid arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, Crohn's disease, autoimmune blood cytopenias, and type I diabetes mellitus.

  1. Diabetes and thalassaemia

    Directory of Open Access Journals (Sweden)

    Maria Barnard

    2013-03-01

    Full Text Available Diabetes is a significant complication of b-thalassaemia major. The aetiology includes iron overload causing b-cell destruction, autoimmunity, insulin resistance secondary to liver disease and development of type 1 or 2 diabetes. There are specific issues for patients with diabetes and thalassaemia which will be discussed here. Impaired carbohydrate metabolism must be detected early, to allow intensification of iron chelation. As life expectancy in thalassaemia rises, diabetic complications are seen. Optimising blood glucose and cardiovascular risk factor control is essential. Insulin remains critical for severely symptomatic patients. With milder hyperglycaemia, oral antidiabetic drugs are increasingly used. At Whittington Hospital, we wanted to address these issues. In 2005, we developed a unique Joint Diabetes Thalassaemia Clinic, where patients are reviewed jointly by specialist teams, including Consultant Diabetologist and Haematologist. The Joint Clinic aims to optimise diabetes, endocrine and thalassaemia care, while supporting patient self-management. A retrospective audit of the Joint Clinic (2005-09, showed improvement in glycaemic control, (Fructosamine falling from 344 umol/l to 319 umol/l. We compared our cohort to the National Diabetes Audit for England (2007-08. Patients attending the Joint Clinic achieved better glycaemic control (target reached: 73% Joint Clinic vs. 63% Nationally, blood pressure control (target reached: 58% Joint Clinic vs. 30% Nationally and cholesterol control (target reached: 81% Joint Clinic vs. 78% Nationally. 22.7% of our patients had ≥1 microvascular complication. A significant proportion had endocrinopathies (86% hypogonadism, 23% hypoparathyroidism, 18% hypothyroidism. Managing diabetes is one of the greatest challenges a person with thalassaemia can face. Training people to self-manage their diabetes and providing support from specialist teams working together are critical. The unique partnership

  2. Autoimmune diseases in pregnancy: maternal and fetal outcomes

    Directory of Open Access Journals (Sweden)

    Pavithra M. Vengetesh

    2015-02-01

    Full Text Available Background: The aim of this study was to assess the impact of autoimmune connective tissue disorders on the outcomes of pregnancy and the influence of treatment on pregnancy. Methods: Thirty-seven antenatal patients with autoimmune connective tissue diseases, comprising of Systemic Lupus Erythematosus (SLE, primary antiphospholipid antibody syndrome (APS, Mixed Connective Tissue Diseases (MCTD, ankylosing spondylitis and Takayasu arteritis were analysed. Results: Multigravidas constituted 89.4% and were associated with bad obstetric history. Before diagnosis and treatment, serious maternal complications of eclampsia and thromboembolism were observed in patients with SLE and APS. The live birth rates were 9% and 2.4% respectively in patients with SLE and APS. With appropriate treatment- aspirin, heparin and immunosuppressant, the live birth rates were raised to 70% in SLE and 100% in APS patients. Investigation for autoimmune disease in recurrent pregnancy loss is important. A rare association between MCTD and congenital anomaly - Rhizomelic chondrodysplasia punctata was observed. Preeclampsia, gestational diabetes, fetal growth restriction and preterm labour were the common complications noted. Conclusions: Active disease at onset of pregnancy, presence of Anti-ds DNA antibodies and secondary APS were strong predictors of poor pregnancy outcomes among patients with SLE. Vigilant monitoring during pregnancy is required for favourable outcomes. [Int J Reprod Contracept Obstet Gynecol 2015; 4(1.000: 9-14

  3. D-vitamin insufficiens - en mulig aetiologisk faktor ved autoimmune sygdomme

    DEFF Research Database (Denmark)

    Jørgensen, Søren Peter; Bartels, Lars Erik; Agnholt, Jørgen;

    2007-01-01

    . In experimental animal and cellular studies in vitro 1.25-(OH)2-vitamin D reduces inflammation. This article discusses the role of vitamin D in inflammatory bowel disease, type 1 diabetes mellitus, multiple sclerosis, and rheumatoid arthritis. Udgivelsesdato: 2007-Oct-22......The primary source of vitamin D in humans is sun exposure to the skin. The incidence of certain autoimmune diseases correlates positively with latitude. As vitamin D production increases with sun exposure, vitamin D insufficiency is hypothesised to influence the development of autoimmune diseases...

  4. In CD4+ T-Cell-Induced Diabetes, Macrophages Are the Final Effector Cells that Mediate Islet β-Cell Killing : Studies from an Acute Model

    OpenAIRE

    Calderon, Boris; Suri, Anish; Unanue, Emil R.

    2006-01-01

    To understand better how diabetogenic CD4+ T cells induce islet β-cell death and cause diabetes, a transfer model of acute diabetes using the diabetogenic CD4+ BDC2.5 T-cell clone was established. Transfer of activated BDC T cells into NOD.scid mice resulted in diabetes within a week, characterized by strong inflammatory reaction. Electron micrographs of pancreas depicted macrophages in close contact with β cells that exhibited signs of apoptosis. Transfer into irradiated recipients inhibited...

  5. Concurrent synthesis and release of nod-gene-inducing flavonoids from alfalfa roots

    International Nuclear Information System (INIS)

    Flavonoid signals from alfalfa (Medicago sativa L.) induce transcription of nodulation (nod) genes in Rhizobium meliloti. Alfalfa roots release three major nod-gene inducers: 4',7-dihydroxyflavanone, 4',7-dihydroxyflavone, and 4,4'-dihydroxy-2'-methoxychalcone. The objective of the present study was to define temporal relationships between synthesis and exudation for those flavonoids. Requirements for concurrent flavonoid biosynthesis were assessed by treating roots of intact alfalfa seedlings with [U-14C]-L-phenylalanine in the presence or absence of the phenylalanine ammonia-lyase inhibitor L-2-aminoxy-3-phenylpropionic acid (AOPP). In the absence of AOPP, each of the three flavonoids in exudates contained 14C. In the presence of AOPP, 14C labeling and release of all the exuded nod-gene inducers were reduced significantly. AOPP inhibited labeling and release of the strongest nod-gene inducer, methoxychalcone, by more than 90%. The release process responsible for exudation of nod-gene inducers appears to be specific rather than a general phenomenon such as a sloughing off of cells during root growth

  6. Establishment of Retinoblastoma Model in NOD-SCID Mice and Study of Metastasis

    Institute of Scientific and Technical Information of China (English)

    Bo Zhang; Yongping Li; Xiufeng Zhong; Wenge Huang; Li Nie; Wenxin Zhang

    2005-01-01

    Purpose: To establish model of retinoblastoma subcutaneously in NOD-SCID mice and study rules of formation and distribution of retinoblastoma metastasis.Methods: Retinoblastoma cells SO-RB50 were inoculated subcutaneously in NOD-SCID mice. Animal acts and tumor formation, growth and metastasis in NOD-SCID mice were observed. Primary and metastatic tumors were studied pathohistologically by HE and immunohistochemical staining.Results: The latent periods of tumor growth were 12~19 days and the taken rate of tumor was 100%. 32 days later, 5 NOD-SCID mice were found with tumors that had metastasized to areas mainly located in the abdominal cavity and the side of the kidney; the metastatic time of tumors in the mice also differed. The tumor cells of the primary nodules and the metastasis were similar with human retinoblastoma cells and positive in immunohistochemical staining of NSE.Conclusion: The subcutaneous model of retinoblastoma in NOD-SCID mice showed a high taken rate and a short latent period of tumor, which had a high metastatic rate and was the best model in research of behaviors of retinoblastoma at present.

  7. Diabetic Retinopathy

    Science.gov (United States)

    ... Disease > Facts About Diabetic Eye Disease Facts About Diabetic Eye Disease Points to Remember Diabetic eye disease ... existing therapies for different patient groups. What is diabetic eye disease? Diabetic eye disease can affect many ...

  8. Diabetes - resources

    Science.gov (United States)

    Resources - diabetes ... The following sites provide further information on diabetes : American Diabetes Association -- www.diabetes.org Juvenile Diabetes Research Foundation International -- www.jdrf.org National Center for Chronic Disease Prevention and Health Promotion -- ...

  9. Autoimmune Thyroid Disease in Rheumatoid Arthritis: A Global Perspective

    Science.gov (United States)

    Cárdenas Roldán, Jorge; Amaya-Amaya, Jenny; Castellanos-de la Hoz, Juan; Giraldo-Villamil, Juliana; Montoya-Ortiz, Gladys; Cruz-Tapias, Paola; Rojas-Villarraga, Adriana; Mantilla, Rubén D.; Anaya, Juan-Manuel

    2012-01-01

    Objective. To determine the prevalence and impact of autoimmune thyroid disease (AITD) in patients with rheumatoid arthritis (RA). Methods. Eight-hundred patients were included. The association between AITD and RA was analyzed was analyzed by bivariate and multivariate analysis. In addition, a literature review was done focusing on geographical variations. Results. In our cohort the prevalence of AITD was 9.8% while the presence of antibodies was 37.8% for antithyroperoxidase enzyme (TPOAb) and 20.8% for antithyroglobulin protein (TgAb). The presence of type 2 diabetes, thrombosis, abnormal body mass index, and a high educational level was positively associated with AITD. The literature review disclosed a geographical variation of AITD in RA ranging from 0.5% to 27%. Autoantibody prevalence ranges from 6% to 31% for TgAb, 5% to 37% for TPOAb, and from 11.4% to 32% for the presence of either of the two. Conclusion. AITD is not uncommon in RA and should be systematically assessed since it is a risk factor for developing diabetes and cardiovascular disease. These results may help to further study the common mechanisms of autoimmune diseases, to improve patients' outcome, and to define public health policies. An international consensus to accurately diagnose AITD is warranted. PMID:23209899

  10. Inflammatory glycoproteins in cardiometabolic disorders, autoimmune diseases and cancer.

    Science.gov (United States)

    Connelly, Margery A; Gruppen, Eke G; Otvos, James D; Dullaart, Robin P F

    2016-08-01

    The physiological function initially attributed to the oligosaccharide moieties or glycans on inflammatory glycoproteins was to improve protein stability. However, it is now clear that glycans play a prominent role in glycoprotein structure and function and in some cases contribute to disease states. In fact, glycan processing contributes to pathogenicity not only in autoimmune disorders but also in atherosclerotic cardiovascular disease, diabetes and malignancy. While most clinical laboratory tests measure circulating levels of inflammatory proteins, newly developed diagnostic and prognostic tests are harvesting the information that can be gleaned by measuring the amount or structure of the attached glycans, which may be unique to individuals as well as various diseases. As such, these newer glycan-based tests may provide future means for more personalized approaches to patient stratification and improved patient care. Here we will discuss recent progress in high-throughput laboratory methods for glycomics (i.e. the study of glycan structures) and glycoprotein quantification by methods such as mass spectrometry and nuclear magnetic resonance spectroscopy. We will also review the clinical utility of glycoprotein and glycan measurements in the prediction of common low-grade inflammatory disorders including cardiovascular disease, diabetes and cancer, as well as for monitoring autoimmune disease activity. PMID:27312321

  11. Interleukin-1 beta targeted therapy for type 2 diabetes

    DEFF Research Database (Denmark)

    Maedler, K.; Dharmadhikari, G.; Schumann, D.M.;

    2009-01-01

    plays a role in various diseases, including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases and type 1 diabetes, as well as in diseases associated with metabolic syndrome such as atherosclerosis, chronic heart failure and type 2 diabetes. Macrophage are the primary source...

  12. Animal Models of Autoimmune Neuropathy

    OpenAIRE

    Soliven, Betty

    2014-01-01

    The peripheral nervous system (PNS) comprises the cranial nerves, the spinal nerves with their roots and rami, dorsal root ganglia neurons, the peripheral nerves, and peripheral components of the autonomic nervous system. Cell-mediated or antibody-mediated immune attack on the PNS results in distinct clinical syndromes, which are classified based on the tempo of illness, PNS component(s) involved, and the culprit antigen(s) identified. Insights into the pathogenesis of autoimmune neuropathy h...

  13. Progranulin antibodies in autoimmune diseases.

    Science.gov (United States)

    Thurner, Lorenz; Preuss, Klaus-Dieter; Fadle, Natalie; Regitz, Evi; Klemm, Philipp; Zaks, Marina; Kemele, Maria; Hasenfus, Andrea; Csernok, Elena; Gross, Wolfgang L; Pasquali, Jean-Louis; Martin, Thierry; Bohle, Rainer Maria; Pfreundschuh, Michael

    2013-05-01

    Systemic vasculitides constitute a heterogeneous group of diseases. Autoimmunity mediated by B lymphocytes and their humoral effector mechanisms play a major role in ANCA-associated vasculitis (AAV) as well as in non-ANCA associated primary systemic vasculitides and in the different types of autoimmune connective tissue disorders and rheumatoid arthritis. In order to detect autoantibodies in systemic vasculitides, we screened protein macroarrays of human cDNA expression libraries with sera from patients with ANCA-associated and ANCA-negative primary systemic vasculitides. This approach led to the identification of antibodies against progranulin, a 88 kDA secreted glycoprotein with strong anti-inflammatory activity in the course of disease of giant-cell arteritis/polymyalgia rheumatica (14/65), Takayasu's arteritis (4/13), classical panarteritis nodosa (4/10), Behcet's disease (2/6) and in the course of disease in granulomatosis with polyangiitis (31/75), Churg-Strauss syndrome (7/23) and in microscopic polyangiitis (7/19). In extended screenings the progranulin antibodies were also detected in other autoimmune diseases such as systemic lupus erythematosus (39/91) and rheumatoid arthritis (16/44). Progranulin antibodies were detected only in 1 of 97 healthy controls. Anti-progranulin positive patients with systemic vasculitides, systemic lupus erythematosus or rheumatoid arthritis had significant lower progranulin plasma levels, indicating a neutralizing effect. In light of the anti-inflammatory effects of progranulin, progranulin antibodies might exert pro-inflammatory effects thus contributing to the pathogenesis of the respective autoimmune diseases and might serve as a marker for disease activity. This hypothesis is supported by the fact that a positive progranulin antibody status was associated with active disease in granulomatosis with polyangiitis. PMID:23149338

  14. Immunotherapeutic strategies in autoimmune uveitis

    OpenAIRE

    Papotto, Pedro Henrique; Marengo, Eliana Blini; Sardinha, Luiz Roberto; Goldberg, Anna Carla; Rizzo, Luiz Vicente

    2014-01-01

    Autoimmune uveitis is an organ-specific disorder characterized by irreversible lesions to the eye that predominantly affect people in their most productive years and is among the leading causes of visual deficit and blindness. Currently available therapies are effective in the treatment of a wide spectrum of uveitis, but are often associated with severe side effects. Here, we review ongoing research with promising immunomodulatory therapeutic strategies, describing their specific features, in...

  15. Cystic Lesions in Autoimmune Pancreatitis

    OpenAIRE

    Gompertz, Macarena; Morales, Claudia; Aldana, Hernán; Castillo, Jaime; Berger, Zoltán

    2015-01-01

    Autoimmune pancreatitis (AIP) can be chronic or recurrent, but frequently completely reversible after steroid treatment. A cystic lesion in AIP is a rare finding, and it can mimic a pancreatic cystic neoplasm. Difficulties in an exact diagnosis interfere with treatment, and surgery cannot be avoided in some cases. We report the history of a 63-year-old male presenting with jaundice and pruritus. AIP was confirmed by imaging and elevated IgG4 blood levels, and the patient completely recovered ...

  16. Historical reflections on autoimmune hepatitis

    Institute of Scientific and Technical Information of China (English)

    Ian R Mackay

    2008-01-01

    Autoimmune hepatitis (AIH),initially known as chronic active or active chronic hepatitis (and by various other names),first came under clinical notice in the late 1940s.However,quite likely,chronic active hepatitis (CAH) had been observed prior to this and was attributed to a persistently destructive virus infection of the liver.An earlier (and controversial) designation in 1956 as lupoid hepatitis was derived from associated L.E.cell test positivity and emphasized accompanying multisystem features and immunological aberrations.Young women featured prominently in early descriptions of CAH.AIH was first applied in 1965 as a descriptive term.Disease-characteristic autoantibodies were defined from the early 1960s,notably antinuclear antibody (ANA),smooth muscle antibody (SMA) and liver-kidney microsomal (LKM) antibody.These are still widely used diagnostically but their relationship to pathogenesis is still not evident.A liver and disease specific autoantigen has long been searched for but unsuccessfully.Prolonged immunosuppressive therapy with predisolone and azathioprine in the 1960s proved beneficial and remains standard therapy today.AIH like many other autoimmune diseases is associated with particular HLA alleles especially with the "ancestral" B8,DR3 haplotype,and also with DR4.Looking forwards,AIH is one of the several enigmatic autoimmune diseases that,despite being (relatively) organ specific,are marked by autoimmune reactivities with non-organ-specific autoantigens.New paradigms are needed to explain the occurrence,expressions and pathogenesis of such diseases.

  17. Historical reflections on autoimmune hepatitis

    OpenAIRE

    Mackay, Ian R.

    2008-01-01

    Autoimmune hepatitis (AIH), initially known as chronic active or active chronic hepatitis (and by various other names), first came under clinical notice in the late 1940s. However, quite likely, chronic active hepatitis (CAH) had been observed prior to this and was attributed to a persistently destructive virus infection of the liver. An earlier (and controversial) designation in 1956 as lupoid hepatitis was derived from associated L.E. cell test positivity and emphasized accompanying multisy...

  18. Mechanism underlying defective interferon gamma-induced IDO expression in non-obese diabetic mouse fibroblasts.

    Directory of Open Access Journals (Sweden)

    Azadeh Hosseini-Tabatabaei

    Full Text Available Indoleamine 2,3-dioxygenase (IDO can locally suppress T cell-mediated immune responses. It has been shown that defective self-tolerance in early prediabetic female non-obese diabetic (NOD mice can be attributed to the impaired interferon-gamma (IFN-γ- induced IDO expression in dendritic cells of these animals. As IFN-γ can induce IDO in both dendritic cells and fibroblasts, we asked the question of whether there exists a similar defect in IFN-γ-induced IDO expression in NOD mice dermal fibroblasts. To this end, we examined the effect of IFN-γ on expression of IDO and its enzymatic activity in NOD dermal fibroblasts. The results showed that fibroblasts from either prediabetic (8 wks of age female or male, and diabetic female or male (12 and 24 wks of age respectively NOD mice failed to express IDO in response to IFN-γ treatment. To find underlying mechanisms, we scrutinized the IFN- γ signaling pathway and investigated expression of other IFN-γ-modulated factors including major histocompatibility complex class I (MHC-I and type I collagen (COL-I. The findings revealed a defect of signal transducer and activator of transcription 1 (STAT1 phosphorylation in NOD cells relative to that of controls. Furthermore, we found an increase in MHC-I and suppression of COL-I expression in fibroblasts from both NOD and control mice following IFN-γ treatment; indicating that the impaired response to IFN-γ in NOD fibroblasts is specific to IDO gene. Finally, we showed that an IFN-γ-independent IDO expression pathway i.e. lipopolysaccharide (LPS-mediated-c-Jun kinase is operative in NOD mice fibroblast. In conclusion, the findings of this study for the first time indicate that IFN-γ fails to induce IDO expression in NOD dermal fibroblasts; this may partially be due to defective STAT1 phosphorylation in IFN-γ-induced-IDO signaling pathway.

  19. Design, automated synthesis and immunological evaluation of NOD2-ligand–antigen conjugates

    Directory of Open Access Journals (Sweden)

    Marian M. J. H. P. Willems

    2014-06-01

    Full Text Available The covalent attachment of an innate immune system stimulating agent to an antigen can provide active vaccine modalities capable of eliciting a potent immune response against the incorporated antigen. Here we describe the design, automated synthesis and immunological evaluation of a set of four muramyl dipeptide–peptide antigen conjugates. Muramyl dipeptide (MDP represents a well-known ligand for the intracellular NOD2 receptor and our study shows that covalently linking an MDP-moiety to an antigenic peptide can lead to a construct that is capable of stimulating the NOD2 receptor if the ligand is attached at the anomeric center of the muramic acid. The constructs can be processed by dendritic cells (DCs and the conjugation does not adversely affect the presentation of the incorporated SIINFEKL epitope on MHC-I molecules. However, stimulation of the NOD2 receptor in DCs was not sufficient to provide a strong immunostimulatory signal.

  20. [Autoimmune hepatitis induced by isotretionine].

    Science.gov (United States)

    Guzman Rojas, Patricia; Gallegos Lopez, Roxana; Ciliotta Chehade, Alessandra; Scavino, Yolanda; Morales, Alejandro; Tagle, Martín

    2016-01-01

    We describe a case of a teenage patient with the diagnosis of drug induced autoimmune hepatitis. The patient is a 16 years old female, with the past medical history of Hashimoto’s hypothyroidism controlled with levothyroxine, who started treatment with Isotretionin (®Accutane) 20 mg q/12 hours for a total of 3 months for the treatment of severe acne. The physical examination was within normal limits and the results of the laboratory exams are: Baseline values of ALT 28 U/L, AST 28 U/L. Three months later: AST 756 U/L, ALT 1199U/L, alkaline phosphatase 114 U/L, with normal bilirrubin levels throughout the process. The serology studies were negative for all viral hepatitis; ANA titers were positive (1/160) and igG levels were also elevated. A liver biopsy was performed, and was compatible with the diagnosis of autoimmune hepatitis. Corticosteroid therapy was started with Prednisone 40 mg per day one week after stopping the treatment with isotretionin, observing an improvement in the laboratory values. We describe this case and review the world literature since there are no reported cases of Isotretinoin-induced autoimmune hepatitis. PMID:27131947

  1. Pancreatic Tuberculosis or Autoimmune Pancreatitis

    Directory of Open Access Journals (Sweden)

    Ayesha Salahuddin

    2014-01-01

    Full Text Available Introduction. Isolated pancreatic and peripancreatic tuberculosis is a challenging diagnosis due to its rarity and variable presentation. Pancreatic tuberculosis can mimic pancreatic carcinoma. Similarly, autoimmune pancreatitis can appear as a focal lesion resembling pancreatic malignancy. Endoscopic ultrasound-guided fine needle aspiration provides an effective tool for differentiating between benign and malignant pancreatic lesions. The immune processes involved in immunoglobulin G4 related systemic diseases and tuberculosis appear to have some similarities. Case Report. We report a case of a 59-year-old Southeast Asian male who presented with fever, weight loss, and obstructive jaundice. CT scan revealed pancreatic mass and enlarged peripancreatic lymph nodes. Endoscopic ultrasound-guided fine needle aspiration confirmed the presence of mycobacterium tuberculosis. Patient also had high immunoglobulin G4 levels suggestive of autoimmune pancreatitis. He was started on antituberculosis medications and steroids. Clinically, he responded to treatment. Follow-up imaging showed findings suggestive of chronic pancreatitis. Discussion. Pancreatic tuberculosis and autoimmune pancreatitis can mimic pancreatic malignancy. Accurate diagnosis is imperative as unnecessary surgical intervention can be avoided. Endoscopic ultrasound-guided fine needle aspiration seems to be the diagnostic test of choice for pancreatic masses. Long-term follow-up is warranted in cases of chronic pancreatitis.

  2. Establishment of NOD/SCID mouse models of human hepatocellular carcinoma via subcutaneous transplantation of histologically intact tumor tissue

    Institute of Scientific and Technical Information of China (English)

    Mingxia Yan; Hong Li; Fangyu Zhao; Lixing Zhang; Chao Ge; Ming Yao; Jinjun Li

    2013-01-01

    Hepatocellular carcinoma (HCC) is one of the most deadly human cancers,but it is very difficult to establish an animal model by using surgical specimens.In the present experiment,histologically intact fresh surgical specimens of HCC were subcutaneously transplanted in non-obese diabetic/severe combined immunodeficienccy (NOD/SCID) mice.The biological characteristics of the original and the corresponding transplanted tumors and cell lines were investigated.The results showed that 5 new animal models and 2 primary cell lines were successfully established from surgical specimens.Hematoxylin-eosin staining showed that xenografts retained major histological features of the original surgical specimens.The two new cell lines had been cultivated for 3 years and successively passaged for more than 100 passages in vitro.The morphological characteristics and biologic features of the two cell lines were genetically similar to the original tumor.The subcutaneous transplant animal models with histologically intact tumor tissue and primary cell lines could be useful for in vivo and in vitro testing of anti-cancer drugs and be ideal models to study various biologic features of HCC.

  3. Species-specific engagement of human nucleotide oligomerization domain 2 (NOD)2 and Toll-like receptor (TLR) signalling upon intracellular bacterial infection: role of Crohn's associated NOD2 gene variants.

    Science.gov (United States)

    Salem, M; Seidelin, J B; Eickhardt, S; Alhede, M; Rogler, G; Nielsen, O H

    2015-03-01

    Recognition of bacterial peptidoglycan-derived muramyl-dipeptide (MDP) by nucleotide oligomerization domain 2 (NOD2) induces crucial innate immune responses. Most bacteria carry the N-acetylated form of MDP (A-MDP) in their cell membranes, whereas N-glycolyl MDP (G-MDP) is typical for mycobacteria. Experimental murine studies have reported G-MDP to have a greater NOD2-stimulating capacity than A-MDP. As NOD2 polymorphisms are associated with Crohn's disease (CD), a link has been suggested between mycobacterial infections and CD. Thus, the aim was to investigate if NOD2 responses are dependent upon type of MDP and further to determine the role of NOD2 gene variants for the bacterial recognition in CD. The response pattern to A-MDP, G-MDP, Mycobacterium segmatis (expressing mainly G-MDP) and M. segmatisΔnamH (expressing A-MDP), Listeria monocytogenes (LM) (an A-MDP-containing bacteria) and M. avium paratuberculosis (MAP) (a G-MDP-containing bacteria associated with CD) was investigated in human peripheral blood mononuclear cells (PBMCs). A-MDP and M. segmatisΔnamH induced significantly higher tumour necrosis factor (TNF)-α protein levels in healthy wild-type NOD2 PBMCs compared with G-MDP and M. segmatis. NOD2 mutations resulted in a low tumour necrosis factor (TNF)-α protein secretion following stimulation with LM. Contrary to this, TNF-α levels were unchanged upon MAP stimulation regardless of NOD2 genotype and MAP solely activated NOD2- and Toll-like receptor (TLRs)-pathway with an enhanced production of interleukin (IL)-1β and IL-10. In conclusion, the results indicate that CD-associated NOD2 deficiencies might affect the response towards a broader array of commensal and pathogenic bacteria expressing A-MDP, whereas they attenuate the role of mycobacteria in the pathogenesis of CD. PMID:25335775

  4. Expressão dos genes nodC, nodW e nopP em Bradyrhizobium japonicum estirpe CPAC 15 avaliada por RT-qPCR Expression of nodC, nodW and nopP genes in Bradyrhizobium japonicum CPAC 15 strain evaluated by RT-qPCR

    Directory of Open Access Journals (Sweden)

    Simone Bortolan

    2009-11-01

    Full Text Available O objetivo deste trabalho foi avaliar a expressão, por RT-qPCR, dos genes de nodulação nodC e nodW e do gene nopP da estirpe CPAC 15, que provavelmente atuam na infecção das raízes da soja. Foram realizados dois experimentos. No primeiro, a expressão dos genes foi avaliada nas células após a incubação com genisteína por 15 min, 1, 4 e 8 horas. Os resultados revelaram que os três genes apresentaram maior expressão imediatamente após o contato com o indutor (15 min. No segundo experimento, a bactéria foi cultivada na presença de indutores (genisteína ou exsudatos de sementes de soja por 48 horas. A expressão dos três genes foi maior na presença de genisteína, com valores de expressão para nodC, nodW e nopP superiores ao controle. Os resultados obtidos confirmam a funcionalidade dos três genes na estirpe CPAC 15, com ênfase para o nopP, cuja funcionalidade em Bradyrhizobium japonicum foi descrita pela primeira vez.The objective of this work was to evaluate, by RT-qPCR, the expression of the nodC and nodW nodulation genes and of the nopP gene of the CPAC 15 strain, which probably play a role in the infection of soybean roots. Two experiments were done. In the first, the gene expression was evaluated in cells after incubation with genistein for 15 min, 1, 4 and 8 hours. Results showed that the three genes showed higher expression immediately after contact with the inducer (15 min. In the second experiment, the bacterium was grown in the presence of inducers (genistein or soybean seed exudates for 48 hours. The expression of the three genes was greater when induced by genistein, and the expression of nodC, nodW and nopP had higher values than the control. The results confirm the functionality of the three genes in the CPAC 15 strain, with an emphasis on the nopP, whose functionality in Bradyrhizobium japonicum was described for the first time.

  5. How Does Age at Onset Influence the Outcome of Autoimmune Diseases?

    Directory of Open Access Journals (Sweden)

    Manuel J. Amador-Patarroyo

    2012-01-01

    Full Text Available The age at onset refers to the time period at which an individual experiences the first symptoms of a disease. In autoimmune diseases (ADs, these symptoms can be subtle but are very relevant for diagnosis. They can appear during childhood, adulthood or late in life and may vary depending on the age at onset. Variables like mortality and morbidity and the role of genes will be reviewed with a focus on the major autoimmune disorders, namely, systemic lupus erythematosus (SLE, rheumatoid arthritis (RA, multiple sclerosis (MS, type 1 diabetes mellitus (T1D, Sjögren's syndrome, and autoimmune thyroiditis (AITD. Early age at onset is a worst prognostic factor for some ADs (i.e., SLE and T1D, while for others it does not have a significant influence on the course of disease (i.e., SS or no unanimous consensus exists (i.e., RA and MS.

  6. Toxins Targeting the KV1.3 Channel: Potential Immunomodulators for Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Yipeng Zhao

    2015-05-01

    Full Text Available Autoimmune diseases are usually accompanied by tissue injury caused by autoantigen-specific T-cells. KV1.3 channels participate in modulating calcium signaling to induce T-cell proliferation, immune activation and cytokine production. Effector memory T (TEM-cells, which play major roles in many autoimmune diseases, are controlled by blocking KV1.3 channels on the membrane. Toxins derived from animal venoms have been found to selectively target a variety of ion channels, including KV1.3. By blocking the KV1.3 channel, these toxins are able to suppress the activation and proliferation of TEM cells and may improve TEM cell-mediated autoimmune diseases, such as multiple sclerosis and type I diabetes mellitus.

  7. [MEDICAL CANNABIS - A SOURCE FOR A NEW TREATMENT FOR AUTOIMMUNE DISEASE?].

    Science.gov (United States)

    Katz, Daphna; Katz, Itay; Golan, Amir

    2016-02-01

    Medical uses of Cannabis sativa have been known for over 6,000 years. Nowadays, cannabis is mostly known for its psychotropic effects and its ability to relieve pain, even though there is evidence of cannabis use for autoimmune diseases like rheumatoid arthritis centuries ago. The pharmacological therapy in autoimmune diseases is mainly based on immunosuppression of diffefent axes of the immune system while many of the drugs have major side effects. In this review we set out to examine the rule of Cannabis sativa as an immunomodulator and its potential as a new treatment option. In order to examine this subject we will focus on some major autoimmune diseases such as diabetes type I and rheumatoid arthritis. PMID:27215114

  8. Radiolabeling of lipo-chitooligosaccharides using the NodH sulfotransferase: a two-step enzymatic procedure

    Directory of Open Access Journals (Sweden)

    Ranjeva Raoul

    2004-04-01

    Full Text Available Abstract Background The NodH sulfotransferase from Sinorhizobium meliloti has been used to radiolabel lipochitooligosaccharidic (LCO Nod factor signals with 35S from inorganic sulfate in a two-step enzymatic procedure. The first step involved the production of 3'-phosphoadenosine 5'-phosphosulfate (PAPS, a sulphate donor, using enzymes contained in a yeast extract, and the second step used the NodH enzyme. However with this established procedure, only a low incorporation of the initial inorganic sulfate into the Nod factors was obtained (about 7% after purification of the labeled compounds. The aim of this work was to optimize the radiolabelling of Nod factors with 35S. Results The limiting step has been shown to be the sulfation of ATP and its subsequent conversion into PAPS (first step, the sulfate donor for the NodH sulfotransferase activity (second step. By the addition of GTP to the reaction mixture and by manipulating the [ATP]/[Mg2+] ratio the yield of PAPS has been increased from 13% to 80%. Using the radiolabeled PAPS we have shown that the efficiency of sulfate transfer to LCOs, by the recombinant S. meliloti NodH sulfotransferase is strongly influenced by the length of the oligosaccharide chain. Variations in the substitutions on the non-reducing sugar, including the structure of the fatty acyl chain, had little effect and Nod factors from the heterologous bacterium Rhizobium tropici could be sulfated by NodH from S. meliloti. Conclusions By characterizing the two steps we have optimized the procedure to radiolabel biologically-important, lipo-chitooligosaccharide (LCO Nod factors to a specific radioactivity of about 800 Ci.mmol-1 with an incorporation of 60% of the initial inorganic sulfate. The two-step sulfation procedure may be used to radiolabel a variety of related LCO molecules.

  9. Pathogenesis of Autoimmune Diseases: A Short Review

    Directory of Open Access Journals (Sweden)

    Jithin Jose

    2014-01-01

    Full Text Available Autoimmunity is characterized by the reaction of cells (auto reactive T-lymphocytes or products (autoantibodies of the immune system against the organism’s own antigens (autoantigen. It may be part of the physiological immune response (natural autoimmunity or pathologically induced, which may eventually lead to development of clinical abnormalities (autoimmune disease. Different mechanisms are involved in the induction and progression of autoimmunity. These include genetic or acquired defects in immune tolerance or immune regulatory pathways, molecular mimicry to viral or bacterial protein, an impaired clearance of apoptotic cell material. A A number of diseases have been identified in which there is autoimmunity, due to copious production of autoantibodies and autoreactive cells. The aim of the present article is to review on the pathogenesis of autoimmune diseases.

  10. Pathogenesis of Fulminant Type 1 Diabetes

    OpenAIRE

    Imagawa, Akihisa; Hanafusa, Toshiaki

    2006-01-01

    Fulminant type 1 diabetes is a new subtype of type 1 diabetes. The term was established in 2000. It is a syndrome characterized by a markedly rapid and almost complete destruction of pancreatic β-cells. Several lines of evidence suggest that both genetic factors, such as human leukocyte antigen (HLA), and environmental factors, such as viral infection, contribute to the development of this disease. It is also suggested that autoimmune processes contribute less critically to fulminant type 1 d...

  11. Diabetes research: are we getting anywhere?

    OpenAIRE

    Zinman, B

    1996-01-01

    Although 75 years have elapsed since the discovery of insulin, diabetes mellitus continues to be a chronic disease associated with significant morbidity and mortality. However, progress in basic and clinical research has advanced our understanding of the pathophysiology of the disease. The development of animal models has facilitated research into the autoimmune processes that underlie insulin-dependent diabetes, although the factors that trigger these mechanisms still remain a mystery. Resea...

  12. Autoimmune disease-associated variants of extracellular endoplasmic reticulum aminopeptidase 1 induce altered innate immune responses by human immune cells.

    Science.gov (United States)

    Aldhamen, Yasser A; Pepelyayeva, Yuliya; Rastall, David P W; Seregin, Sergey S; Zervoudi, Efthalia; Koumantou, Despoina; Aylsworth, Charles F; Quiroga, Dionisia; Godbehere, Sarah; Georgiadis, Dimitris; Stratikos, Efstratios; Amalfitano, Andrea

    2015-01-01

    Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms have been linked to several autoimmune diseases; however, the molecular mechanisms underlying these associations are not well understood. Recently, we demonstrated that ERAP1 regulates key aspects of the innate immune response. Previous studies show ERAP1 to be endoplasmic reticulum-localized and secreted during inflammation. Herein, we investigate the possible roles that ERAP1 polymorphic variants may have in modulating the innate immune responses of human peripheral blood mononuclear cells (hPBMCs) using two experimental methods: extracellular exposure of hPBMCs to ERAP1 variants and adenovirus (Ad)-based ERAP1 expression. We found that exposure of hPBMCs to ERAP1 variant proteins as well as ERAP1 overexpression by Ad5 vectors increased inflammatory cytokine and chemokine production, and enhanced immune cell activation. Investigating the molecular mechanisms behind these responses revealed that ERAP1 is able to activate innate immunity via multiple pathways, including the NLRP3 (NOD-like receptor, pyrin domain-containing 3) inflammasome. Importantly, these responses varied if autoimmune disease-associated variants of ERAP1 were examined in the assay systems. Unexpectedly, blocking ERAP1 cellular internalization augmented IL-1β production. To our knowledge, this is the first report identifying ERAP1 as being involved in modulating innate responses of human immune cells, a finding that may explain why ERAP1 has been genetically associated with several autoimmune diseases. PMID:25591727

  13. Hepatitis C virus infection in a child with autoimmune polyendocrine syndrome type 2: a case report

    Directory of Open Access Journals (Sweden)

    Metwalley Kotb

    2012-07-01

    Full Text Available Abstract Introduction Autoimmune polyendocrine syndrome type 2 is a rare disorder. Its prevalence in western populations has been reported as 1.5 to 4.5/100,000. On the other hand, its prevalence in Egypt is unknown. It is characterized by the association of autoimmune Addison’s disease with thyroid autoimmune diseases and/or type I diabetes mellitus. Hepatitis C virus infection is an important public health issue worldwide. Egypt has the highest prevalence of hepatitis C virus infection of any country in the world. It is estimated to be 8% in urban and 25% in rural areas. We present the case of an Egyptian child with autoimmune polyendocrine syndrome type 2 associated with chronic hepatitis C infection. Case presentation A 14-year-old Egyptian boy with type 1 diabetes mellitus was referred to our institution for an evaluation of recurrent attacks of hypoglycemia of two months duration. The initial clinical examination revealed hypotension as well as vitiligo of the skin. He had high potassium, low sodium, low cortisol, high adrenocorticotropic hormone, slightly high thyroid stimulating levels with strong positivity of anti-thyroglobulin and anti-thyroid peroxidase antibodies. The hepatitis C antibody and hepatitis C virus–polymerase chain reaction were positive. Based on these findings, a diagnosis of autoimmune polyendocrine syndrome type 2 with chronic hepatitis C was made. He was started on hydrocortisone (10mg twice daily, fludrocortisone (0.1mg twice daily and multiple daily doses of insulin. He showed great improvement of his symptoms on the prescribed treatment. Conclusions The importance of the early diagnosis of autoimmune polyendocrine syndrome type 2 and the possibility of its association with chronic hepatitis C infection should be considered in order to implement the proper management of such cases.

  14. Type I Diabetes-Associated Tolerogenic Properties of Interleukin-2

    OpenAIRE

    Aziz Alami Chentoufi; Simon Gaudreau; Alex Nguyen; Mahmoud Sabha; Abdelaziz Amrani; Geyhad ElGhazali

    2011-01-01

    Type 1 Diabetes (T1D) results from insulin-producing beta cells destruction by diabetogenic T lymphocytes in humans and nonobese diabetic (NOD) mice. The breakdown of tolerance has been associated with a defect in the number and the function of naturally occurring regulatory T cells (nTreg) that are the master player in peripheral tolerance. Gene knockout experiments in mouse models have shown a nonredundant activity of IL-2 related to its critical role in inducing nTreg and controlling perip...

  15. Mitochondria as a Target for Future Diabetes Treatments

    OpenAIRE

    Franziska Thimm; Marten Szibor

    2015-01-01

    Diabetes mellitus is rapidly becoming the world’s most dangerous serial killer. Type 1 diabetes (T1D) is a currently incurable autoimmune disease marked by progressive, and eventually exhaustive, destruction of the insulin-producing pancreatic beta cells. Type 2 diabetes (T2D) describes the combination of insulin resistance in peripheral tissue, insufficient insulin secretion from the pancreatic beta cells, and excessive glucagon secretion from the pancreatic alpha cells. T1D as well as sever...

  16. Abdominal manifestations of autoimmune disorders

    International Nuclear Information System (INIS)

    Full text: Immunoglobulin G4-related disease was recognized as a systemic disease since various extrapancreatic lesions were observed in patients with autoimmune pancreatitis (AIP). The real etiology and pathogenesis of IgG4-RD is still not clearly understood. Moreover the exact role of IgG4 or IgG4-positive plasma cells in this disease has not yet been elucidated. only some inconsistent biological features such as hypergammaglobulinemia or hypocomplementemia support the autoimmune nature of the disease process. various names have been ascribed to this clinicopathological entity including IgG4-related sclerosing disease, IgG4-related systemic sclerosing disease, IgG4-related disease, IgG4-related autoimmune disease, hyper-IgG4 disease and IgG4-related systemic disease. The extrapancreatic lesions of IgG4-RD also exhibit the same characteristic histologic features including dense lymphoplasmacytic infiltrate, massive storiform fibrosis, and obliterative phlebitis as seen in IgG4-related pancreatitis. Abdominal manifestations include the following organs/systems: Bile ducts: Sclerosing cholangitis; Gallbladder and liver: Acalculous sclerosis cholecytitis with diffuse wall thickening; hepatic inflammatory pseudotumorts; Kidneys: round or wedge-shaped renal cortical nodules, peripheral cortical; lesions, mass like lesions or renal pelvic involvement; Prostate, urethra, seminal vesicle, vas deferens, uterine cervix; Autoimmune prostatitis; Retroperitoneum: Retroperitoneal fibrosis. thin or mildly thick homogeneous soft tissue lesion surrounding the abdominal aorta and its branches but also bulky masses causing hydronephroureterosis; Mesentery: Sclerosing mesenteritis usually involving the root of the mesentery; Bowel: Inflammatory bowel diseases mimicking Crohn’s disease or ulcerative colitis. various types of sclerosing nodular lesions of the bowel wall; Stomach: Gastritis, gastric ulcers and focal masses mimicking submucosal tumor; omentum: Infiltration mimicking

  17. The NOD2 Single Nucleotide Polymorphism rs72796353 (IVS4+10 A>C Is a Predictor for Perianal Fistulas in Patients with Crohn's Disease in the Absence of Other NOD2 Mutations.

    Directory of Open Access Journals (Sweden)

    Fabian Schnitzler

    Full Text Available A previous study suggested an association of the single nucleotide polymorphism (SNP rs72796353 (IVS4+10 A>C in the NOD2 gene with susceptibility to Crohn's disease (CD. However, this finding has not been confirmed. Given that NOD2 variants still represent the most important predictors for CD susceptibility and phenotype, we evaluated the association of rs72796353 with inflammatory bowel disease (IBD susceptibility and the IBD phenotype.Genomic DNA from 2256 Caucasians, including 1073 CD patients, 464 patients with ulcerative colitis (UC, and 719 healthy controls, was genotyped for the NOD2 SNP rs72796353 and the three main CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847. Subsequently, IBD association and genotype-phenotype analyses were conducted.In contrast to the strong associations of the NOD2 SNPs rs2066844 (p=3.51 x 10(-3, rs2066845 (p=1.54 x 10(-2, and rs2066847 (p=1.61 x 10(-20 with CD susceptibility, no significant association of rs72796353 with CD or UC susceptibility was found. However, in CD patients without the three main CD-associated NOD2 mutations, rs72796353 was significantly associated with the development of perianal fistulas (p=2.78 x 10(-7, OR 5.27, [95% CI 2.75-10.12] vs. NOD2 wild-type carriers.Currently, this study represents the largest genotype-phenotype analysis of the impact of the NOD2 variant rs72796353 on the disease phenotype in IBD. Our data demonstrate that in CD patients the IVS4+10 A>C variant is strongly associated with the development of perianal fistulas. This association is particularly pronounced in patients who are not carriers of the three main CD-associated NOD2 mutations, suggesting rs72796353 as additional genetic marker for the CD disease behaviour.

  18. Penetrance of NOD2/CARD15 genetic variants in the general population

    DEFF Research Database (Denmark)

    Yazdanyar, Shiva; Kamstrup, Pia R; Tybjaerg-Hansen, Anne;

    2010-01-01

    In case-control studies of Europeans, heterozygosity for Arg702Trp(rs2066844), Gly908Arg(rs2066845) and Leu1007fsinsC(rs5743293) on the NOD2/CARD15 gene is associated with a 2-fold greater risk of Crohn disease, whereas homozygosity or compound heterozygosity is associated with a 17-fold greater...

  19. A Nod to disease vectors: mitigation of pathogen sensing by arthropod saliva

    Czech Academy of Sciences Publication Activity Database

    Sakhon, O. S.; Severo, M. S.; Kotsyfakis, Michalis; Pedra, J. H. F.

    2013-01-01

    Roč. 4, OCT 2013 (2013), a308. ISSN 1664-302X Institutional support: RVO:60077344 Keywords : nod-like receptors * inflammasome * vector-borne pathogens * vector-borne diseases * arthropod saliva * salivary proteins Subject RIV: EC - Immunology Impact factor: 3.941, year: 2013

  20. Penetrance of NOD2/CARD15 genetic variants in the general population

    DEFF Research Database (Denmark)

    Yazdanyar, Shiva; Kamstrup, Pia R; Tybjaerg-Hansen, Anne; Nordestgaard, Børge G

    2010-01-01

    In case-control studies of Europeans, heterozygosity for Arg702Trp(rs2066844), Gly908Arg(rs2066845) and Leu1007fsinsC(rs5743293) on the NOD2/CARD15 gene is associated with a 2-fold greater risk of Crohn disease, whereas homozygosity or compound heterozygosity is associated with a 17-fold greater ...