WorldWideScience

Sample records for immune complexes induce

  1. Regulatory effects of intrinsic IL-10 in IgG immune complex-induced lung injury

    DEFF Research Database (Denmark)

    Shanley, T P; Schmal, H; Friedl, H P

    1995-01-01

    IL-10 has regulatory effects in vitro on cytokine production by activated macrophages. In the IgG immune complex model of lung injury, exogenously administered IL-10 has been shown to suppress in vivo formation of TNF-alpha, up-regulation of vascular ICAM-1, neutrophil recruitment, and ensuing lung....... Blocking of IL-10 by Ab resulted in a 52% increase in lung vascular permeability, a 56% increase in TNF-alpha activity in bronchoalveolar lavage fluids, and a 47 to 48% increase in bronchoalveolar lavage neutrophils and lung myeloperoxidase content. These findings suggest that IL-10 is an important natural...

  2. α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8.

    LENUS (Irish Health Repository)

    Bergin, David A

    2010-12-01

    Hereditary deficiency of the protein α-1 antitrypsin (AAT) causes a chronic lung disease in humans that is characterized by excessive mobilization of neutrophils into the lung. However, the reason for the increased neutrophil burden has not been fully elucidated. In this study we have demonstrated using human neutrophils that serum AAT coordinates both CXCR1- and soluble immune complex (sIC) receptor-mediated chemotaxis by divergent pathways. We demonstrated that glycosylated AAT can bind to IL-8 (a ligand for CXCR1) and that AAT-IL-8 complex formation prevented IL-8 interaction with CXCR1. Second, AAT modulated neutrophil chemotaxis in response to sIC by controlling membrane expression of the glycosylphosphatidylinositol-anchored (GPI-anchored) Fc receptor FcγRIIIb. This process was mediated through inhibition of ADAM-17 enzymatic activity. Neutrophils isolated from clinically stable AAT-deficient patients were characterized by low membrane expression of FcγRIIIb and increased chemotaxis in response to IL-8 and sIC. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased AAT binding to IL-8, increased AAT binding to the neutrophil membrane, decreased FcγRIIIb release from the neutrophil membrane, and normalization of chemotaxis. These results provide new insight into the mechanism underlying the effect of AAT augmentation therapy in the pulmonary disease associated with AAT deficiency.

  3. Two complex, adenovirus-based vaccines that together induce immune responses to all four dengue virus serotypes.

    Science.gov (United States)

    Holman, David H; Wang, Danher; Raviprakash, Kanakatte; Raja, Nicholas U; Luo, Min; Zhang, Jianghui; Porter, Kevin R; Dong, John Y

    2007-02-01

    Dengue virus infections can cause hemorrhagic fever, shock, encephalitis, and even death. Worldwide, approximately 2.5 billion people live in dengue-infested regions with about 100 million new cases each year, although many of these infections are believed to be silent. There are four antigenically distinct serotypes of dengue virus; thus, immunity from one serotype will not cross-protect from infection with the other three. The difficulties that hamper vaccine development include requirements of the natural conformation of the envelope glycoprotein to induce neutralizing immune responses and the necessity of presenting antigens of all four serotypes. Currently, the only way to meet these requirements is to use a mixture of four serotypes of live attenuated dengue viruses, but safety remains a major problem. In this study, we have developed the basis for a tetravalent dengue vaccine using a novel complex adenovirus platform that is capable of expressing multiple antigens de novo. This dengue vaccine is constructed as a pair of vectors that each expresses the premembrane and envelope genes of two different dengue virus serotypes. Upon vaccination, the vaccine expressed high levels of the dengue virus antigens in cells to mimic a natural infection and induced both humoral and cellular immune responses against multiple serotypes of dengue virus in an animal model. Further analyses show the humoral responses were indeed neutralizing against all four serotypes. Our studies demonstrate the concept of mimicking infections to induce immune responses by synthesizing dengue virus membrane antigens de novo and the feasibility of developing an effective tetravalent dengue vaccine by vector-mediated expression of glycoproteins of the four serotypes.

  4. Platelet 3H-serotonin releasing immune complexes induced by pseudomonas aeruginosa in cystic fibrosis

    International Nuclear Information System (INIS)

    Permin, H.; Stahl Skov, P.; Norn, S.; Hoeiby, N.; Schioetz, P.O.

    1982-01-01

    In vitro formation of immune complexes was studied by 3 H-serotonin release from human platelets by P. aeruginosa antigens in the presence of serum from 22 cyctic fibrosis patients, chronically infected with mucoid P. aeruginosa (CF+P) and with a pronounced antibody response against these bacteria, and in 24 patients without P. aeruginosa (CF-P). All CF+P patients responded with 3 H-serotonin release (16-34%), whereas CF-P patients released less than 15%. In the group of CF+P patients the number of P. aeruginosa precipitins was correlated to the serotonin titer. Time courses indicated that 3 H-serotonin release was maximal between 2 and 5 min, and that no further release was observed up to 20 min. There was a gradual increase in 3 H-serotonin release with higher platelet concentrations. The response was not changed by complement inactivation, and fractionation of serum demonstrated that the serotonin release was dependent on the presence of the immunoglobulin fraction. These experiments support the suggestion of a type III reaction being involved in the lung damage in CF+P patients and also suggest a possible involvement of serotonin in the inflammatory reaction during chronic P. aeruginosa lung infection. (author)

  5. The RAB2B-GARIL5 Complex Promotes Cytosolic DNA-Induced Innate Immune Responses.

    Science.gov (United States)

    Takahama, Michihiro; Fukuda, Mitsunori; Ohbayashi, Norihiko; Kozaki, Tatsuya; Misawa, Takuma; Okamoto, Toru; Matsuura, Yoshiharu; Akira, Shizuo; Saitoh, Tatsuya

    2017-09-19

    Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that induces the IFN antiviral response. However, the regulatory mechanisms that mediate cGAS-triggered signaling have not been fully explored. Here, we show the involvement of a small GTPase, RAB2B, and its effector protein, Golgi-associated RAB2B interactor-like 5 (GARIL5), in the cGAS-mediated IFN response. RAB2B-deficiency affects the IFN response induced by cytosolic DNA. Consistent with this, RAB2B deficiency enhances replication of vaccinia virus, a DNA virus. After DNA stimulation, RAB2B colocalizes with stimulator of interferon genes (STING), the downstream signal mediator of cGAS, on the Golgi apparatus. The GTP-binding activity of RAB2B is required for its localization on the Golgi apparatus and for recruitment of GARIL5. GARIL5 deficiency also affects the IFN response induced by cytosolic DNA and enhances replication of vaccinia virus. These findings indicate that the RAB2B-GARIL5 complex promotes IFN responses against DNA viruses by regulating the cGAS-STING signaling axis. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  6. The RAB2B-GARIL5 Complex Promotes Cytosolic DNA-Induced Innate Immune Responses

    Directory of Open Access Journals (Sweden)

    Michihiro Takahama

    2017-09-01

    Full Text Available Cyclic GMP-AMP synthase (cGAS is a cytosolic DNA sensor that induces the IFN antiviral response. However, the regulatory mechanisms that mediate cGAS-triggered signaling have not been fully explored. Here, we show the involvement of a small GTPase, RAB2B, and its effector protein, Golgi-associated RAB2B interactor-like 5 (GARIL5, in the cGAS-mediated IFN response. RAB2B-deficiency affects the IFN response induced by cytosolic DNA. Consistent with this, RAB2B deficiency enhances replication of vaccinia virus, a DNA virus. After DNA stimulation, RAB2B colocalizes with stimulator of interferon genes (STING, the downstream signal mediator of cGAS, on the Golgi apparatus. The GTP-binding activity of RAB2B is required for its localization on the Golgi apparatus and for recruitment of GARIL5. GARIL5 deficiency also affects the IFN response induced by cytosolic DNA and enhances replication of vaccinia virus. These findings indicate that the RAB2B-GARIL5 complex promotes IFN responses against DNA viruses by regulating the cGAS-STING signaling axis.

  7. Requirement for C-X-C chemokines (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant) in IgG immune complex-induced lung injury

    DEFF Research Database (Denmark)

    Shanley, T P; Schmal, H; Warner, R L

    1997-01-01

    chemokines, macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC). Both mRNA and protein for MIP-2 and CINC appeared in a time-dependent manner after initiation of IgG immune complex deposition in lung. There exists a 69% homology between the amino acid sequences...... for these proteins, and we found cross-reactivity between polyclonal Abs raised to these chemokines. By purifying the blocking Abs using double affinity methods (with Ag-immobilized beads), this cross-reactivity was removed. Individually, anti-MIP-2 and anti-CINC Ab significantly reduced lung injury (as measured...... activity in BAL fluids collected 2 h after injury from animals undergoing immune complex deposition could be shown to be chiefly due to the combined contributions of MIP-2 (39%), CINC (28%), and C5a (21%). When either MIP-2 or CINC was blocked in vivo, up-regulation of Mac-1 expression on neutrophils...

  8. Inactivated probiotic Bacillus coagulans GBI-30 induces complex immune activating, anti-inflammatory, and regenerative markers in vitro

    Science.gov (United States)

    Jensen, Gitte S; Cash, Howard A; Farmer, Sean; Keller, David

    2017-01-01

    Objective The aim of this study was to document the immune activating and anti-inflammatory effects of inactivated probiotic Bacillus coagulans GBI-30, 6086 (Staimune™) cells on human immune cells in vitro. Methods In vitro cultures of human peripheral blood mononuclear cells (PBMC) from healthy blood donors were treated with inactivated B. coagulans GBI-30, 6086 cells for 24 hours. After incubation, the PBMC were stained with fluorochrome-labeled monoclonal antibodies for CD3, CD56, and CD69 to monitor cellular activation by flow cytometry. The culture supernatants were tested for cytokine profile using a 27-plex Luminex array, including pro- and anti-inflammatory cytokines, chemokines, and growth factors. Results Inactivated B. coagulans GBI-30, 6086 cells induced the CD69 early activation marker on CD3+ CD56− T lymphocytes, CD3+ CD56+ NKT cells, CD3−CD56+ NK cells, and also some cells within the CD3−CD56− non-T non-NK cell subset. Culture supernatants showed robust increases in the immune-activating cytokines IL-1β, IL-6, IL-17A, and TNF-α. IFN-γ levels were increased, along with three chemokines, MCP-1, MIP-1α, and MIP-1β. The two anti-inflammatory cytokines IL-1ra and IL-10 showed increases, as well as the G-CSF growth factor involved in repair and stem cell biology. In contrast, GM-CSF levels showed a mild decrease, showing a highly selective growth factor response. Conclusion The inactivated B. coagulans GBI-30, 6086 cells activated human immune cells and altered the production of both immune activating and anti-inflammatory cytokines and chemokines. Of special importance is the novel demonstration of a selective upregulation of the G-CSF growth factor involved in postinjury and postinflammation repair and regeneration. This suggests that important immunogenic cell wall components, such as lipoteichoic acid, are undamaged after the inactivation and retain the complex beneficial biological activities previously demonstrated for the cell walls

  9. Inactivated probiotic Bacillus coagulans GBI-30 induces complex immune activating, anti-inflammatory, and regenerative markers in vitro

    Directory of Open Access Journals (Sweden)

    Jensen GS

    2017-08-01

    Full Text Available Gitte S Jensen,1 Howard A Cash,2 Sean Farmer,2 David Keller2 1NIS Labs, Esplanade, Klamath Falls, OR, USA, 2Ganeden Biotech Inc., Landerbrook Drive Suite, Mayfield Heights, OH, USA Objective: The aim of this study was to document the immune activating and anti-inflammatory effects of inactivated probiotic Bacillus coagulans GBI-30, 6086 (Staimune™ cells on human immune cells in vitro.Methods: In vitro cultures of human peripheral blood mononuclear cells (PBMC from healthy blood donors were treated with inactivated B. coagulans GBI-30, 6086 cells for 24 hours. After incubation, the PBMC were stained with fluorochrome-labeled monoclonal antibodies for CD3, CD56, and CD69 to monitor cellular activation by flow cytometry. The culture supernatants were tested for cytokine profile using a 27-plex Luminex array, including pro- and anti-inflammatory cytokines, chemokines, and growth factors.Results: Inactivated B. coagulans GBI-30, 6086 cells induced the CD69 early activation marker on CD3+ CD56− T lymphocytes, CD3+ CD56+ NKT cells, CD3−CD56+ NK cells, and also some cells within the CD3−CD56− non-T non-NK cell subset. Culture supernatants showed robust increases in the immune-activating cytokines IL-1β, IL-6, IL-17A, and TNF-α. IFN-γ levels were increased, along with three chemokines, MCP-1, MIP-1α, and MIP-1β. The two anti-inflammatory cytokines IL-1ra and IL-10 showed increases, as well as the G-CSF growth factor involved in repair and stem cell biology. In contrast, GM-CSF levels showed a mild decrease, showing a highly selective growth factor response.Conclusion: The inactivated B. coagulans GBI-30, 6086 cells activated human immune cells and altered the production of both immune activating and anti-inflammatory cytokines and chemokines. Of special importance is the novel demonstration of a selective upregulation of the G-CSF growth factor involved in postinjury and postinflammation repair and regeneration. This suggests that

  10. Inactivated probiotic Bacillus coagulans GBI-30 induces complex immune activating, anti-inflammatory, and regenerative markers in vitro.

    Science.gov (United States)

    Jensen, Gitte S; Cash, Howard A; Farmer, Sean; Keller, David

    2017-01-01

    The aim of this study was to document the immune activating and anti-inflammatory effects of inactivated probiotic Bacillus coagulans GBI-30, 6086 (Staimune™) cells on human immune cells in vitro. In vitro cultures of human peripheral blood mononuclear cells (PBMC) from healthy blood donors were treated with inactivated B. coagulans GBI-30, 6086 cells for 24 hours. After incubation, the PBMC were stained with fluorochrome-labeled monoclonal antibodies for CD3, CD56, and CD69 to monitor cellular activation by flow cytometry. The culture supernatants were tested for cytokine profile using a 27-plex Luminex array, including pro- and anti-inflammatory cytokines, chemokines, and growth factors. Inactivated B. coagulans GBI-30, 6086 cells induced the CD69 early activation marker on CD3 + CD56 - T lymphocytes, CD3 + CD56 + NKT cells, CD3 - CD56 + NK cells, and also some cells within the CD3 - CD56 - non-T non-NK cell subset. Culture supernatants showed robust increases in the immune-activating cytokines IL-1β, IL-6, IL-17A, and TNF-α. IFN-γ levels were increased, along with three chemokines, MCP-1, MIP-1α, and MIP-1β. The two anti-inflammatory cytokines IL-1ra and IL-10 showed increases, as well as the G-CSF growth factor involved in repair and stem cell biology. In contrast, GM-CSF levels showed a mild decrease, showing a highly selective growth factor response. The inactivated B. coagulans GBI-30, 6086 cells activated human immune cells and altered the production of both immune activating and anti-inflammatory cytokines and chemokines. Of special importance is the novel demonstration of a selective upregulation of the G-CSF growth factor involved in postinjury and postinflammation repair and regeneration. This suggests that important immunogenic cell wall components, such as lipoteichoic acid, are undamaged after the inactivation and retain the complex beneficial biological activities previously demonstrated for the cell walls from live B. coagulans GBI-30, 6086

  11. Soluble immune complexes shift the TLR-induced cytokine production of distinct polarized human macrophage subsets towards IL-10.

    Directory of Open Access Journals (Sweden)

    Carmen A Ambarus

    Full Text Available BACKGROUND: Costimulation of murine macrophages with immune complexes (ICs and TLR ligands leads to alternative activation. Studies on human myeloid cells, however, indicate that ICs induce an increased pro-inflammatory cytokine production. This study aimed to clarify the effect of ICs on the pro- versus anti-inflammatory profile of human polarized macrophages. MATERIALS AND METHODS: Monocytes isolated from peripheral blood of healthy donors were polarized for four days with IFN-γ, IL-4, IL-10, GM-CSF, M-CSF, or LPS, in the presence or absence of heat aggregated gamma-globulins (HAGGs. Phenotypic polarization markers were measured by flow cytometry. Polarized macrophages were stimulated with HAGGs or immobilized IgG alone or in combination with TLR ligands. TNF, IL-6, IL-10, IL-12, and IL-23 were measured by Luminex and/or RT-qPCR. RESULTS: HAGGs did not modulate the phenotypic polarization and the cytokine production of macrophages. However, HAGGs significantly altered the TLR-induced cytokine production of all polarized macrophage subsets, with the exception of MΦ(IL-4. In particular, HAGGs consistently enhanced the TLR-induced IL-10 production in both classically and alternatively polarized macrophages (M1 and M2. The effect of HAGGs on TNF and IL-6 production was less pronounced and depended on the polarization status, while IL-23p19 and IL-12p35 expression was not affected. In contrast with HAGGs, immobilized IgG induced a strong upregulation of not only IL-10, but also TNF and IL-6. CONCLUSION: HAGGs alone do not alter the phenotype and cytokine production of in vitro polarized human macrophages. In combination with TLR-ligands, however, HAGGs but not immobilized IgG shift the cytokine production of distinct macrophage subsets toward IL-10.

  12. Inactivated probiotic Bacillus coagulans GBI-30 induces complex immune activating, anti-inflammatory, and regenerative markers in vitro

    OpenAIRE

    Jensen, Gitte S; Cash, Howard A; Farmer, Sean; Keller, David

    2017-01-01

    Gitte S Jensen,1 Howard A Cash,2 Sean Farmer,2 David Keller2 1NIS Labs, Esplanade, Klamath Falls, OR, USA, 2Ganeden Biotech Inc., Landerbrook Drive Suite, Mayfield Heights, OH, USA Objective: The aim of this study was to document the immune activating and anti-inflammatory effects of inactivated probiotic Bacillus coagulans GBI-30, 6086 (Staimune™) cells on human immune cells in vitro.Methods: In vitro cultures of human peripheral blood mononuclear cells (PBMC) from healthy blood do...

  13. 3D analysis of the TCR/pMHCII complex formation in monkeys vaccinated with the first peptide inducing sterilizing immunity against human malaria.

    Directory of Open Access Journals (Sweden)

    Manuel A Patarroyo

    Full Text Available T-cell receptor gene rearrangements were studied in Aotus monkeys developing high antibody titers and sterilizing immunity against the Plasmodium falciparum malaria parasite upon vaccination with the modified synthetic peptide 24112, which was identified in the Merozoite Surface Protein 2 (MSP-2 and is known to bind to HLA-DRbeta1*0403 molecules with high capacity. Spectratyping analysis showed a preferential usage of Vbeta12 and Vbeta6 TCR gene families in 67% of HLA-DRbeta1*0403-like genotyped monkeys. Docking of peptide 24112 into the HLA-DRbeta1*0401-HA peptide-HA1.7TCR complex containing the VDJ rearrangements identified in fully protected monkeys showed a different structural signature compared to nonprotected monkeys. These striking results show the exquisite specificity of the TCR/pMHCII complex formation needed for inducing sterilizing immunity and provide important hints for a logical and rational methodology to develop multiepitopic, minimal subunit-based synthetic vaccines against infectious diseases, among them malaria.

  14. Studies on pathogenesis and treatment of experimental immune complex glomerulonephrtis.

    NARCIS (Netherlands)

    Fleuren, Gerard Johannes Maria

    1976-01-01

    Chapter 1. In this thesis an investigation into pathogenetic mechanisms of epimembranous immune complex depostion in the glomeruli was described. For this study we used two related models of experimental immune complex glemerulonephritis: the heterologous and the autologous immune complex

  15. Immune Algorithm Complex Method for Transducer Calibration

    Directory of Open Access Journals (Sweden)

    YU Jiangming

    2014-08-01

    Full Text Available As a key link in engineering test tasks, the transducer calibration has significant influence on accuracy and reliability of test results. Because of unknown and complex nonlinear characteristics, conventional method can’t achieve satisfactory accuracy. An Immune algorithm complex modeling approach is proposed, and the simulated studies on the calibration of third multiple output transducers is made respectively by use of the developed complex modeling. The simulated and experimental results show that the Immune algorithm complex modeling approach can improve significantly calibration precision comparison with traditional calibration methods.

  16. Bronchial lesions of mouse model of asthma are preceded by immune complex vasculitis and induced bronchial associated lymphoid tissue (iBALT).

    Science.gov (United States)

    Guest, Ian C; Sell, Stewart

    2015-08-01

    We systematically examined by immune histology the lungs of some widely used mouse models of asthma. These models include sensitization by multiple intraperitoneal injections of soluble ovalbumin (OVA) or of OVA with alum, followed by three intranasal or aerosol challenges 3 days apart. Within 24 h after a single challenge there is fibrinoid necrosis of arterial walls with deposition of immunoglobulin (Ig) and OVA and infiltration of eosinophilic polymorphonuclear cells that lasts for about 3 days followed by peribronchial B-cell infiltration and slight reversible goblet cell hypertrophy (GCHT). After two challenges, severe eosinophilic vasculitis is present at 6 h, increases by 72 h, and then declines; B-cell proliferation and significant GCHT and hyperplasia (GCHTH) and bronchial smooth muscle hypertrophy recur more prominently. After three challenges, there is significantly increased induced bronchus-associated lymphoid tissue (iBALT) formation, GCHTH, and smooth muscle hypertrophy. Elevated levels of Th2 cytokines, IL-4, IL-5, and IL-13, are present in bronchial lavage fluids. Sensitized mice have precipitating antibody and positive Arthus skin reactions but also develop significant levels of IgE antibody to OVA but only 1 week after challenge. We conclude that the asthma like lung lesions induced in these models is preceded by immune complex-mediated eosinophilic vasculitis and iBALT formation. There are elevations of Th2 cytokines that most likely produce bronchial lesions that resemble human asthma. However, it is unlikely that mast cell-activated atopic mechanisms are responsible as we found only a few presumed mast cells by toluidine blue and metachromatic staining limited to the most proximal part of the main stem bronchus, and none in the remaining main stem bronchus or in the lung periphery.

  17. Radioimmunological determination of soluble immune complexes

    Energy Technology Data Exchange (ETDEWEB)

    Falck, P; Meffert, H; Diezel, W; Schmidt, E; Soennichsen, N [Humboldt-Universitaet, Berlin (German Democratic Republic). Bereich Medizin (Charite)

    1979-04-01

    Soluble immune complexes were determined in sera from patients with systemic lupus erythematosus, using /sup 125/I-labelled anti-Ig-antibody and plastics-fixed C1q (component of complement). The detection limit of the method is 0.1 ..mu..g of aggregated human IgG and the range is between 0.1 ..mu..g and 10 ..mu..g per 0.5 ml serum. In 58% of the sera tested an increase of the number of immune complexes was found.

  18. Antigen Cross-Presentation of Immune Complexes

    Science.gov (United States)

    Platzer, Barbara; Stout, Madeleine; Fiebiger, Edda

    2014-01-01

    The ability of dendritic cells (DCs) to cross-present tumor antigens has long been a focus of interest to physicians, as well as basic scientists, that aim to establish efficient cell-based cancer immune therapy. A prerequisite for exploiting this pathway for therapeutic purposes is a better understanding of the mechanisms that underlie the induction of tumor-specific cytotoxic T-lymphocyte (CTL) responses when initiated by DCs via cross-presentation. The ability of humans DC to perform cross-presentation is of utmost interest, as this cell type is a main target for cell-based immunotherapy in humans. The outcome of a cross-presentation event is guided by the nature of the antigen, the form of antigen uptake, and the subpopulation of DCs that performs presentation. Generally, CD8α+ DCs are considered to be the most potent cross-presenting DCs. This paradigm, however, only applies to soluble antigens. During adaptive immune responses, immune complexes form when antibodies interact with their specific epitopes on soluble antigens. Immunoglobulin G (IgG) immune complexes target Fc-gamma receptors on DCs to shuttle exogenous antigens efficiently into the cross-presentation pathway. This receptor-mediated cross-presentation pathway is a well-described route for the induction of strong CD8+ T cell responses. IgG-mediated cross-presentation is intriguing because it permits the CD8− DCs, which are commonly considered to be weak cross-presenters, to efficiently cross-present. Engaging multiple DC subtypes for cross-presentation might be a superior strategy to boost CTL responses in vivo. We here summarize our current understanding of how DCs use IgG-complexed antigens for the efficient induction of CTL responses. Because of its importance for human cell therapy, we also review the recent advances in the characterization of cross-presentation properties of human DC subsets. PMID:24744762

  19. Integration of the immune system: a complex adaptive supersystem

    Science.gov (United States)

    Crisman, Mark V.

    2001-10-01

    Immunity to pathogenic organisms is a complex process involving interacting factors within the immune system including circulating cells, tissues and soluble chemical mediators. Both the efficiency and adaptive responses of the immune system in a dynamic, often hostile, environment are essential for maintaining our health and homeostasis. This paper will present a brief review of one of nature's most elegant, complex adaptive systems.

  20. Circulating immune complexes – reviewing the biological roles in ...

    African Journals Online (AJOL)

    Circulating immune complexes – reviewing the biological roles in human immune function and exercise. ... studies that have investigated CIC's following exercise and proposes that a comprehensive understanding and interpretation of immune system responses to exercise should take these complexes into consideration.

  1. Immunization of chickens with an agonistic monoclonal anti-chicken CD40 antibody-hapten complex: rapid and robust IgG response induced by a single subcutaneous injection.

    Science.gov (United States)

    Chen, Chang-Hsin; Abi-Ghanem, Daad; Waghela, Suryakant D; Chou, Wen-Ko; Farnell, Morgan B; Mwangi, Waithaka; Berghman, Luc R

    2012-04-30

    Producing diagnostic antibodies in chicken egg yolk represents an alternate animal system that offers many advantages including high productivity at low cost. Despite being an excellent counterpart to mammalian antibodies, chicken IgG from yolk still represents an underused resource. The potential of agonistic monoclonal anti-CD40 antibodies (mAb) as a powerful immunological adjuvant has been demonstrated in mammals, but not in chickens. We recently reported an agonistic anti-chicken CD40 mAb (designated mAb 2C5) and showed that it may have potential as an immunological adjuvant. In this study, we examined the efficacy of targeting a short peptide to chicken CD40 [expressed by the antigen-presenting cells (APCs)] in enhancing an effective IgG response in chickens. For this purpose, an immune complex consisting of one streptavidin molecule, two directionally biotinylated mAb 2C5 molecules, and two biotinylated peptide molecules was produced. Chickens were immunized subcutaneously with doses of this complex ranging from 10 to 90 μg per injection once, and relative quantification of the peptide-specific IgG response showed that the mAb 2C5-based complex was able to elicit a strong IgG response as early as four days post-immunization. This demonstrates that CD40-targeting antigen to chicken APCs can significantly enhance antibody responses and induce immunoglobulin isotype-switching. This immunization strategy holds promise for rapid production of hapten-specific IgG in chickens. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. The deconvolution of complex spectra by artificial immune system

    Science.gov (United States)

    Galiakhmetova, D. I.; Sibgatullin, M. E.; Galimullin, D. Z.; Kamalova, D. I.

    2017-11-01

    An application of the artificial immune system method for decomposition of complex spectra is presented. The results of decomposition of the model contour consisting of three components, Gaussian contours, are demonstrated. The method of artificial immune system is an optimization method, which is based on the behaviour of the immune system and refers to modern methods of search for the engine optimization.

  3. Circulating Immune Complexes among Diabetic Children

    Directory of Open Access Journals (Sweden)

    George Nicoloff

    2004-01-01

    Full Text Available Insulin dependent diabetes mellitus (IDDM is an autoimmune disease associated with the presence of different types of autoantibodies. The presence of these antibodies and the corresponding antigens in the circulation leads to the formation of circulating immune complexes (CIC. CIC are known to persist in the blood for long periods of time. Such CIC following deposition in the small blood vessels have the potential to lead to microangiopathy with debilitating clinical consequences. The aim of our pilot study was to investigate whether a correlation exists between CIC and the development of microvascular complications in diabetic children. Isolation of a new glycoprotein complement inhibition factor (CIF from the parasitic plant Cuscuta europea seed, which appears to bind specifically to complement component C3 has provided an unique tool for the measurement of immune complexes by means of ELISA-type techniques (CIF-ELISA. We studied the levels of CIC (IgG, IgM and IgA in 58 diabetic children (mean age 12.28±4.04 years, diabetes duration 5.3±3.7 years, 29 of them had vascular complications (group 1 and the other 29 were without vascular complications (group 2. As controls, we studied sera samples from 21 healthy children (mean age 13.54±4.03 years. Sera from the diabetic patients showed statistically significant higher levels of CIC IgG ( p=0.03 than sera from the control group. In sera from group 1 values of CIC IgG showed statistically significant higher levels than controls (0.720±0.31 vs. 0.46±0.045; p=0.011 Sera from 59% of the patients were positive for CIC IgG, 36% for CIC IgM and 9% for CIC IgA. Among 26 patients with microalbuminuria, sera from 17/26 (65% were positive for CIC IgG, 8/26 (31% for CIC IgM and 2/26 (8% for CIC IgA. CIC IgG correlated with HbA1c (r=0.51; p=0.005 and microalbuminuria (r=0.42, p=0.033. CIC IgA correlated with age (r=0.44, p=0.03. CIC IgM correlated with the duration of diabetes (r=0.63, p=0.02. These

  4. The Missing Link in Epstein-Barr Virus Immune Evasion: the BDLF3 Gene Induces Ubiquitination and Downregulation of Major Histocompatibility Complex Class I (MHC-I) and MHC-II.

    Science.gov (United States)

    Quinn, Laura L; Williams, Luke R; White, Claire; Forrest, Calum; Zuo, Jianmin; Rowe, Martin

    2016-01-01

    The ability of Epstein-Barr virus (EBV) to spread and persist in human populations relies on a balance between host immune responses and EBV immune evasion. CD8(+) cells specific for EBV late lytic cycle antigens show poor recognition of target cells compared to immediate early and early antigen-specific CD8(+) cells. This phenomenon is due in part to the early EBV protein BILF1, whose immunosuppressive activity increases with lytic cycle progression. However, published data suggest the existence of a hitherto unidentified immune evasion protein further enhancing protection against late EBV antigen-specific CD8(+) cells. We have now identified the late lytic BDLF3 gene as the missing link accounting for efficient evasion during the late lytic cycle. Interestingly, BDLF3 also contributes to evasion of CD4(+) cell responses to EBV. We report that BDLF3 downregulates expression of surface major histocompatibility complex (MHC) class I and class II molecules in the absence of any effect upon other surface molecules screened, including CD54 (ICAM-1) and CD71 (transferrin receptor). BDLF3 both enhanced internalization of surface MHC molecules and reduced the rate of their appearance at the cell surface. The reduced expression of surface MHC molecules correlated with functional protection against CD8(+) and CD4(+) T cell recognition. The molecular mechanism was identified as BDLF3-induced ubiquitination of MHC molecules and their subsequent downregulation in a proteasome-dependent manner. Immune evasion is a necessary feature of viruses that establish lifelong persistent infections in the face of strong immune responses. EBV is an important human pathogen whose immune evasion mechanisms are only partly understood. Of the EBV immune evasion mechanisms identified to date, none could explain why CD8(+) T cell responses to late lytic cycle genes are so infrequent and, when present, recognize lytically infected target cells so poorly relative to CD8(+) T cells specific for

  5. Acute Inflammatory Demyelinating Neuropathy : Immunoglobulin And Immune Complex Profile

    Directory of Open Access Journals (Sweden)

    Shripad A

    2003-01-01

    Full Text Available Serum immunoglobulins (IgG, IgA and IgM and immune complexes IgG (IcG were measured in 58 cases of acute inflammatory demyelinating neuropathy, popularly known as Guillian Barre′ syndrome, and in 30 healthy controls using single radial immunodiffusion assay. Immunoglobulin and immune complex levels were significantly elevated in patients as compared to controls. The increased levels of immunoglobulins and immune complexes may contribute to the pathogenesis of the disease and provide rationale for therapeutic plasmapheresis.

  6. Binding of properdin to solid-phase immune complexes

    DEFF Research Database (Denmark)

    Junker, A; Baatrup, G; Svehag, S E

    1998-01-01

    The capacity of serum to support deposition of C3, properdin and factor B was studied by enzyme-linked immunosorbent assay using solid-phase immune complexes (IC) for activation of complement. Deposition of C3 and properdin occurred in fairly dilute normal human serum (NHS), but factor B uptake...... fixed to IC was the principal ligand for properdin in the assay. The findings could have biological implications relating to complement-mediated modification of immune complexes in disease....

  7. Systemic activation of the immune system in HIV infection: The role of the immune complexes (hypothesis).

    Science.gov (United States)

    Korolevskaya, Larisa B; Shmagel, Konstantin V; Shmagel, Nadezhda G; Saidakova, Evgeniya V

    2016-03-01

    Currently, immune activation is proven to be the basis for the HIV infection pathogenesis and a strong predictor of the disease progression. Among the causes of systemic immune activation the virus and its products, related infectious agents, pro-inflammatory cytokines, and regulatory CD4+ T cells' decrease are considered. Recently microbial translocation (bacterial products yield into the bloodstream as a result of the gastrointestinal tract mucosal barrier integrity damage) became the most popular hypothesis. Previously, we have found an association between immune complexes present in the bloodstream of HIV infected patients and the T cell activation. On this basis, we propose a significantly modified hypothesis of immune activation in HIV infection. It is based on the immune complexes' participation in the immunocompetent cells' activation. Immune complexes are continuously formed in the chronic phase of the infection. Together with TLR-ligands (viral antigens, bacterial products coming from the damaged gut) present in the bloodstream they interact with macrophages. As a result macrophages are transformed into the type II activated forms. These macrophages block IL-12 production and start synthesizing IL-10. High level of this cytokine slows down the development of the full-scale Th1-response. The anti-viral reactions are shifted towards the serogenesis. Newly synthesized antibodies' binding to viral antigens leads to continuous formation of the immune complexes capable of interacting with antigen-presenting cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. The Smc5/6 Complex Restricts HBV when Localized to ND10 without Inducing an Innate Immune Response and Is Counteracted by the HBV X Protein Shortly after Infection

    Science.gov (United States)

    Daffis, Stephane; Ramakrishnan, Dhivya; Burdette, Dara; Peiser, Leanne; Salas, Eduardo; Ramos, Hilario; Yu, Mei; Cheng, Guofeng; Strubin, Michel; Delaney IV, William E.; Fletcher, Simon P.

    2017-01-01

    The structural maintenance of chromosome 5/6 complex (Smc5/6) is a restriction factor that represses hepatitis B virus (HBV) transcription. HBV counters this restriction by expressing HBV X protein (HBx), which targets Smc5/6 for degradation. However, the mechanism by which Smc5/6 suppresses HBV transcription and how HBx is initially expressed is not known. In this study we characterized viral kinetics and the host response during HBV infection of primary human hepatocytes (PHH) to address these unresolved questions. We determined that Smc5/6 localizes with Nuclear Domain 10 (ND10) in PHH. Co-localization has functional implications since depletion of ND10 structural components alters the nuclear distribution of Smc6 and induces HBV gene expression in the absence of HBx. We also found that HBV infection and replication does not induce a prominent global host transcriptional response in PHH, either shortly after infection when Smc5/6 is present, or at later times post-infection when Smc5/6 has been degraded. Notably, HBV and an HBx-negative virus establish high level infection in PHH without inducing expression of interferon-stimulated genes or production of interferons or other cytokines. Our study also revealed that Smc5/6 is degraded in the majority of infected PHH by the time cccDNA transcription could be detected and that HBx RNA is present in cell culture-derived virus preparations as well as HBV patient plasma. Collectively, these data indicate that Smc5/6 is an intrinsic antiviral restriction factor that suppresses HBV transcription when localized to ND10 without inducing a detectable innate immune response. Our data also suggest that HBx protein may be initially expressed by delivery of extracellular HBx RNA into HBV-infected cells. PMID:28095508

  9. CD1d-restricted IFN-γ-secreting NKT cells promote immune complex-induced acute lung injury by regulating macrophage-inflammatory protein-1α production and activation of macrophages and dendritic cells.

    Science.gov (United States)

    Kim, Ji Hyung; Chung, Doo Hyun

    2011-02-01

    Immune complex-induced acute lung injury (IC-ALI) has been implicated in various pulmonary disease states. However, the role of NKT cells in IC-ALI remains unknown. Therefore, we explored NKT cell functions in IC-ALI using chicken egg albumin and anti-chicken egg albumin IgG. The bronchoalveolar lavage fluid of CD1d(-/-) and Jα18(-/-) mice contained few Ly6G(+)CD11b(+) granulocytes, whereas levels in B6 mice were greater and were increased further by α-galactosyl ceramide. IFN-γ and MIP-1α production in the lungs was greater in B6 than CD1d(-/-) mice. Adoptive transfer of wild type (WT) but not IFN-γ-, MIP-1α-, or FcγR-deficient NKT cells into CD1d(-/-) mice caused recruitment of inflammatory cells to the lungs. Moreover, adoptive transfer of IFN-γR-deficient NKT cells enhanced MIP-1α production and cell recruitment in the lungs of CD1d(-/-) or CD1d(-/-)IFN-γ(-/-) mice, but to a lesser extent than WT NKT cells. This suggests that IFN-γ-producing NKT cells enhance MIP-1α production in both an autocrine and a paracrine manner. IFN-γ-deficient NKT cells induced less IL-1β and TNF-α production by alveolar macrophages and dendritic cells in CD1d(-/-) mice than did WT NKT cells. Taken together, these data suggest that CD1d-restricted IFN-γ-producing NKT cells promote IC-ALI by producing MIP-1α and enhancing proinflammatory cytokine production by alveolar macrophages and dendritic cells.

  10. Drug-induced immune hemolytic anemia

    Science.gov (United States)

    Immune hemolytic anemia secondary to drugs; Anemia - immune hemolytic - secondary to drugs ... Drugs that can cause this type of hemolytic anemia include: Cephalosporins (a class of antibiotics), most common ...

  11. Two different mechanisms of immune-complex trapping in the mouse spleen during immune responses

    NARCIS (Netherlands)

    Yoshida, K.; van den Berg, T. K.; Dijkstra, C. D.

    1993-01-01

    The capacity of immune-complex (IC) trapping was examined using purified horse radish peroxidase (HRP)-anti-HRP (PAP) on frozen sections of mouse spleen in vitro. We investigated the trapping mechanisms by applying the IC with or without fresh mouse serum added on the spleen sections of naive as

  12. PF4-HIT antibody (KKO) complexes activate broad innate immune and inflammatory responses.

    Science.gov (United States)

    Haile, Lydia A; Rao, Roshni; Polumuri, Swamy K; Arepally, Gowthami M; Keire, David A; Verthelyi, Daniela; Sommers, Cynthia D

    2017-11-01

    Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication of heparin anticoagulation therapy resulting in thrombocytopenia frequently accompanied by thrombosis. Current evidence suggests that HIT is associated with antibodies developed in response to multi-molecular complexes formed by platelet factor 4 (PF4) bound to heparin or cell surface glycosaminoglycans. These antibody complexes activate platelets and monocytes typically through FcγRIIA receptors increasing the production of PF4, inflammatory mediators, tissue factor and thrombin. The influence of underlying events in HIT including complex-induced pro-inflammatory cell activation and structural determinants leading to local inflammatory responses are not fully understood. The stoichiometry and complex component requirements were determined by incubating fresh peripheral blood mononuclear cells (PBMC) with different concentrations of unfractionated heparin (H), low molecular weight heparin (LMWH), PF4- and anti-PF4-H complex antibodies (KKO). Cytokine mRNA or protein were measured by qRT-PCR or Meso Scale Discovery technology, respectively. Gene expression profile analysis for 594 genes was performed using Nanostring technology and analyzed using Ingenuity Pathway Analysis software. The data show that antibodies magnify immune responses induced in PBMCs by PF4 alone or in complex with heparin or LMWH. We propose that following induction of HIT antibodies by heparin-PF4 complexes, binding of the antibodies to PF4 is sufficient to induce a local pro-inflammatory response which may play a role in the progression of HIT. In vitro assays using PBMCs may be useful in characterizing local inflammatory and innate immune responses induced by HIT antibodies in the presence of PF4 and different sources of heparins. The findings and conclusions in this article are solely the responsibility of the authors and are not being formally disseminated by the Food and Drug Administration. Thus, they should not be

  13. Reversibility of alcohol-induced immune depression

    DEFF Research Database (Denmark)

    Tønnesen, H; Kaiser, A H; Nielsen, B B

    1992-01-01

    Alcohol abusers have suppressed cellular immune function. The aim of the study was to investigate the time of sobriety required to normalize immune function. Delayed hypersensitivity was investigated during disulfiram controlled abstinence in ten heavy alcoholics and in seven moderate drinkers...... months of abstinence. The results suggest that while 2 weeks of abstinence from alcohol will improve the depressed cellular immunity, 2 months of sobriety is necessary to normalize it....

  14. Complex Immune Evasion Strategies in Classical Hodgkin Lymphoma.

    Science.gov (United States)

    Wein, Frederik; Weniger, Marc A; Höing, Benedikt; Arnolds, Judith; Hüttmann, Andreas; Hansmann, Martin-Leo; Hartmann, Sylvia; Küppers, Ralf

    2017-12-01

    The cellular microenvironment in classical Hodgkin lymphoma (cHL) is dominated by a mixed infiltrate of inflammatory cells with typically only about 1% Hodgkin and Reed/Sternberg (HRS) tumor cells. T cells are usually the largest population of cells in the cHL microenvironment, encompassing T helper (Th) cells, regulatory T cells (Tregs), and cytotoxic T cells. Th cells and Tregs presumably provide essential survival signals for HRS cells. Tregs are also involved in rescuing HRS cells from antitumor immune responses. An understanding of the immune evasion strategies of HRS cells is not only relevant for a characterization of the pathophysiology of cHL but is also clinically relevant, given the current treatment approaches targeting checkpoint inhibitors. Here, we characterized the cHL-specific CD4 + T-cell infiltrate regarding its role in immune evasion. Global gene expression analysis of CD4 + Th cells and Tregs isolated from cHL lymph nodes and reactive tonsils revealed that Treg signatures were enriched in CD4 + Th cells of cHL. Hence, HRS cells may induce Treg differentiation in Th cells, a conclusion supported by in vitro studies with Th cells and cHL cell lines. We also found evidence for immune-suppressive purinergic signaling and a role of the inhibitory receptor-ligand pairs B- and T-cell lymphocyte attenuator-herpesvirus entry mediator and CD200R-CD200 in promoting immune evasion. Taken together, this study highlights the relevance of Treg induction and reveals new immune checkpoint-driven immune evasion strategies in cHL. Cancer Immunol Res; 5(12); 1122-32. ©2017 AACR . ©2017 American Association for Cancer Research.

  15. Gut microbiota, immunity and disease: a complex relationship

    Directory of Open Access Journals (Sweden)

    Michele M Kosiewicz

    2011-09-01

    Full Text Available Our immune system has evolved to recognize and eradicate pathogenic microbes. However, we have a symbiotic relationship with multiple species of bacteria that occupy the gut and comprise the natural commensal flora or microbiota. The microbiota is critically important for the breakdown of nutrients, and also assists in preventing colonization by potentially pathogenic bacteria. In addition, the gut commensal bacteria appears to be critical for the development of an optimally functioning immune system. Various studies have shown that individual species of the microbiota can induce very different types of immune cells (e.g., Th17 cells, Foxp3+ regulatory T cells and responses, suggesting that the composition of the microbiota can have an important influence on the immune response. Although the microbiota resides in the gut, it appears to have a significant impact on the systemic immune response. Indeed, specific gut commensal bacteria have been shown to affect disease development in organs other than the gut, and depending on the species, have been found to have a wide range of effects on diseases from induction and exacerbation to inhibition and protection. In this review, we will focus on the role that the gut microbiota plays in the development and progression of inflammatory/autoimmune disease, and we will also touch upon its role in allergy and cancer.

  16. Protective immunity to UV radiation-induced skin tumours induced by skin grafts and epidermal cells

    International Nuclear Information System (INIS)

    Ronald Sluyter; Kylie S Yuen; Gary M Halliday

    2001-01-01

    There is little evidence that cutaneous dendritic cells (DC), including epidermal Langerhans cells (LC), can induce immunity to UV radiation (UVR)-induced skin tumours. Here, it is shown that cells within skin can induce protective antitumour immunity against a UVR-induced fibrosarcoma. Transplantation of the skin overlying subcutaneous tumours onto naive recipients could induce protective antitumour immunity, probably because the grafting stimulated the tumour Ag-loaded DC to migrate to local lymph nodes. This suggests that cutaneous APC can present tumour Ag to induce protective antitumour immunity. Previously, it has been shown that immunization of mice with MHC class II+ epidermal cells (EC) pulsed with tumour extracts could induce delayed-type hypersensitivity against tumour cells. Here, this same immunization protocol could induce protective immunity against a minimum tumorigenic dose of UVR-induced fibrosarcoma cells, but not higher doses. Epidermal cells obtained from semiallogeneic donors and pulsed with tumour extract could also induce protective immunity. However, presentation of BSA Ag from the culture medium was found to contribute to this result using semiallogeneic EC. The results suggest that LC overlying skin tumours may be able to induce protective immunity to UVR-induced tumours if stimulated to migrate from the skin. Copyright (2001) Australasian Society of Immunology Inc

  17. The function of the Mediator complex in plant immunity.

    Science.gov (United States)

    An, Chuanfu; Mou, Zhonglin

    2013-03-01

    Upon pathogen infection, plants undergo dramatic transcriptome reprogramming to shift from normal growth and development to immune response. During this rapid process, the multiprotein Mediator complex has been recognized as an important player to fine-tune gene-specific and pathway-specific transcriptional reprogramming by acting as an adaptor/coregulator between sequence-specific transcription factor and RNA polymerase II (RNAPII). Here, we review current understanding of the role of five functionally characterized Mediator subunits (MED8, MED15, MED16, MED21 and MED25) in plant immunity. All these Mediator subunits positively regulate resistance against leaf-infecting biotrophic bacteria or necrotrophic fungi. While MED21 appears to regulate defense against fungal pathogens via relaying signals from upstream regulators and chromatin modification to RNAPII, the other four Mediator subunits locate at different positions of the defense network to convey phytohormone signal(s). Fully understanding the role of Mediator in plant immunity needs to characterize more Mediator subunits in both Arabidopsis and other plant species. Identification of interacting proteins of Mediator subunits will further help to reveal their specific regulatory mechanisms in plant immunity.

  18. Perturbation of gut bacteria induces a coordinated cellular immune response in the purple sea urchin larva

    Science.gov (United States)

    CH Ho, Eric; Buckley, Katherine M; Schrankel, Catherine S; Schuh, Nicholas W; Hibino, Taku; Solek, Cynthia M; Bae, Koeun; Wang, Guizhi; Rast, Jonathan P

    2016-01-01

    The purple sea urchin (Strongylocentrotus purpuratus) genome sequence contains a complex repertoire of genes encoding innate immune recognition proteins and homologs of important vertebrate immune regulatory factors. To characterize how this immune system is deployed within an experimentally tractable, intact animal, we investigate the immune capability of the larval stage. Sea urchin embryos and larvae are morphologically simple and transparent, providing an organism-wide model to view immune response at cellular resolution. Here we present evidence for immune function in five mesenchymal cell types based on morphology, behavior and gene expression. Two cell types are phagocytic; the others interact at sites of microbial detection or injury. We characterize immune-associated gene markers for three cell types, including a perforin-like molecule, a scavenger receptor, a complement-like thioester-containing protein and the echinoderm-specific immune response factor 185/333. We elicit larval immune responses by (1) bacterial injection into the blastocoel and (2) seawater exposure to the marine bacterium Vibrio diazotrophicus to perturb immune state in the gut. Exposure at the epithelium induces a strong response in which pigment cells (one type of immune cell) migrate from the ectoderm to interact with the gut epithelium. Bacteria that accumulate in the gut later invade the blastocoel, where they are cleared by phagocytic and granular immune cells. The complexity of this coordinated, dynamic inflammatory program within the simple larval morphology provides a system in which to characterize processes that direct both aspects of the echinoderm-specific immune response as well as those that are shared with other deuterostomes, including vertebrates. PMID:27192936

  19. Detection of circulating immune complexes in hepatitis by means of a new method employing /sup 125/I-antibody. Circulating immune complexes in hepatitis

    Energy Technology Data Exchange (ETDEWEB)

    Fresco, G F [Genoa Univ. (Italy). Dept. of Internal Medicine

    1978-06-01

    A new RIA method for the detection of circulating immune complexes and antibodies arising in the course of viral hepatitis is described. It involves the use of /sup 125/I-labeled antibodies and foresees the possibility of employing immune complex-coated polypropylene tubes. This simple and sensitive procedure takes into account the possibility that the immune complexes may be absorbed by the surface of polypropylene tubes during the period in which the serum remains there.

  20. Expression of an immunogenic Ebola immune complex in Nicotiana benthamiana.

    Science.gov (United States)

    Phoolcharoen, Waranyoo; Bhoo, Seong H; Lai, Huafang; Ma, Julian; Arntzen, Charles J; Chen, Qiang; Mason, Hugh S

    2011-09-01

    Filoviruses (Ebola and Marburg viruses) cause severe and often fatal haemorrhagic fever in humans and non-human primates. The US Centers for Disease Control identifies Ebola and Marburg viruses as 'category A' pathogens (defined as posing a risk to national security as bioterrorism agents), which has lead to a search for vaccines that could prevent the disease. Because the use of such vaccines would be in the service of public health, the cost of production is an important component of their development. The use of plant biotechnology is one possible way to cost-effectively produce subunit vaccines. In this work, a geminiviral replicon system was used to produce an Ebola immune complex (EIC) in Nicotiana benthamiana. Ebola glycoprotein (GP1) was fused at the C-terminus of the heavy chain of humanized 6D8 IgG monoclonal antibody, which specifically binds to a linear epitope on GP1. Co-expression of the GP1-heavy chain fusion and the 6D8 light chain using a geminiviral vector in leaves of N. benthamiana produced assembled immunoglobulin, which was purified by ammonium sulphate precipitation and protein G affinity chromatography. Immune complex formation was confirmed by assays to show that the recombinant protein bound the complement factor C1q. Size measurements of purified recombinant protein by dynamic light scattering and size-exclusion chromatography also indicated complex formation. Subcutaneous immunization of BALB/C mice with purified EIC resulted in anti-Ebola virus antibody production at levels comparable to those obtained with a GP1 virus-like particle. These results show excellent potential for a plant-expressed EIC as a human vaccine. © 2011 The Authors. Plant Biotechnology Journal © 2011 Society for Experimental Biology, Association of Applied Biologists and Blackwell Publishing Ltd.

  1. Immune markers and correlates of protection for vaccine induced immune responses

    DEFF Research Database (Denmark)

    Thakur, Aneesh; Pedersen, Lasse Eggers; Jungersen, Gregers

    2012-01-01

    of an appropriate humoral response currently remain the best validated correlates of protective immunity after vaccination. Despite advancements in the field of immunology over the past few decades currently there are, however, no sufficiently validated immune correlates of vaccine induced protection against......-specific production of interferon-gamma (IFN-γ) has been promoted as a quantitative marker of protective cell-mediated immune responses over the past couple of decades. More recently, however, evidence from several infections has pointed towards the quality of the immune response, measured through increased levels...... of antigen-specific polyfunctional T cells capable of producing a triad of relevant cytokines, as a better correlate of sustained protective immunity against this type of infections. Also the possibilities to measure antigen-specific cytotoxic T cells (CTL) during infection or in response to vaccination...

  2. Clearing the complexity: immune complexes and their treatment in lupus nephritis

    Directory of Open Access Journals (Sweden)

    Catherine Toong

    2011-01-01

    Full Text Available Catherine Toong1, Stephen Adelstein1, Tri Giang Phan21Department of Clinical Immunology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW, Australia; 2Immunology Program, Garvan Institute of Medical Research and St. Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW, AustraliaAbstract: Systemic lupus erythematosus (SLE is a classic antibody-mediated systemic autoimmune disease characterised by the development of autoantibodies to ubiquitous self-antigens (such as antinuclear antibodies and antidouble-stranded DNA antibodies and widespread deposition of immune complexes in affected tissues. Deposition of immune complexes in the kidney results in glomerular damage and occurs in all forms of lupus nephritis. The development of nephritis carries a poor prognosis and high risk of developing end-stage renal failure despite recent therapeutic advances. Here we review the role of DNA-anti-DNA immune complexes in the pathogenesis of lupus nephritis and possible new treatment strategies aimed at their control.Keywords: immune complex, systemic lupus erythematosus, nephritis, therapy

  3. Dynamics of interaction between complement-fixing antibody/dsDNA immune complexes and erythrocytes. In vitro studies and potential general applications to clinical immune complex testing

    International Nuclear Information System (INIS)

    Taylor, R.P.; Horgan, C.; Hooper, M.; Burge, J.

    1985-01-01

    Soluble antibody/ 3 H-double-stranded PM2 DNA (dsDNA) immune complexes were briefly opsonized with complement and then allowed to bind to human erythrocytes (via complement receptors). The cells were washed and subsequently a volume of autologous blood in a variety of media was added, and the release of the bound immune complexes from the erythrocytes was studied as a function of temperature and time. After 1-2 h, the majority of the bound immune complexes were not released into the serum during blood clotting at either 37 degrees C or room temperature, but there was a considerably greater release of the immune complexes into the plasma of blood that was anticoagulated with EDTA. Similar results were obtained using various conditions of opsonization and also using complexes that contained lower molecular weight dsDNA. Thus, the kinetics of release of these antibody/dsDNA immune complexes differed substantially from the kinetics of release of antibody/bovine serum albumin complexes that was reported by others. Studies using the solution phase C1q immune complex binding assay confirmed that in approximately half of the SLE samples that were positive for immune complexes, there was a significantly higher level of detectable immune complexes in plasma vs. serum. Freshly drawn erythrocytes from some SLE patients exhibiting this plasma/serum discrepancy had IgG antigen on their surface that was released by incubation in EDTA plasma. Thus, the higher levels of immune complexes observed in EDTA plasma vs. serum using the C1q assay may often reflect the existence of immune complexes circulating in vivo bound to erythrocytes

  4. Mechanisms underlying UV-induced immune suppression

    International Nuclear Information System (INIS)

    Ullrich, Stephen E.

    2005-01-01

    Skin cancer is the most prevalent form of human neoplasia. Estimates suggest that in excess of one million new cases of skin cancer will be diagnosed this year alone in the United States (www.cancer.org/statistics). Fortunately, because of their highly visible location, skin cancers are more rapidly diagnosed and more easily treated than other types of cancer. Be that as it may, approximately 10,000 Americans a year die from skin cancer. The cost of treating non-melanoma skin cancer is estimated to be in excess of US$ 650 million a year [J.G. Chen, A.B. Fleischer, E.D. Smith, C. Kancler, N.D. Goldman, P.M. Williford, S.R. Feldman, Cost of non-melanoma skin cancer treatment in the United States, Dermatol. Surg. 27 (2001) 1035-1038], and when melanoma is included, the estimated cost of treating skin cancer in the United States is estimated to rise to US$ 2.9 billion annually (www.cancer.org/statistics). Because the morbidity and mortality associated with skin cancer is a major public health problem, it is important to understand the mechanisms underlying skin cancer development. The primary cause of skin cancer is the ultraviolet (UV) radiation found in sunlight. In addition to its carcinogenic potential, UV radiation is also immune suppressive. In fact, data from studies with both experimental animals and biopsy proven skin cancer patients suggest that there is an association between the immune suppressive effects of UV radiation and its carcinogenic potential. The focus of this manuscript will be to review the mechanisms underlying the induction of immune suppression following UV exposure. Particular attention will be directed to the role of soluble mediators in activating immune suppression

  5. SIGNALING MECHANISMS IN SEPSIS-INDUCED IMMUNE DYSFUNCTION

    OpenAIRE

    Hasan, Zirak

    2013-01-01

    Sepsis and subsequent organ failure remain the major cause of mortality in intensive care units in spite of significant research efforts. The lung is the most vulnerable organ affected by early hyper-inflammatory immune response in septic patients. On the other hand, the septic insult induces immune dysfunction in later phases of sepsis which in turn increases susceptibility to infections. The aim of this thesis was to investigate early and late inflammatory mechanisms in abdominal sepsis ind...

  6. Effect of Scoparia dulcis on noise stress induced adaptive immunity and cytokine response in immunized Wistar rats.

    Science.gov (United States)

    Sundareswaran, Loganathan; Srinivasan, Sakthivel; Wankhar, Wankupar; Sheeladevi, Rathinasamy

    Noise acts as a stressor and is reported to have impact on individual health depending on nature, type, intensity and perception. Modern medicine has no effective drugs or cure to prevent its consequences. Being an environmental stressor noise cannot be avoided; instead minimizing its exposure or consuming anti-stressor and adaptogens from plants can be considered. The present study was carried out to evaluate the anti-stressor, adaptogen and immunostimulatory activity of Scoparia dulcis against noise-induced stress in Wistar rat models. Noise stress in rats was created by broadband white noise generator, 100 dB A/4 h daily/15 days and S. dulcis (200 mg/kg b.w.) was administered orally. 8 groups of rats were used consisting of 6 animals each; 4 groups for unimmunized and 4 groups for immunized. For immunization, sheep red blood cells (5 × 10 9  cells/ml) were injected intraperitoneally. Sub-acute noise exposed rats showed a significant increase in corticosterone and IL-4 levels in both immunized and unimmunized rats whereas lymphocytes, antibody titration, soluble immune complex, IL-4 showed a marked increase with a significant decrease in IL-2, TNF-α, IFN-γ cytokines only in unimmunized rats. Immunized noise exposed rats presented increased leukocyte migration index and decreased foot pad thickness, IL-2, TNF-α, IFN-γ with no changes in the lymphocytes. S. dulcis (SD) has normalized and prevented the noise induced changes in cell-mediated and humoral immunity and it could be the presence of anti-stressor and immuno stimulant activity of the plant. Copyright © 2016 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

  7. Increased immune complexes of hypocretin autoantibodies in narcolepsy.

    Science.gov (United States)

    Deloumeau, Aude; Bayard, Sophie; Coquerel, Quentin; Déchelotte, Pierre; Bole-Feysot, Christine; Carlander, Bertrand; Cochen De Cock, Valérie; Fetissov, Sergueï O; Dauvilliers, Yves

    2010-10-13

    Hypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. However, the mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. Here we studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes. Serum levels of free and dissociated (total) autoantibodies reacting with hypocretin-1 peptide were measured by enzyme-linked immunosorbent assay and analyzed with regard to clinical parameters in 82 subjects with narcolepsy-cataplexy, narcolepsy without cataplexy or idiopathic hypersomnia and were compared to 25 healthy controls. Serum levels of total but not free IgG autoantibodies against hypocretin-1 were increased in narcolepsy-cataplexy. Increased levels of complexed IgG autoantibodies against hypocretin-1 were found in all patients groups with a further increase in narcolepsy-cataplexy. Levels of total IgM hypocretin-1 autoantibodies were also elevated in all groups of patients. Increased levels of anti-idiotypic IgM autoantibodies reacting with hypocretin-1 IgG autoantibodies affinity purified from sera of subjects with narcolepsy-cataplexy were found in all three groups of patients. Disease duration correlated negatively with serum levels of hypocretin-1 IgG and IgM autoantibodies and with anti-idiotypic IgM autoantibodies. Central hypersomnias and particularly narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation.

  8. Increased immune complexes of hypocretin autoantibodies in narcolepsy.

    Directory of Open Access Journals (Sweden)

    Aude Deloumeau

    Full Text Available BACKGROUND: Hypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. However, the mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. Here we studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes. METHODOLOGY: Serum levels of free and dissociated (total autoantibodies reacting with hypocretin-1 peptide were measured by enzyme-linked immunosorbent assay and analyzed with regard to clinical parameters in 82 subjects with narcolepsy-cataplexy, narcolepsy without cataplexy or idiopathic hypersomnia and were compared to 25 healthy controls. PRINCIPAL FINDINGS: Serum levels of total but not free IgG autoantibodies against hypocretin-1 were increased in narcolepsy-cataplexy. Increased levels of complexed IgG autoantibodies against hypocretin-1 were found in all patients groups with a further increase in narcolepsy-cataplexy. Levels of total IgM hypocretin-1 autoantibodies were also elevated in all groups of patients. Increased levels of anti-idiotypic IgM autoantibodies reacting with hypocretin-1 IgG autoantibodies affinity purified from sera of subjects with narcolepsy-cataplexy were found in all three groups of patients. Disease duration correlated negatively with serum levels of hypocretin-1 IgG and IgM autoantibodies and with anti-idiotypic IgM autoantibodies. CONCLUSION: Central hypersomnias and particularly narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation.

  9. Macrophage Inducible C-Type Lectin As a Multifunctional Player in Immunity

    Directory of Open Access Journals (Sweden)

    Emmanuel C. Patin

    2017-07-01

    Full Text Available The macrophage-inducible C-type lectin (Mincle is an innate immune receptor on myeloid cells sensing diverse entities including pathogens and damaged cells. Mincle was first described as a receptor for the mycobacterial cell wall glycolipid, trehalose-6,6′-dimycolate, or cord factor, and the mammalian necrotic cell-derived alarmin histone deacetylase complex unit Sin3-associated protein 130. Upon engagement by its ligands, Mincle induces secretion of innate cytokines and other immune mediators modulating inflammation and immunity. Since its discovery more than 25 years ago, the understanding of Mincle’s immune function has made significant advances in recent years. In addition to mediating immune responses to infectious agents, Mincle has been linked to promote tumor progression, autoimmunity, and sterile inflammation; however, further studies are required to completely unravel the complex role of Mincle in these distinct host responses. In this review, we discuss recent findings on Mincle’s biology with an emphasis on its diverse functions in immunity.

  10. The inhibitory receptor FcgammaRII reduces joint inflammation and destruction in experimental immune complex-mediated arthritides not only by inhibition of FcgammaRI/III but also by efficient clearance and endocytosis of immune complexes.

    NARCIS (Netherlands)

    Lent, P.L.E.M. van; Nabbe, K.C.A.M.; Boross, P.; Blom, A.B.; Roth, J.; Holthuysen, A.E.M.; Sloetjes, A.W.; Verbeek, S.; Berg, W.B. van den

    2003-01-01

    Studies of FcgammaRII-/- mice identified the inhibitory function of this receptor in joint inflammation and cartilage destruction induced with immune complexes (ICs). To extend our insight in the role of FcgammaRII in arthritis, we explored the role of FcgammaRII in the absence of activating

  11. The role of epidermal cytokines in the generation of cutaneous immune reactions and ultraviolet radiation-induced immune suppression

    International Nuclear Information System (INIS)

    Ullrich, S.E.

    1995-01-01

    The immune suppression generated by UV exposure is a major risk factor for skin cancer patients. This finding has fuelled efforts to understand the mechanisms involved in the immune suppression induced by exposure to UV radiation. This article reviews the recent findings on the role of epidermal cytokines in the generation of an immune response and their role in the induction of immune suppression induced by UV exposure. (UK)

  12. Maternal immunity enhances Mycoplasma hyopneumoniae vaccination induced cell-mediated immune responses in piglets.

    Science.gov (United States)

    Bandrick, Meggan; Theis, Kara; Molitor, Thomas W

    2014-06-05

    Passively acquired maternal derived immunity (MDI) is a double-edged sword. Maternal derived antibody-mediated immunity (AMI) and cell-mediated immunity (CMI) are critical immediate defenses for the neonate; however, MDI may interfere with the induction of active immunity in the neonate, i.e. passive interference. The effect of antigen-specific MDI on vaccine-induced AMI and CMI responses to Mycoplasma hyopneumoniae (M. hyopneumoniae) was assessed in neonatal piglets. To determine whether CMI and AMI responses could be induced in piglets with MDI, piglets with high and low levels of maternal M. hyopneumoniae-specific immunity were vaccinated against M. hyopneumoniae at 7 d of age. Piglet M. hyopneumoniae-specific antibody, lymphoproliferation, and delayed type hypersensitivity (DTH) responses were measured 7 d and 14 d post vaccination. Piglets with M. hyopneumoniae-specific MDI failed to show vaccine-induced AMI responses; there was no rise in M. hyopneumoniae antibody levels following vaccination of piglets in the presence of M. hyopneumoniae-specific MDI. However, piglets with M. hyopneumoniae-specific MDI had primary (antigen-specific lymphoproliferation) and secondary (DTH) M. hyopneumoniae-specific CMI responses following vaccination. In this study neonatal M. hyopneumoniae-specific CMI was not subject to passive interference by MDI. Further, it appears that both maternal derived and endogenous CMI contribute to M. hyopneumoniae-specific CMI responses in piglets vaccinated in the face of MDI.

  13. Circulating immune complexes contain citrullinated fibrinogen in rheumatoid arthritis

    Science.gov (United States)

    Zhao, Xiaoyan; Okeke, Nwora Lance; Sharpe, Orr; Batliwalla, Franak M; Lee, Annette T; Ho, Peggy P; Tomooka, Beren H; Gregersen, Peter K; Robinson, William H

    2008-01-01

    Introduction There is increasing evidence that autoantibodies and immune complexes (ICs) contribute to synovitis in rheumatoid arthritis (RA), yet the autoantigens incorporated in ICs in RA remain incompletely characterised. Methods We used the C1q protein to capture ICs from plasma derived from human RA and control patients. Antibodies specific for immunoglobulin were used to detect ICs, and fibrinogen antibodies were used to detect fibrinogen-containing ICs. RA and control plasma were separated by liquid chromatography, and fractions then characterised by ELISA, immunoblotting and mass spectrometry. Immunohistochemical staining was performed on rheumatoid synovial tissue. Results C1q-immunoassays demonstrated increased levels of IgG (p = 0.01) and IgM (p = 0.0002) ICs in plasma derived from RA patients possessing anti-cyclic citrullinated peptide (CCP+) autoantibodies as compared with healthy controls. About one-half of the anti-CCP+ RA possessed circulating ICs containing fibrinogen (p = 0.0004). Fractionation of whole RA plasma revealed citrullinated fibrinogen in the high molecular weight fractions that contained ICs. Positive correlations were observed between fibrinogen-containing ICs and anti-citrullinated fibrinogen autoantibodies, anti-CCP antibody, rheumatoid factor and certain clinical characteristics. Immunohistochemical staining demonstrated co-localisation of fibrinogen, immunoglobulin and complement component C3 in RA pannus tissue. Mass spectrometry analysis of immune complexes immunoprecipitated from RA pannus tissue lysates demonstrated the presence of citrullinated fibrinogen. Conclusion Circulating ICs containing citrullinated fibrinogen are present in one-half of anti-CCP+ RA patients, and these ICs co-localise with C3 in the rheumatoid synovium suggesting that they contribute to synovitis in a subset of RA patients. PMID:18710572

  14. [Mechanisms of retroviral immunosuppressive domain-induced immune modulation].

    Science.gov (United States)

    Blinov, V M; Krasnov, G S; Shargunov, A V; Shurdov, M A; Zverev, V V

    2013-01-01

    Immunosuppressive domains (ISD) of viral envelope glycoproteins provide highly pathogenic phenotypes of various retroviruses. ISD interaction with immune cells leads to an inhibition of a response. In the 1980s it was shown that the fragment of ISD comprising of 17 amino acids (named CKS-17) is carrying out such immune modulation. However the underlying mechanisms were not known. The years of thorough research allowed to identify the regulation of Ras-Raf-MEK-MAPK and PI3K-AKT-mTOR cellular pathways as a result of ISD interaction with immune cells. By the way, this leads to decrease of secretion of stimulatory cytokines (e.g., IL-12) and increase of inhibitory, anti-inflammatory ones (e.g., IL-10). One of the receptor tyrosine kinases inducing signal in these pathways acts as the primary target of ISD while other key regulators--cAMP and diacylglycerol (DAG), act as secondary messengers of signal transduction. Immunosuppressive-like domains can be found not only in retroviruses; the presence of ISD within Ebola viral envelope glycoproteins caused extremely hard clinical course of virus-induced hemorrhagic fever. A number of retroviral-origin fragments encoding ISD can be found in the human genome. These regions are expressed in the placenta within genes of syncytins providing a tolerance of mother's immune system to an embryo. The present review is devoted to molecular aspects of retroviral ISD-induced modulation of host immune system.

  15. Cross-serotype immunity induced by immunization with a conserved rhinovirus capsid protein.

    Directory of Open Access Journals (Sweden)

    Nicholas Glanville

    Full Text Available Human rhinovirus (RV infections are the principle cause of common colds and precipitate asthma and COPD exacerbations. There is currently no RV vaccine, largely due to the existence of ∼150 strains. We aimed to define highly conserved areas of the RV proteome and test their usefulness as candidate antigens for a broadly cross-reactive vaccine, using a mouse infection model. Regions of the VP0 (VP4+VP2 capsid protein were identified as having high homology across RVs. Immunization with a recombinant VP0 combined with a Th1 promoting adjuvant induced systemic, antigen specific, cross-serotype, cellular and humoral immune responses. Similar cross-reactive responses were observed in the lungs of immunized mice after infection with heterologous RV strains. Immunization enhanced the generation of heterosubtypic neutralizing antibodies and lung memory T cells, and caused more rapid virus clearance. Conserved domains of the RV capsid therefore induce cross-reactive immune responses and represent candidates for a subunit RV vaccine.

  16. Memory B-Cell and Antibody Responses Induced by Plasmodium falciparum Sporozoite Immunization

    NARCIS (Netherlands)

    Nahrendorf, W.; Scholzen, A.; Bijker, E.M.; Teirlinck, A.C.; Bastiaens, G.J.H.; Schats, R.; Hermsen, C.C.; Visser, L.G.; Langhorne, J.; Sauerwein, R.W.

    2014-01-01

    BACKGROUND: Immunization of healthy volunteers during receipt of chemoprophylaxis with Plasmodium falciparum sporozoites (CPS-immunization) induces sterile protection from malaria. Antibody responses have long been known to contribute to naturally acquired immunity against malaria, but their

  17. Radiation-induced augmentation of the immune response

    International Nuclear Information System (INIS)

    Anderson, R.E.; Lefkovits, I.; Troup, G.M.

    1980-01-01

    Radiation-induced augmentation of the immune response has been shown to occur both in vivo and in vitro. Evidence is presented to implicate injury to an extremely radiosensitive T cell in the expression of this phenomenon. Experiments are outlined which could be employed to support or reflect this hypothesis

  18. A simple method for determining polymeric IgA-containing immune complexes.

    Science.gov (United States)

    Sancho, J; Egido, J; González, E

    1983-06-10

    A simplified assay to measure polymeric IgA-immune complexes in biological fluids is described. The assay is based upon the specific binding of a secretory component for polymeric IgA. In the first step, multimeric IgA (monomeric and polymeric) immune complexes are determined by the standard Raji cell assay. Secondly, labeled secretory component added to the assay is bound to polymeric IgA-immune complexes previously fixed to Raji cells, but not to monomeric IgA immune complexes. To avoid false positives due to possible complement-fixing IgM immune complexes, prior IgM immunoadsorption is performed. Using anti-IgM antiserum coupled to CNBr-activated Sepharose 4B this step is not time-consuming. Polymeric IgA has a low affinity constant and binds weakly to Raji cells, as Scatchard analysis of the data shows. Thus, polymeric IgA immune complexes do not bind to Raji cells directly through Fc receptors, but through complement breakdown products, as with IgG-immune complexes. Using this method, we have been successful in detecting specific polymeric-IgA immune complexes in patients with IgA nephropathy (Berger's disease) and alcoholic liver disease, as well as in normal subjects after meals of high protein content. This new, simple, rapid and reproducible assay might help to study the physiopathological role of polymeric IgA immune complexes in humans and animals.

  19. Immune complex-based vaccine for pig protection against parvovirus.

    Science.gov (United States)

    Roić, B; Cajavec, S; Ergotić, N; Lipej, Z; Madić, J; Lojkić, M; Pokrić, B

    2006-02-01

    The insoluble immune complexes (ICs) were prepared under the conditions of double immunodiffusion in gel, using the suspension of the ultrasound treated PK-15 cell-line infected with porcine parvovirus (PPV) containing both viral particles and viral proteins, as well as pig or rabbit anti-PPV polyclonal immune sera. The immunodiffusion performed in an agarose gel allows only viral subunits with a molecular mass equal to or less than 1000 kDa, rather than the viral particles, to diffuse through the gel and reach the point where the immunoprecipitate is to be formed. The immunoprecipitation under the conditions of the diffusion ensures the optimal, i.e. equimolar ratio of both immunoprecipitating components, antibody/antigen in the IC. The sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the Western blot analyses showed the ICs were composed of two proteins, a protein in which molecular mass corresponded to the VP2 of the PPV and a protein with a molecular mass of the IgG. This suggests that the ICs are mainly composed of the VP2 antigen and IgG class antibodies. The potency of the IC-vaccines prepared in the form of a water-in-oil-in-water emulsion was compared with that of a commercially available, inactivated oil vaccine. The vaccination of gilts, 6 weeks before mating, with the IC containing allogeneic pig antibodies, resulted in the development of high and long-lasting anti-PPV antibody titres, similar to those generated by the licenced vaccine (P > 0.01). The content of the virus material administered by the IC was twice lower than that in the licenced vaccine. Neither systemic nor local reactions were observed in the gilts during the period of the trial with the IC vaccine. The number of viable piglets per litter varied between 9 and 12 and no signs of the PPV infection were detected. Rabbits were used as one of the alternative laboratory animal models accepted for the testing of the vaccine against the PPV. The rabbit humoral immune response

  20. Inducible immune proteins in the dampwood termite Zootermopsis angusticollis

    Science.gov (United States)

    Rosengaus, Rebeca B.; Cornelisse, Tara; Guschanski, Katerina; Traniello, James F. A.

    2007-01-01

    Dampwood termites, Zootermopsis angusticollis (Isoptera: Termopsidae), mount an immune response to resist microbial infection. Here we report on results of a novel analysis that allowed us to electrophoretically assess changes in hemolymph proteins in the same individual before and after exposure to a pathogen. We demonstrate that contact with a sublethal concentration of the entomopathogenic fungus Metarhizium anisopliae (Deuteromycotina:Hypomycetes) induces the production of protective proteins in nymphs, pseudergates (false workers), and soldiers. Termites exposed to an immunizing dosage of fungal conidia consistently showed an enhancement of constitutive proteins (62-85 kDa) in the hemolymph as well as an induction of novel proteins (28-48 kDa) relative to preimmunization levels. No significant differences in protein banding patterns relative to baseline levels in control and naïve termites were observed. Incubating excised and eluted induced proteins produced by immunized pseudergates or immunized soldiers with conidia significantly reduced the germination of the fungus. The fungistatic effect of eluted proteins differed significantly among five colonies examined. Our results show that the upregulation of protective proteins in the hemolymph underscores the in vivo immune response we previously recorded in Z. angusticollis.

  1. Inducible cell death in plant immunity

    DEFF Research Database (Denmark)

    Hofius, Daniel; Tsitsigiannis, Dimitrios I; Jones, Jonathan D G

    2006-01-01

    Programmed cell death (PCD) occurs during vegetative and reproductive plant growth, as typified by autumnal leaf senescence and the terminal differentiation of the endosperm of cereals which provide our major source of food. PCD also occurs in response to environmental stress and pathogen attack......, and these inducible PCD forms are intensively studied due their experimental tractability. In general, evidence exists for plant cell death pathways which have similarities to the apoptotic, autophagic and necrotic forms described in yeast and metazoans. Recent research aiming to understand these pathways...

  2. Ternary WD40 repeat-containing protein complexes: evolution, composition and roles in plant immunity

    Directory of Open Access Journals (Sweden)

    Jimi C. Miller

    2016-01-01

    Full Text Available Plants, like mammals, rely on their innate immune system to perceive and discriminate among the majority of their microbial pathogens. Unlike mammals, plants respond to this molecular dialogue by unleashing a complex chemical arsenal of defense metabolites to resist or evade pathogen infection. In basal or non-host resistance, plants utilize signal transduction pathways to detect non-self, damaged-self and altered-self-associated molecular patterns and translate these danger signals into largely inducible chemical defenses. The WD40 repeat (WDR-containing proteins Gβ and TTG1 are constituents of two independent ternary protein complexes functioning at opposite ends of a plant immune signaling pathway. Gβ and TTG1 are also encoded by single-copy genes that are ubiquitous in higher plants, implying the limited diversity and functional conservation of their respective complexes. In this review, we summarize what is currently known about the evolutionary history of these WDR-containing ternary complexes, their repertoire and combinatorial interactions, and their downstream effectors and pathways in plant defense.

  3. A Drosophila immune response against Ras-induced overgrowth

    Directory of Open Access Journals (Sweden)

    Thomas Hauling

    2014-03-01

    Full Text Available Our goal is to characterize the innate immune response against the early stage of tumor development. For this, animal models where genetic changes in specific cells and tissues can be performed in a controlled way have become increasingly important, including the fruitfly Drosophila melanogaster. Many tumor mutants in Drosophila affect the germline and, as a consequence, also the immune system itself, making it difficult to ascribe their phenotype to a specific tissue. Only during the past decade, mutations have been induced systematically in somatic cells to study the control of tumorous growth by neighboring cells and by immune cells. Here we show that upon ectopic expression of a dominant-active form of the Ras oncogene (RasV12, both imaginal discs and salivary glands are affected. Particularly, the glands increase in size, express metalloproteinases and display apoptotic markers. This leads to a strong cellular response, which has many hallmarks of the granuloma-like encapsulation reaction, usually mounted by the insect against larger foreign objects. RNA sequencing of the fat body reveals a characteristic humoral immune response. In addition we also identify genes that are specifically induced upon expression of RasV12. As a proof-of-principle, we show that one of the induced genes (santa-maria, which encodes a scavenger receptor, modulates damage to the salivary glands. The list of genes we have identified provides a rich source for further functional characterization. Our hope is that this will lead to a better understanding of the earliest stage of innate immune responses against tumors with implications for mammalian immunity.

  4. Skin immunization by microneedle patch overcomes statin-induced suppression of immune responses to influenza vaccine.

    Science.gov (United States)

    Vassilieva, Elena V; Wang, Shelly; Li, Song; Prausnitz, Mark R; Compans, Richard W

    2017-12-19

    Recent studies indicated that in elderly individuals, statin therapy is associated with a reduced response to influenza vaccination. The present study was designed to determine effects on the immune response to influenza vaccination induced by statin administration in a mouse model, and investigate potential approaches to improve the outcome of vaccination on the background of statin therapy. We fed middle aged BALB/c mice a high fat "western" diet (WD) alone or supplemented with atorvastatin (AT) for 14 weeks, and control mice were fed with the regular rodent diet. Mice were immunized with a single dose of subunit A/Brisbane/59/07 (H1N1) vaccine, either systemically or with dissolving microneedle patches (MNPs). We observed that a greater age-dependent decline in the hemagglutinin inhibition titers occurred in systemically-immunized mice than in MNP- immunized mice. AT dampened the antibody response in the animals vaccinated by either route of vaccine delivery. However, the MNP-vaccinated AT-treated animals had ~20 times higher total antibody levels to the influenza vaccine than the systemically vaccinated group one month postvaccination. We propose that microneedle vaccination against influenza provides an approach to ameliorate the immunosuppressive effect of statin therapy observed with systemic immunization.

  5. Immunization with avian metapneumovirus harboring chicken Fc induces higher immune responses.

    Science.gov (United States)

    Paudel, Sarita; Easwaran, Maheswaran; Jang, Hyun; Jung, Ho-Kyoung; Kim, Joo-Hun; Shin, Hyun-Jin

    2016-07-15

    In this study, we evaluated the immune responses of avian metapneumovirus harboring chicken Fc molecule. Stable Vero cells expressing chicken Fc chimera on its surface (Vero-cFc) were established, and we confirmed that aMPV grown in Vero-cFc incorporated host derived chimera Fc into the aMPV virions. Immunization of chicken with aMPV-cFc induced higher level of antibodies and inflammatory cytokines; (Interferon (IFN)-γ and Interleukin (IL)-1β) compared to those of aMPV. The increased levels of antibodies and inflammatory cytokines in chicken immunized with aMPV-cFc were statistically significantly (p<0.05) to that of aMPV and control. The aMPV-cFc group also generated the highest neutralizing antibody response. After challenges, chickens immunized with aMPV-cFc showed much less pathological signs in nasal turbinates and trachea so that we could confirm aMPV-cFc induced higher protection than that of aMPV. The greater ability of aMPV harboring chicken Fc to that of aMPV presented it as a possible vaccine candidate. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Temperature effects on vaccine induced immunity to viruses in fish

    DEFF Research Database (Denmark)

    Lorenzen, Niels; Lorenzen, Ellen; Rasmussen, Jesper Skou

    a problem in terms of inducing a protective immune response by vaccination in aquaculture, since it is often desirable to vaccinate fish during autumn, winter, or spring. In experimental vaccination trials with rainbow trout (Oncorhynchus mykiss) using a DNA-vaccine encoding the viral glycoprotein of viral...... haemorrhagic septicaemia virus (VHSV), non-specific as well as specific immune mechanisms seemed to be delayed at low temperature. At five weeks post vaccination fish kept at 5C had no detectable response of neutralising antibodies while two thirds of the fish kept at 15C had sero-converted. While protective...... immunity was still established at both temperatures, specificity analysis suggested that protection at the lower temperature was mainly due to non-specific innate antiviral mechanisms, which appeared to last longer at low temperature. This was presumably related to a prolonged persistence of the vaccine...

  7. Radiation-induced effects and the immune system in cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kaur, Punit; Asea, Alexzander, E-mail: aasea@msm.edu [Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA (United States)

    2012-12-17

    Chemotherapy and radiation therapy (RT) are standard therapeutic modalities for patients with cancers, and could induce various tumor cell death modalities, releasing tumor-derived antigens as well as danger signals that could either be captured for triggering anti-tumor immune response. Historic studies examining tissue and cellular responses to RT have predominantly focused on damage caused to proliferating malignant cells leading to their death. However, there is increasing evidence that RT also leads to significant alterations in the tumor microenvironment, particularly with respect to effects on immune cells and infiltrating tumors. This review will focus on immunologic consequences of RT and discuss the therapeutic reprogramming of immune responses in tumors and how it regulates efficacy and durability to RT.

  8. Complex pattern of immune evasion in MSI colorectal cancer.

    Science.gov (United States)

    Ozcan, Mine; Janikovits, Jonas; von Knebel Doeberitz, Magnus; Kloor, Matthias

    2018-01-01

    Mismatch repair (MMR)-deficient cancers accumulate multiple insertion/deletion mutations at coding microsatellites (cMS), which give rise to frameshift peptide neoantigens. The high mutational neoantigen load of MMR-deficient cancers is reflected by pronounced anti-tumoral immune responses of the host and high responsiveness towards immune checkpoint blockade. However, immune evasion mechanisms can interfere with the immune response against MMR-deficient tumors. We here performed a comprehensive analysis of immune evasion in MMR-deficient colorectal cancers, focusing on HLA class I-mediated antigen presentation. 72% of MMR-deficient colorectal cancers of the DFCI database harbored alterations affecting genes involved in HLA class I-mediated antigen presentation, and 54% of these mutations were predicted to abrogate function. Mutations affecting the HLA class I transactivator NLRC5 were observed as a potential new immune evasion mechanism in 26% (6% abrogating) of the analyzed tumors. NLRC5 mutations in MMR-deficient cancers were associated with decreased levels of HLA class I antigen expression. In summary, the majority of MMR-deficient cancers display mutations interfering with HLA class I antigen presentation that reflect active immune surveillance and immunoselection during tumor development. Clinical studies focusing on immune checkpoint blockade in MSI cancer should account for the broad variety of immune evasion mechanisms as potential biomarkers of therapy success.

  9. Candida albicans infection of Caenorhabditis elegans induces antifungal immune defenses.

    Directory of Open Access Journals (Sweden)

    Read Pukkila-Worley

    2011-06-01

    Full Text Available Candida albicans yeast cells are found in the intestine of most humans, yet this opportunist can invade host tissues and cause life-threatening infections in susceptible individuals. To better understand the host factors that underlie susceptibility to candidiasis, we developed a new model to study antifungal innate immunity. We demonstrate that the yeast form of C. albicans establishes an intestinal infection in Caenorhabditis elegans, whereas heat-killed yeast are avirulent. Genome-wide, transcription-profiling analysis of C. elegans infected with C. albicans yeast showed that exposure to C. albicans stimulated a rapid host response involving 313 genes (124 upregulated and 189 downregulated, ~1.6% of the genome many of which encode antimicrobial, secreted or detoxification proteins. Interestingly, the host genes affected by C. albicans exposure overlapped only to a small extent with the distinct transcriptional responses to the pathogenic bacteria Pseudomonas aeruginosa or Staphylococcus aureus, indicating that there is a high degree of immune specificity toward different bacterial species and C. albicans. Furthermore, genes induced by P. aeruginosa and S. aureus were strongly over-represented among the genes downregulated during C. albicans infection, suggesting that in response to fungal pathogens, nematodes selectively repress the transcription of antibacterial immune effectors. A similar phenomenon is well known in the plant immune response, but has not been described previously in metazoans. Finally, 56% of the genes induced by live C. albicans were also upregulated by heat-killed yeast. These data suggest that a large part of the transcriptional response to C. albicans is mediated through "pattern recognition," an ancient immune surveillance mechanism able to detect conserved microbial molecules (so-called pathogen-associated molecular patterns or PAMPs. This study provides new information on the evolution and regulation of the innate

  10. Membrane attack complex of complement is not essential for immune mediated demyelination in experimental autoimmune neuritis.

    Science.gov (United States)

    Tran, Giang T; Hodgkinson, Suzanne J; Carter, Nicole M; Killingsworth, Murray; Nomura, Masaru; Verma, Nirupama D; Plain, Karren M; Boyd, Rochelle; Hall, Bruce M

    2010-12-15

    Antibody deposition and complement activation, especially membrane attack complex (MAC) formation are considered central for immune mediated demyelination. To examine the role of MAC in immune mediated demyelination, we studied experimental allergic neuritis (EAN) in Lewis rats deficient in complement component 6 (C6) that cannot form MAC. A C6 deficient Lewis (Lewis/C6-) strain of rats was bred by backcrossing the defective C6 gene, from PVG/C6- rats, onto the Lewis background. Lewis/C6- rats had the same C6 gene deletion as PVG/C6- rats and their sera did not support immune mediated haemolysis unless C6 was added. Active EAN was induced in Lewis and Lewis/C6- rats by immunization with bovine peripheral nerve myelin in complete Freund's adjuvant (CFA), and Lewis/C6- rats had delayed clinical EAN compared to the Lewis rats. Peripheral nerve demyelination in Lewis/C6- was also delayed but was similar in extent at the peak of disease. Compared to Lewis, Lewis/C6- nerves had no MAC deposition, reduced macrophage infiltrate and IL-17A, but similar T cell infiltrate and Th1 cytokine mRNA expression. ICAM-1 and P-selectin mRNA expression and immunostaining on vascular endothelium were delayed in Lewis C6- compared to Lewis rats' nerves. This study found that MAC was not required for immune mediated demyelination; but that MAC enhanced early symptoms and early demyelination in EAN, either by direct lysis or by sub-lytic induction of vascular endothelial expression of ICAM-1 and P-selectin. Copyright © 2010 Elsevier B.V. All rights reserved.

  11. The role of probiotics and prebiotics inducing gut immunity

    Directory of Open Access Journals (Sweden)

    Angelica Thomaz Vieira

    2013-12-01

    Full Text Available The gut immune system is influenced by many factors, including dietary components and commensal bacteria. Nutrients that affect gut immunity and strategies that restore a healthy gut microbial community by affecting the microbial composition are being developed as new therapeutic approaches to treat several inflammatory diseases. Although probiotics (live microorganisms and prebiotics (food components have shown promise as treatments for several diseases in both clinical and animal studies, an understanding of the molecular mechanisms behind the direct and indirect effects on the gut immune response will facilitate better and possibly more efficient therapy for diseases. In this review, we will first describe the concept of prebiotics, probiotics and symbiotics and cover the most recently well-established scientific findings regarding the direct and indirect mechanisms by which these dietary approaches can influence gut immunity. Emphasis will be placed on the relationship of diet, the microbiota and the gut immune system. Second, we will highlight recent results from our group, which suggest a new dietary manipulation that includes the use of nutrient products (organic selenium and Lithothamnium muelleri and probiotics (Saccharomyces boulardii UFMG 905 and Bifidobacterium sp. that can stimulate and manipulate the gut immune response, inducing intestinal homeostasis. Furthermore, the purpose of this review is to discuss and translate all of this knowledge into therapeutic strategies and into treatment for extra-intestinal compartment pathologies. We will conclude by discussing perspectives and molecular advances regarding the use of prebiotics or probiotics as new therapeutic strategies that manipulate the microbial composition and the gut immune responses of the host.

  12. [Autoantibody formation against the antigens of the synaptonemal complex in the syngeneic immunization of male Mus musculus].

    Science.gov (United States)

    Dadashev, S Ia; Gorach, G G; Kolomiets, O L

    1994-01-01

    Male mice were immunized with the suspension of synaptonemal complexes (SC) isolated from mouse spermatocytes nuclei. The indirect immunofluorescent analysis showed the active binding of sera obtained from immunized mice to SC of mouse spermatocyte spreads. At early and mid-pachytene, SC can be clearly identified in 19 autosome bivalents and in sex chromosome bivalent. According to the electron microscopic analysis, all structural elements of SC bind antibodies. Metaphase chromosomes were not stained with the immune sera. Specificity of interaction between SC components and antibodies was confirmed in a series of control experiments. Analysis of sera obtained from mice after their syngeneic immunization with isolated SC fraction suggested that certain mouse SC components induce the formation of autoantibodies. This, in turn, suggests that these SC components are meiosis-specific.

  13. Flagella-induced immunity against experimental cholera in adult rabbits.

    Science.gov (United States)

    Yancey, R J; Willis, D L; Berry, L J

    1979-07-01

    The adult rabbit ligated ileal loop model was used to evaluate the prophylactic potential of a crude flagellar (CF) vaccine produced from the classical. Inaba strain CA401. A greater than 1,000-fold increase in the challenge inoculum was required to induce an intestinal fluid response in actively immunized adult rabbits equivalent to that produced in unimmunized animals. Similar protection was afforded against challenge with classical and El Tor biotypes of both Inaba and Ogawa serotypes. Highly virulent 35S-labeled vibrios were inhibited in their ability to associated with the intestinal mucosa of CF-immunized rabbits. The protection conferred by CF immunization was found to be superior to that of a commercial bivalent vaccine and also to that of glutaraldehyde-treated cholera toxoid. The critical immunogenic component of CF appears to be a flagella-derived protein. The immunogenicity of CF was destroyed by heat treatment, and absorption of CF-immune serum with aflagellated mutant vibrios did not diminish its ability to confer a high level of passive protection. The intestinal protection of CF-immunized rabbits was completely reversed by the introduction of both goat anti-rabbit immunoglobulins A and G, but by neither alone.

  14. Sporothrix schenckii Immunization, but Not Infection, Induces Protective Th17 Responses Mediated by Circulating Memory CD4+ T Cells

    Directory of Open Access Journals (Sweden)

    Alberto García-Lozano

    2018-06-01

    Full Text Available Sporotrichosis is a chronic subcutaneous mycosis caused by the Sporothrix schenckii species complex and it is considered an emerging opportunistic infection in countries with tropical and subtropical climates. The host’s immune response has a main role in the development of this disease. However, it is unknown the features of the memory cellular immune response that could protect against the infection. Our results show that i.d. immunization in the ears of mice with inactivated S. schenckii conidia (iC combined with the cholera toxin (CT induces a cellular immune response mediated by circulating memory CD4+ T cells, which mainly produce interleukin 17 (IL-17. These cells mediate a strong delayed-type hypersensitivity (DTH reaction. Systemic and local protection against S. schenckii was mediated by circulating CD4+ T cells. In contrast, the infection induces a potent immune response in the skin mediated by CD4+ T cells, which have an effector phenotype that preferentially produce interferon gamma (IFN-γ and mediate a transitory DTH reaction. Our findings prove the potential value of the CT as a potent skin adjuvant when combined with fungal antigens, and they also have important implications for our better understanding of the differences between the memory immune response induced by the skin immunization and those induced by the infection; this knowledge enhances our understanding of how a protective immune response against a S. schenckii infection is developed.

  15. Salmonella enterica Induces And Subverts The Plant Immune System

    Directory of Open Access Journals (Sweden)

    Ana Victoria Garcia

    2014-04-01

    Full Text Available Infections with Salmonella enterica belong to the most prominent causes of food poisoning and infected fruits and vegetables represent important vectors for salmonellosis. Whereas it was shown that plants raise defense responses against Salmonella, these bacteria persist and proliferate in various plant tissues. Recent reports shed light into the molecular interaction between plants and Salmonella, highlighting the defense pathways induced and the means used by the bacteria to escape the plant immune system and accomplish colonization. It was recently shown that plants detect Salmonella pathogen-associated molecular patterns (PAMPs, such as the flagellin peptide flg22, and activate hallmarks of the defense program known as PAMP-triggered immunity (PTI. Interestingly, certain Salmonella strains carry mutations in the flg22 domain triggering PTI, suggesting that a strategy of Salmonella is to escape plant detection by mutating PAMP motifs. Another strategy may rely on the type III secretion system (T3SS as T3SS mutants were found to induce stronger plant defense responses than wild type bacteria. Although Salmonella effector delivery into plant cells has not been shown, expression of Salmonella effectors in plant tissues shows that these bacteria also possess powerful means to manipulate the plant immune system. Altogether, the data gathered suggest that Salmonella triggers PTI in plants and evolved strategies to avoid or subvert plant immunity.

  16. Salmonella enterica induces and subverts the plant immune system

    KAUST Repository

    García, Ana V.

    2014-04-04

    Infections with Salmonella enterica belong to the most prominent causes of food poisoning and infected fruits and vegetables represent important vectors for salmonellosis. Although it was shown that plants raise defense responses against Salmonella, these bacteria persist and proliferate in various plant tissues. Recent reports shed light into the molecular interaction between plants and Salmonella, highlighting the defense pathways induced and the means used by the bacteria to escape the plant immune system and accomplish colonization. It was recently shown that plants detect Salmonella pathogen-associated molecular patterns (PAMPs), such as the flagellin peptide flg22, and activate hallmarks of the defense program known as PAMP-triggered immunity (PTI). Interestingly, certain Salmonella strains carry mutations in the flg22 domain triggering PTI, suggesting that a strategy of Salmonella is to escape plant detection by mutating PAMP motifs. Another strategy may rely on the type III secretion system (T3SS) as T3SS mutants were found to induce stronger plant defense responses than wild type bacteria. Although Salmonella effector delivery into plant cells has not been shown, expression of Salmonella effectors in plant tissues shows that these bacteria also possess powerful means to manipulate the plant immune system. Altogether, these data suggest that Salmonella triggers PTI in plants and evolved strategies to avoid or subvert plant immunity. 2014 Garca and Hirt.

  17. Immune complexes stimulate CCR7-dependent dendritic cell migration to lymph nodes

    Science.gov (United States)

    Clatworthy, Menna R.; Aronin, Caren E. Petrie; Mathews, Rebeccah J.; Morgan, Nicole; Smith, Kenneth G.C.; Germain, Ronald N.

    2014-01-01

    Antibodies are critical for defence against a variety of microbes but may also be pathogenic in some autoimmune diseases. Many effector functions of antibody are mediated by Fcγ receptors (FcγRs), which are found on most immune cells, including dendritic cells (DCs). DCs are important antigen presenting cells and play a central role in inducing antigen-specific tolerance or immunity1,2. Following antigen acquisition in peripheral tissues, DCs migrate to draining lymph nodes via lymphatics to present antigen to T cells. In this study we demonstrate that FcγR engagement by IgG immune complexes (IC) stimulates DC migration from peripheral tissues to the paracortex of draining lymph nodes. In vitro, IC-stimulated murine and human DCs showed enhanced directional migration in a CCL19 gradient and increased CCR7 expression. Using intravital two-photon microscopy, we observed that local administration of IC resulted in dermal DC mobilisation. We confirmed that dermal DC migration to lymph nodes was CCR7-dependent and increased in the absence of the inhibitory receptor, FcγRIIb. These observations have relevance to autoimmunity, because autoantibody-containing serum from mice and humans with SLE also increased dermal DC migration to lymph nodes in vivo, suggesting that this process may occur in lupus, potentially driving the inappropriate localisation of autoantigen-bearing DCs. PMID:25384086

  18. Complex role for the immune system in initiation and progression of pancreatic cancer.

    Science.gov (United States)

    Inman, Kristin S; Francis, Amanda A; Murray, Nicole R

    2014-08-28

    The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound systemic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma (PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed.

  19. A mechanism for trauma induced muscle wasting and immune dysfunction

    Science.gov (United States)

    Madihally, S.; Toner, M.; Yarmush, M.; Mitchell, R.

    A diverse physiological conditions lead to a hypercatabolic state marked by the loss of proteins, primarily derived from skeletal muscle. The sustained loss of proteins results in loss of muscle mass and strength, poor healing, and long-term hospitalization. These problems are further compounded by the deterioration of immunity to infection which is a leading cause of morbidity and mortality of traumatic patients. In an attempt to understand the signal propagation mechanism(s), we tested the role of Interferon-? (IFN-? ) in an animal burn injury model; IFN-? is best conceptualized as a macrophage activating protein and known to modulate a variety of intracellular processes potentially relevant to muscle wasting and immune dysfunction. Mice congenitally -deficient in IFN-? , and IFN-? -Receptor, and wild type (WT) animals treated with IFN-? neutralizing antibody received either a 20% total body surface area burn or a control sham treatment. At days 1, 2, and 7 following treatment, skeletal muscle, peripheral blood, and spleen were harvested from both groups. Overall body weight, protein turnovers, changes in the lymphocyte subpopulations and alterations in the major histocompatibility complex I expression (MHC I) and proliferation capacity of lymphocytes was measured using mixed lymphocyte reaction (MLR). These results indicate that we can prevent both muscle wasting and immune dysfunction. Based on these observations and our previous other animal model results (using insulin therapy), a novel mechanism of interactions leading to muscle wasting and immune dysfunction will be discussed. Further, implications of these findings on future research and clinical therapies will be discussed in detail.

  20. Focal glomerular immune complex deposition: possible role of periglomerular fibrosis/atubular glomeruli.

    Science.gov (United States)

    Satoskar, Anjali A; Calomeni, Edward; Bott, Cherri; Nadasdy, Gyongyi M; Nadasdy, Tibor

    2009-02-01

    Consensus exists among renal pathologists that, in biopsies with immune complex glomerulonephritis, even a single glomerulus with open capillary loops may be sufficient for immunofluorescence and/or electron microscopy evaluation because immune complex deposition is a diffuse phenomenon. However, we have encountered renal biopsies with focal absence of immune complexes in glomeruli on either immunofluorescence or electron microscopy examination despite presence of open glomerular capillary loops. To evaluate renal biopsies with focal immune complex deposition and look for any subtle or unusual morphologic changes in the glomeruli (and in the biopsy in general). Native and transplant renal biopsies were reviewed. All biopsies had been triaged and processed according to our routine protocol for light microscopy, immunofluorescence, and electron microscopy examination. Of 2018 renal biopsies from December 2005 to December 2007, we found 10 such biopsies; 5 native and 5 transplant kidney biopsies. We found that the glomeruli with absent immune complex deposits had periglomerular fibrosis with open, albeit, wrinkled appearing capillary loops but no glomerular sclerosis. We hypothesize that these histologic features are indicative of nonfunctional glomeruli and may be associated with disconnection between the Bowman capsule and proximal tubule (atubular glomeruli). These glomeruli may not have effective filtration, despite some degree of circulation through the open capillary loops, and therefore are unable to accumulate immune complex deposits. If biopsies are small and only such glomeruli are available for immunofluorescence or electron microscopy examination, the absence of immune complex deposition in them should be evaluated carefully.

  1. Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells

    OpenAIRE

    Wang, Xiaomei; Su, Jin; Sherman, Alexandra; Rogers, Geoffrey L.; Liao, Gongxian; Hoffman, Brad E.; Leong, Kam W.; Terhorst, Cox; Daniell, Henry; Herzog, Roland W.

    2015-01-01

    Coadministering FIX orally and systemically induces tolerance via complex immune regulation, involving tolerogenic dendritic and T-cell subsets.Induced CD4+CD25−LAP+ regulatory T cells with increased IL-10 and TGF-β expression and CD4+CD25+ regulatory T cells suppress antibody formation against FIX.

  2. Circulating IgA immune complexes in patients with psoriasis

    International Nuclear Information System (INIS)

    Hall, R.P.; Peck, G.L.; Lawley, T.J.

    1983-01-01

    The sera of 21 patients with psoriasis were examined for the presence of IgA-containing circulating immune complexes (CIC) using the Raji IgA radioimmunoassay. In addition, the Raji IgG radioimmunoassay and 125I-Clq binding assay were used to detect IgG- and IgM-containing CIC. Twenty-five patients with other hyperkeratotic skin disorders were studied as controls. Patients were studied before institution of systemic therapy with etretinate (20 patients) or 13-cis-retinoic acid (1 patient). In addition, sera of 15 of the patients treated with etretinate were studied before, during, and after therapy. The extent of pretreatment disease involvement as well as response to therapy were evaluated in a blinded fashion. Fourteen of 21 (67%) patients with psoriasis had evidence of IgA-containing CIC at some time during the course of their disease, as compared to only 1 of 25 patients with other hyperkeratotic skin disorders. In contrast, only 2 of 19 (11%) had evidence of IgG-containing CIC using the Raji IgG assay, and only 1 of 19 (5%) had evidence of IgG- or IgM-containing CIC using the 125I-Clq binding assay. A positive correlation was found between the extent of pretreatment disease involvement and the level of IgA-containing CIC by linear regression analysis (p . 0.01). There was, however, no correlation between clinical improvement and the presence or level of IgA-containing CIC in 15 patients followed during therapy. Sucrose density gradient analysis of the IgA-containing CIC found in 2 of these patients demonstrated IgA-containing CIC in the 9S to 13S region. The finding of IgA-containing CIC in a significant number of patients with psoriasis and the relative absence of IgG- or IgM-containing CIC suggest that IgA-containing CIC may play a role in psoriasis

  3. Acute lung injury in rat caused by immunoglobulin A immune complexes.

    OpenAIRE

    Johnson, K J; Wilson, B S; Till, G O; Ward, P A

    1984-01-01

    Mouse IgG and IgA, with reactivity to dinitrophenol conjugated to carrier protein, have been isolated from myeloma proteins by means of a variety of affinity techniques. The IgA was predominantly in the dimeric form. The in vitro and in vivo biological activities of IgA-containing immune complexes were assessed in the rat. IgA-containing immune complexes were demonstrated, in a dose-dependent manner in vitro, to activate neutrophils and to generate O.-2. In addition, these immune complexes sh...

  4. Immune response to uv-induced tumors: transplantation immunity and lymphocyte populations exhibiting anti-tumor activity

    International Nuclear Information System (INIS)

    Streeter, P.R.

    1985-01-01

    Ultraviolet light-induced murine skin tumors were analyzed for their ability to induce tumor-specific and cross-protective transplantation immunity in immunocompetent syngeneic mice. These studies revealed that progressor UV-tumors, like regressor UV-tumors, possess tumor-specific transplantation antigens. Cross-protective transplantation immunity to UV-tumors, however, was associated with sensitization to the serum used to culture the tumor lines rather than to cross-reactive or common determinants on UV-tumors. An analysis of the cytolytic activity of lymphocytes from the spleens of mice immunized with either regressor or progressor UV-tumors revealed a striking difference between the two immune splenocyte populations. From regressor tumor-immune animals, cytolytic T (Tc) lymphocytes with specificity for the immunizing tumor were found. However, the analysis of splenic lymphocytes from progressor tumor immune animals revealed no such effector cells. To more effectively examine those lymphocytes exhibiting cytolytic activity in vitro, T lymphocyte cloning technology was used as a means of isolating homogeneous lymphocyte populations with the effector activities described above. The mechanisms where NK cells and other nonspecific effector cells could be induced in tumor-immune animals are discussed in the context of class II restricted immune responses

  5. Spatio-temporal regulation of Hsp90-ligand complex leads to immune activation.

    Directory of Open Access Journals (Sweden)

    Yasuaki eTamura

    2016-05-01

    Full Text Available Hsp90 is the most abundant cytosolic HSP and is known to act as a molecular chaperone. We found that an Hsp90-cancer antigen peptide complex was efficiently cross-presented by human monocyte-derived dendritic cells and induced peptide-specific cytotoxic T lymphocytes. Furthermore, we observed that the internalized Hsp90-peptide complex was strictly sorted to the Rab5+, EEA1+ static early endosome and the Hsp90-chaperoned peptide was processed and bound to MHC class I molecules through a endosome-recycling pathway. We also found that extracellular Hsp90 complexed with CpG-A or self-DNA stimulates production of a large amount of IFN-α from pDCs via static early endosome targeting. Thus, extracellular Hsp90 can target the antigen or nucleic acid to a static early endosome by spatio-temporal regulation. Moreover, we showed that Hsp90 associates with and delivers TLR7/9 from the ER to early endosomes for ligand recognition. Hsp90 inhibitor, geldanamycin derivative inhibited the Hsp90 association with TLR7/9, resulting in inhibition IFN-α production, leading to improvement of SLE symptoms. Interstingly, we observed that serum Hsp90 is clearly increased in patients with active SLE compared with that in patients with inactive disease. Serum Hsp90 detected in SLE patients binds to self-DNA and/or anti-DNA Ab, thus leading to stimulation of pDCs to produce IFN-α. Thus, Hsp90 plays a crucial role in the pathogenesis of SLE and that an Hsp90 inhibitor will therefore provide a new therapeutic approach to SLE and other nucleic acid-related autoimmune diseases. We will discuss how spatio-temporal regulation of Hsp90-ligand complexes within antigen-presenting cells affects the innate immunity and adaptive immunity.

  6. Computational Strategies for Dissecting the High-Dimensional Complexity of Adaptive Immune Repertoires

    Directory of Open Access Journals (Sweden)

    Enkelejda Miho

    2018-02-01

    Full Text Available The adaptive immune system recognizes antigens via an immense array of antigen-binding antibodies and T-cell receptors, the immune repertoire. The interrogation of immune repertoires is of high relevance for understanding the adaptive immune response in disease and infection (e.g., autoimmunity, cancer, HIV. Adaptive immune receptor repertoire sequencing (AIRR-seq has driven the quantitative and molecular-level profiling of immune repertoires, thereby revealing the high-dimensional complexity of the immune receptor sequence landscape. Several methods for the computational and statistical analysis of large-scale AIRR-seq data have been developed to resolve immune repertoire complexity and to understand the dynamics of adaptive immunity. Here, we review the current research on (i diversity, (ii clustering and network, (iii phylogenetic, and (iv machine learning methods applied to dissect, quantify, and compare the architecture, evolution, and specificity of immune repertoires. We summarize outstanding questions in computational immunology and propose future directions for systems immunology toward coupling AIRR-seq with the computational discovery of immunotherapeutics, vaccines, and immunodiagnostics.

  7. An immune stimulating complex (iscom) subunit rabies vaccine protects dogs and mice against street rabies challenge.

    NARCIS (Netherlands)

    M. Fekadu; J.H. Schaddock; J. Ekströ m; A.D.M.E. Osterhaus (Albert); D.W. Sanderlin; B. Sundquist; B. Morein (Bror)

    1992-01-01

    textabstractDogs and mice were immunized with either a rabies glycoprotein subunit vaccine incorporated into an immune stimulating complex (ISCOM) or a commercial human diploid cell vaccine (HDCV) prepared from a Pitman Moore (PM) rabies vaccine strain. Pre-exposure vaccination of mice with two

  8. Effect of Scoparia dulcis on noise stress induced adaptive immunity and cytokine response in immunized Wistar rats

    Directory of Open Access Journals (Sweden)

    Loganathan Sundareswaran

    2017-01-01

    Conclusion: S. dulcis (SD has normalized and prevented the noise induced changes in cell-mediated and humoral immunity and it could be the presence of anti-stressor and immuno stimulant activity of the plant.

  9. Persistence of the immune response induced by BCG vaccination

    Directory of Open Access Journals (Sweden)

    Blitz Rose

    2008-01-01

    Full Text Available Abstract Background Although BCG vaccination is recommended in most countries of the world, little is known of the persistence of BCG-induced immune responses. As novel TB vaccines may be given to boost the immunity induced by neonatal BCG vaccination, evidence concerning the persistence of the BCG vaccine-induced response would help inform decisions about when such boosting would be most effective. Methods A randomised control study of UK adolescents was carried out to investigate persistence of BCG immune responses. Adolescents were tested for interferon-gamma (IFN-γ response to Mycobacterium tuberculosis purified protein derivative (M.tb PPD in a whole blood assay before, 3 months, 12 months (n = 148 and 3 years (n = 19 after receiving teenage BCG vaccination or 14 years after receiving infant BCG vaccination (n = 16. Results A gradual reduction in magnitude of response was evident from 3 months to 1 year and from 1 year to 3 years following teenage vaccination, but responses 3 years after vaccination were still on average 6 times higher than before vaccination among vaccinees. Some individuals (11/86; 13% failed to make a detectable antigen-specific response three months after vaccination, or lost the response after 1 (11/86; 13% or 3 (3/19; 16% years. IFN-γ response to Ag85 was measured in a subgroup of adolescents and appeared to be better maintained with no decline from 3 to 12 months. A smaller group of adolescents were tested 14 years after receiving infant BCG vaccination and 13/16 (81% made a detectable IFN-γ response to M.tb PPD 14 years after infant vaccination as compared to 6/16 (38% matched unvaccinated controls (p = 0.012; teenagers vaccinated in infancy were 19 times more likely to make an IFN-γ response of > 500 pg/ml than unvaccinated teenagers. Conclusion BCG vaccination in infancy and adolescence induces immunological memory to mycobacterial antigens that is still present and measurable for at least 14 years in the

  10. Genes of the major histocompatibility complex highlight interactions of the innate and adaptive immune system

    Directory of Open Access Journals (Sweden)

    Barbara Lukasch

    2017-08-01

    Full Text Available Background A well-functioning immune defence is crucial for fitness, but our knowledge about the immune system and its complex interactions is still limited. Major histocompatibility complex (MHC molecules are involved in T-cell mediated adaptive immune responses, but MHC is also highly upregulated during the initial innate immune response. The aim of our study was therefore to determine to what extent the highly polymorphic MHC is involved in interactions of the innate and adaptive immune defence and if specific functional MHC alleles (FA or heterozygosity at the MHC are more important. Methods To do this we used captive house sparrows (Passer domesticus to survey MHC diversity and immune function controlling for several environmental factors. MHC class I alleles were identified using parallel amplicon sequencing and to mirror immune function, several immunological tests that correspond to the innate and adaptive immunity were conducted. Results Our results reveal that MHC was linked to all immune tests, highlighting its importance for the immune defence. While all innate responses were associated with one single FA, adaptive responses (cell-mediated and humoral were associated with several different alleles. Discussion We found that repeated injections of an antibody in nestlings and adults were linked to different FA and hence might affect different areas of the immune system. Also, individuals with a higher number of different FA produced a smaller secondary response, indicating a disadvantage of having numerous MHC alleles. These results demonstrate the complexity of the immune system in relation to the MHC and lay the foundation for other studies to further investigate this topic.

  11. Genes of the major histocompatibility complex highlight interactions of the innate and adaptive immune system.

    Science.gov (United States)

    Lukasch, Barbara; Westerdahl, Helena; Strandh, Maria; Winkler, Hans; Moodley, Yoshan; Knauer, Felix; Hoi, Herbert

    2017-01-01

    A well-functioning immune defence is crucial for fitness, but our knowledge about the immune system and its complex interactions is still limited. Major histocompatibility complex (MHC) molecules are involved in T-cell mediated adaptive immune responses, but MHC is also highly upregulated during the initial innate immune response. The aim of our study was therefore to determine to what extent the highly polymorphic MHC is involved in interactions of the innate and adaptive immune defence and if specific functional MHC alleles (FA) or heterozygosity at the MHC are more important. To do this we used captive house sparrows ( Passer domesticus ) to survey MHC diversity and immune function controlling for several environmental factors. MHC class I alleles were identified using parallel amplicon sequencing and to mirror immune function, several immunological tests that correspond to the innate and adaptive immunity were conducted. Our results reveal that MHC was linked to all immune tests, highlighting its importance for the immune defence. While all innate responses were associated with one single FA, adaptive responses (cell-mediated and humoral) were associated with several different alleles. We found that repeated injections of an antibody in nestlings and adults were linked to different FA and hence might affect different areas of the immune system. Also, individuals with a higher number of different FA produced a smaller secondary response, indicating a disadvantage of having numerous MHC alleles. These results demonstrate the complexity of the immune system in relation to the MHC and lay the foundation for other studies to further investigate this topic.

  12. Alemtuzumab-induced elimination of HIV-1-infected immune cells.

    Science.gov (United States)

    Ruxrungtham, Kiat; Sirivichayakul, Sunee; Buranapraditkun, Supranee; Krause, Werner

    2016-01-01

    Currently, there is no drug known that is able to eradicate either HIV or HIV-infected host cells. The effectiveness of all available treatments is based on the prevention of viral replication. We investigated whether the monoclonal, CD52 receptor-targeting antibody, alemtuzumab, which is currently approved for the treatment of multiple sclerosis, is able to eliminate HIV-infected immune cells. In blood samples from healthy donors and from HIV-1-infected subjects who were either treatment-naïve or resistant to HAART, we studied whether the CD52 expression on T cells and their subsets (CD3, CD4, CD8), B cells (CD19), dendritic cells (CD123) and monocytes (CD11c) is retained in HIV-1 infection and whether alemtuzumab is able to eradicate infected cells, using four-colour flow cytometry. We found that CD52 expression on immune cells is retained in HIV-1 infection regardless of CD4 cell count, viral load and treatment status, and is amenable to alemtuzumab-induced depletion. For the first time it could be shown in vitro that HIV-1-infected immune cells can be eliminated by using the monoclonal antibody alemtuzumab.

  13. Candesartan ameliorates impaired fear extinction induced by innate immune activation.

    Science.gov (United States)

    Quiñones, María M; Maldonado, Lizette; Velazquez, Bethzaly; Porter, James T

    2016-02-01

    Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 μg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 μg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 μg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 μg/kg) which impaired locomotion without affecting extinction. In addition, 15 h after an injection of 250 μg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Different protein of Echinococcus granulosus stimulates dendritic induced immune response.

    Science.gov (United States)

    Wang, Yana; Wang, Qiang; Lv, Shiyu; Zhang, Shengxiang

    2015-06-01

    Cystic echinococcosis is a chronic infectious disease that results from a host/parasite interaction. Vaccination with ferritin derived from Echinococcus granulosus is a potential preventative treatment. To understand whether ferritin is capable of inducing a host immune response, we investigated the response of dendritic cells (DCs) to both recombinant ferritin protein and the hydatid fluid (HF) of E. granulosus. We evaluated the immunomodulatory potential of these antigens by performing, immunocytochemistry, electron microscopy and in vivo imaging of monocyte-derived murine DCs. During antigen stimulation of DCs, ferritin cause DCs maturation and induced higher levels of surface marker expression and activated T-cell proliferation and migration. On contrary, HF failed to induce surface marker expression and to stimulate T-cell proliferation. In response to HF, DCs produced interleukin-6 (IL-6), but no IL-12 and IL-10. DCs stimulated with ferritin produced high levels of cytokines. Overall, HF appears to induce host immunosuppression in order to ensure parasite survival via inhibits DC maturation and promotes Th2-dependent secretion of cytokines. Although ferritin also promoted DC maturation and cytokine release, it also activates CD4+T-cell proliferation, but regard of the mechanism of the Eg.ferritin induce host to eradicate E. granulosus were not clear.

  15. Sulfasalazine Attenuates Staphylococcal Enterotoxin B-Induced Immune Responses

    Directory of Open Access Journals (Sweden)

    Teresa Krakauer

    2015-02-01

    Full Text Available Staphylococcal enterotoxin B (SEB and related exotoxins are important virulence factors produced by Staphylococcus aureus as they cause human diseases such as food poisoning and toxic shock. These toxins bind directly to cells of the immune system resulting in hyperactivation of both T lymphocytes and monocytes/macrophages. The excessive release of proinflammatory cytokines from these cells mediates the toxic effects of SEB. This study examined the inhibitory activities of an anti-inflammatory drug, sulfasalazine, on SEB-stimulated human peripheral blood mononuclear cells (PBMC. Sulfasalazine dose-dependently inhibited tumor necrosis factor α, interleukin 1 (IL-1 β, IL-2, IL-6, interferon γ (IFNγ, and various chemotactic cytokines from SEB-stimulated human PBMC. Sulfasalazine also potently blocked SEB-induced T cell proliferation and NFκB activation. These results suggest that sulfasalazine might be useful in mitigating the toxic effects of SEB by blocking SEB-induced host inflammatory cascade and signaling pathways.

  16. Immune complexes, gallium lung scans, and bronchoalveolar lavage in idiopathic interstitial pneumonitis-fibrosis

    International Nuclear Information System (INIS)

    Gelb, A.F.; Dreisen, R.B.; Epstein, J.D.; Silverthorne, J.D.; Bickel, Y.; Fields, M.; Border, W.A.; Taylor, C.R.

    1983-01-01

    We obtained results of lung immune complexes (LIC), circulating immune complexes (CIC), 48-hour gallium lung scans (scans), bronchoalveolar lavage (BAL), and pulmonary function tests in 20 patients with idiopathic interstitial pneumonitis-fibrosis. Sixteen patients had predominantly interstitial (13 cases UIP) and/or intraalveolar (3 cases DIP) cellular disease (group 1). Prior to corticosteroid therapy in group 1, scans were positive in 75 percent, CIC were elevated in 86 percent, LIC were present in 64 percent, and BAL was abnormal in 90 percent. Duration of follow-up after treatment was 3.5 +/- 1.0 year. In group 1 after treatment with corticosteroids in 13 patients and corticosteroids and penicillamine (three patients) and plasmapheresis (one patient), only four patients remain stable or improved. After corticosteroid therapy, elevated CIC returned to normal values despite progressive patient deterioration. In three patients, lung immune complexes were still detected after circulating immune complexes had returned to normal after corticosteroid therapy. In group 2 were four patients with fibrotic disease; scans and CIC were uniformly negative, LIC were weakly present in only one patient, and BAL was abnormal in all. Despite corticosteroid therapy, all have died or deteriorated. These results suggest that positive gallium lung scans, BAL, circulating immune complexes, and to a lesser extent, lung immune complexes are associated with the cellular phase of interstitial pneumonia, but do not reliably identify a corticosteroid-responsive group

  17. Aggregate complexes of HIV-1 induced by multimeric antibodies.

    Science.gov (United States)

    Stieh, Daniel J; King, Deborah F; Klein, Katja; Liu, Pinghuang; Shen, Xiaoying; Hwang, Kwan Ki; Ferrari, Guido; Montefiori, David C; Haynes, Barton; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Rerks-Ngarm, Supachai; Michael, Nelson L; Robb, Merlin L; Kim, Jerome H; Denny, Thomas N; Tomaras, Georgia D; Shattock, Robin J

    2014-10-02

    Antibody mediated viral aggregation may impede viral transfer across mucosal surfaces by hindering viral movement in mucus, preventing transcytosis, or reducing inter-cellular penetration of epithelia thereby limiting access to susceptible mucosal CD4 T cells and dendritic cells. These functions may work together to provide effective immune exclusion of virus from mucosal tissue; however little is known about the antibody characteristics required to induce HIV aggregation. Such knowledge may be critical to the design of successful immunization strategies to facilitate viral immune exclusion at the mucosal portals of entry. The potential of neutralizing and non-neutralizing IgG and IgA monoclonals (mAbs) to induce HIV-1 aggregation was assessed by Dynamic light scattering (DLS). Although neutralizing and non-neutralizing IgG mAbs and polyclonal HIV-Ig efficiently aggregated soluble Env trimers, they were not capable of forming viral aggregates. In contrast, dimeric (but not monomeric) IgA mAbs induced stable viral aggregate populations that could be separated from uncomplexed virions. Epitope specificity influenced both the degree of aggregation and formation of higher order complexes by dIgA. IgA purified from serum of uninfected RV144 vaccine trial responders were able to efficiently opsonize viral particles in the absence of significant aggregation, reflective of monomeric IgA. These results collectively demonstrate that dIgA is capable of forming stable viral aggregates providing a plausible basis for testing the effectiveness of aggregation as a potential protection mechanism at the mucosal portals of viral entry.

  18. Focal cerebral vasculitis associated with circulating immune complexes and brain irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Groothuis, D.R.; Mikhael, M.A.

    1986-06-01

    In this report we describe a patient with a benign glioma treated with surgery and radiation. After a period of stability he developed subacute bacterial endocarditis, and deteriorated neurologically. Computed tomographic scans did not show recurrent tumor. An angiogram showed vasculitis restricted to the previously irradiated area. Secondary to subacute bacterial endocarditis was the presence of high levels of circulating immune complexes. His neurological status was unchanged after antibiotics, but improved after treatment with dexamethasone. We interpret the clinical course as an immune-complex-mediated vasculitis superimposed on a subclinical radiation vasculitis. This case supports the hypothesis that immune mechanisms may be involved in delayed radiation injury to the nervous system.

  19. Focal cerebral vasculitis associated with circulating immune complexes and brain irradiation

    International Nuclear Information System (INIS)

    Groothuis, D.R.; Mikhael, M.A.

    1986-01-01

    In this report we describe a patient with a benign glioma treated with surgery and radiation. After a period of stability he developed subacute bacterial endocarditis, and deteriorated neurologically. Computed tomographic scans did not show recurrent tumor. An angiogram showed vasculitis restricted to the previously irradiated area. Secondary to subacute bacterial endocarditis was the presence of high levels of circulating immune complexes. His neurological status was unchanged after antibiotics, but improved after treatment with dexamethasone. We interpret the clinical course as an immune-complex-mediated vasculitis superimposed on a subclinical radiation vasculitis. This case supports the hypothesis that immune mechanisms may be involved in delayed radiation injury to the nervous system

  20. B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex.

    Science.gov (United States)

    Wallace, Caroline H; Wu, Bill X; Salem, Mohammad; Ansa-Addo, Ephraim A; Metelli, Alessandra; Sun, Shaoli; Gilkeson, Gary; Shlomchik, Mark J; Liu, Bei; Li, Zihai

    2018-04-05

    GARP, a cell surface docking receptor for binding and activating latent TGF-β, is highly expressed by platelets and activated Tregs. While GARP is implicated in immune invasion in cancer, the roles of the GARP-TGF-β axis in systemic autoimmune diseases are unknown. Although B cells do not express GARP at baseline, we found that the GARP-TGF-β complex is induced on activated human and mouse B cells by ligands for multiple TLRs, including TLR4, TLR7, and TLR9. GARP overexpression on B cells inhibited their proliferation, induced IgA class-switching, and dampened T cell-independent antibody production. In contrast, B cell-specific deletion of GARP-encoding gene Lrrc32 in mice led to development of systemic autoimmune diseases spontaneously as well as worsening of pristane-induced lupus-like disease. Canonical TGF-β signaling more readily upregulates GARP in Peyer patch B cells than in splenic B cells. Furthermore, we demonstrated that B cells are required for the induction of oral tolerance of T cell-dependent antigens via GARP. Our studies reveal for the first time to our knowledge that cell surface GARP-TGF-β is an important checkpoint for regulating B cell peripheral tolerance, highlighting a mechanism of autoimmune disease pathogenesis.

  1. Novel vaccination approach for dengue infection based on recombinant immune complex universal platform.

    Science.gov (United States)

    Kim, Mi-Young; Reljic, Rajko; Kilbourne, Jacquelyn; Ceballos-Olvera, Ivonne; Yang, Moon-Sik; Reyes-del Valle, Jorge; Mason, Hugh S

    2015-04-08

    Dengue infection is on the rise in many endemic areas of the tropics. Vaccination remains the most realistic strategy for prevention of this potentially fatal viral disease but there is currently no effective vaccine that could protect against all four known serotypes of the dengue virus. This study describes the generation and testing of a novel vaccination approach against dengue based on recombinant immune complexes (RIC). We modelled the dengue RIC on the existing Ebola RIC (Phoolcharoen, et al. Proc Natl Acad Sci USA 2011;108(Dec (51)):20695) but with a key modification that allowed formation of a universal RIC platform that can be easily adapted for use for other pathogens. This was achieved by retaining only the binding epitope of the 6D8 ant-Ebola mAb, which was then fused to the consensus dengue E3 domain (cEDIII), resulting in a hybrid dengue-Ebola RIC (DERIC). We expressed human and mouse versions of these molecules in tobacco plants using a geminivirus-based expression system. Following purification from the plant extracts by protein G affinity chromatography, DERIC bound to C1q component of complement, thus confirming functionality. Importantly, following immunization of mice, DERIC induced a potent, virus-neutralizing anti-cEDIII humoral immune response without exogenous adjuvants. We conclude that these self-adjuvanting immunogens have the potential to be developed as a novel vaccine candidate for dengue infection, and provide the basis for a universal RIC platform for use with other antigens. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Protective Immunity Induced by DNA Vaccination against Ranavirus Infection in Chinese Giant Salamander Andrias davidianus

    Directory of Open Access Journals (Sweden)

    Zhong-Yuan Chen

    2018-01-01

    Full Text Available Andrias davidianus ranavirus (ADRV is an emerging viral pathogen that causes severe systemic hemorrhagic disease in Chinese giant salamanders. There is an urgent need for developing an effective vaccine against this fatal disease. In this study, DNA vaccines containing the ADRV 2L gene (pcDNA-2L and the 58L gene (pcDNA-58L were respectively constructed, and their immune protective effects were evaluated in Chinese giant salamanders. In vitro and in vivo expression of the vaccine plasmids were confirmed in transfected cells and muscle tissues of vaccinated Chinese giant salamanders by using immunoblot analysis or RT-PCR. Following ADRV challenge, the Chinese giant salamanders vaccinated with pcDNA-2L showed a relative percent survival (RPS of 66.7%, which was significant higher than that in Chinese giant salamanders immunized with pcDNA-58L (RPS of 3.3%. Moreover, the specific antibody against ADRV was detected in Chinese giant salamanders vaccinated with pcDNA-2L at 14 and 21 days post-vaccination by indirect enzyme-linked immunosorbent assay (ELISA. Transcriptional analysis revealed that the expression levels of immune-related genes including type I interferon (IFN, myxovirus resistance (Mx, major histocompatibility complex class IA (MHC IA, and immunoglobulin M (IgM were strongly up-regulated after vaccination with pcDNA-2L. Furthermore, vaccination with pcDNA-2L significantly suppressed the virus replication, which was seen by a low viral load in the spleen of Chinese giant salamander survivals after ADRV challenge. These results indicated that pcDNA-2L could induce a significant innate immune response and an adaptive immune response involving both humoral and cell-mediated immunity that conferred effective protection against ADRV infection, and might be a potential vaccine candidate for controlling ADRV disease in Chinese giant salamanders.

  3. Protective Immunity and Reduced Renal Colonization Induced by Vaccines Containing Recombinant Leptospira interrogans Outer Membrane Proteins and Flagellin Adjuvant

    Science.gov (United States)

    Monaris, D.; Sbrogio-Almeida, M. E.; Dib, C. C.; Canhamero, T. A.; Souza, G. O.; Vasconcellos, S. A.; Ferreira, L. C. S.

    2015-01-01

    Leptospirosis is a global zoonotic disease caused by different Leptospira species, such as Leptospira interrogans, that colonize the renal tubules of wild and domestic animals. Thus far, attempts to develop effective leptospirosis vaccines, both for humans and animals, have failed to induce immune responses capable of conferring protection and simultaneously preventing renal colonization. In this study, we evaluated the protective immunity induced by subunit vaccines containing seven different recombinant Leptospira interrogans outer membrane proteins, including the carboxy-terminal portion of the immunoglobulinlike protein A (LigAC) and six novel antigens, combined with aluminum hydroxide (alum) or Salmonella flagellin (FliC) as adjuvants. Hamsters vaccinated with the different formulations elicited high antigen-specific antibody titers. Immunization with LigAC, either with alum or flagellin, conferred protective immunity but did not prevent renal colonization. Similarly, animals immunized with LigAC or LigAC coadministered with six leptospiral proteins with alum adjuvant conferred protection but did not reduce renal colonization. In contrast, immunizing animals with the pool of seven antigens in combination with flagellin conferred protection and significantly reduced renal colonization by the pathogen. The present study emphasizes the relevance of antigen composition and added adjuvant in the efficacy of antileptospirosis subunit vaccines and shows the complex relationship between immune responses and renal colonization by the pathogen. PMID:26108285

  4. Immune response of calves inoculated with proteins ofAnaplasma marginale bound to an immunostimulant complex

    Directory of Open Access Journals (Sweden)

    Marcela Ribeiro Gasparini

    Full Text Available Despite our current knowledge of the immunology, pathology, and genetics of Anaplasma marginale, prevention in cattle is currently based on old standbys, including live attenuated vaccines, antibiotic treatment, and maintaining enzootic stability in cattle herds. In the present study, we evaluated the use of an immunostimulant complex (ISCOMATRIX adjuvant, associated with a pool of recombinant major surface proteins (rMSP1a, rMSP1b, rMSP4 and rMSP5 to improve the humoral immune response triggered in calves mainly by IgG2. Ten calves were divided in three groups: 4 calves were inoculated with the ISCOMATRIX/rMSPs (G1; 2 calves were inoculated with ISCOMATRIX adjuvant (G2; and 4 calves received saline (G3. Three inoculations were administered at 21-day intervals. In G1, the calves showed significant increases in total IgG, IgG1 and IgG2 levels 21 days after the second inoculation, compared to the control group (p < 0.05, and G1 calves remained above the cut-off value 28 days after the third inoculation (p < 0.05. The post-immunized sera from calves in G1 reacted specifically for each of the rMSPs used. In conclusion, the ISCOMATRIX/rMSPs induced antigen-specific seroconversion in calves. Therefore, additional testing to explore the protection induced by rMSPs, both alone and in conjunction with proteins previously identified as subdominant epitopes, is warranted.

  5. An immunoproteomic approach revealing peptides from Sporothrix brasiliensis that induce a cellular immune response in subcutaneous sporotrichosis.

    Science.gov (United States)

    de Almeida, José Roberto Fogaça; Jannuzzi, Grasielle Pereira; Kaihami, Gilberto Hideo; Breda, Leandro Carvalho Dantas; Ferreira, Karen Spadari; de Almeida, Sandro Rogério

    2018-03-08

    Sporothrix brasiliensis is the most virulent fungus of the Sporothrix complex and is the main species recovered in the sporotrichosis zoonotic hyperendemic area in Rio de Janeiro. A vaccine against S. brasiliensis could improve the current sporotrichosis situation. Here, we show 3 peptides from S. brasiliensis immunogenic proteins that have a higher likelihood for engaging MHC-class II molecules. We investigated the efficiency of the peptides as vaccines for preventing subcutaneous sporotrichosis. In this study, we observed a decrease in lesion diameters in peptide-immunized mice, showing that the peptides could induce a protective immune response against subcutaneous sporotrichosis. ZR8 peptide is from the GP70 protein, the main antigen of the Sporothrix complex, and was the best potential vaccine candidate by increasing CD4 + T cells and higher levels of IFN-γ, IL-17A and IL-1β characterizing a strong cellular immune response. This immune environment induced a higher number of neutrophils in lesions that are associated with fungus clearance. These results indicated that the ZR8 peptide induces a protective immune response against subcutaneous sporotrichosis and is a vaccine candidate against S. brasiliensis infection.

  6. Mechanisms of Host-Pathogen Protein Complex Formation and Bacterial Immune Evasion of Streptococcus suis Protein Fhb.

    Science.gov (United States)

    Li, Xueqin; Liu, Peng; Gan, Shuzhen; Zhang, Chunmao; Zheng, Yuling; Jiang, Yongqiang; Yuan, Yuan

    2016-08-12

    Streptococcus suis serotype 2 (S. suis 2)-induced sepsis and meningitis are often accompanied by bacteremia. The evasion of polymorphonuclear leukocyte-mediated phagocytic clearance is central to the establishment of bacteremia caused by S. suis 2 and is facilitated by the ability of factor H (FH)-binding protein (Fhb) to bind FH on the bacterial surface, thereby impeding alternative pathway complement activation and phagocytic clearance. Here, C3b/C3d was found to bind to Fhb, along with FH, forming a large immune complex. The formation of this immune complex was mediated by domain II of Fhb via electrostatic and hydrophobic interactions, which, to our knowledge, is a new type of interaction. Interestingly, Fhb was found to be associated with the cell envelope and also present in the culture supernatant, where secreted Fhb inhibited complement activation via interactions with domain II, thereby enhancing antiphagocytic clearance by polymorphonuclear leukocytes. Thus, Fhb is a multifunctional bacterial protein, which binds host complement component C3 as well as FH and interferes with innate immune recognition in a secret protein manner. S. suis 2 therefore appears to have developed a new strategy to combat host innate immunity and enhance survival in host blood. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. Mechanisms of Host-Pathogen Protein Complex Formation and Bacterial Immune Evasion of Streptococcus suis Protein Fhb*

    Science.gov (United States)

    Li, Xueqin; Liu, Peng; Gan, Shuzhen; Zhang, Chunmao; Zheng, Yuling; Jiang, Yongqiang; Yuan, Yuan

    2016-01-01

    Streptococcus suis serotype 2 (S. suis 2)-induced sepsis and meningitis are often accompanied by bacteremia. The evasion of polymorphonuclear leukocyte-mediated phagocytic clearance is central to the establishment of bacteremia caused by S. suis 2 and is facilitated by the ability of factor H (FH)-binding protein (Fhb) to bind FH on the bacterial surface, thereby impeding alternative pathway complement activation and phagocytic clearance. Here, C3b/C3d was found to bind to Fhb, along with FH, forming a large immune complex. The formation of this immune complex was mediated by domain II of Fhb via electrostatic and hydrophobic interactions, which, to our knowledge, is a new type of interaction. Interestingly, Fhb was found to be associated with the cell envelope and also present in the culture supernatant, where secreted Fhb inhibited complement activation via interactions with domain II, thereby enhancing antiphagocytic clearance by polymorphonuclear leukocytes. Thus, Fhb is a multifunctional bacterial protein, which binds host complement component C3 as well as FH and interferes with innate immune recognition in a secret protein manner. S. suis 2 therefore appears to have developed a new strategy to combat host innate immunity and enhance survival in host blood. PMID:27342778

  8. Immunizations, neonatal hyperbilirubinemia and animal-induced injuries.

    Science.gov (United States)

    Bennett, Sean R; Brennan, Beth; Bernstein, Henry H

    2007-08-01

    To report recent research findings and new recommendations on immunizations, neonatal hyperbilirubinemia, and animal-induced injuries. Vaccines against rotavirus and human papilloma virus have entered clinical use. Varicella outbreaks among previously vaccinated children have prompted the recommendation for a two-dose varicella vaccine series. Broader coverage for influenza vaccination is now recommended in the US and Canada. Diagnosis and treatment of neonatal hyperbilirubinemia uses population and hour-based norms for total serum bilirubin and assessment of risk factors. Delayed cord clamping is not apparently a risk factor for jaundice but warrants more study. Universal predischarge screening shows promise but is not yet officially recommended. New treatments for hyperbilirubinemia are being evaluated. Dogs are the chief cause of animal bites in children and the largest reservoir for rabies worldwide. In North America and Europe, cats and wild animals cause most human rabies. Postexposure prophylaxis should follow region-appropriate guidelines. New vaccines are available against rotavirus and human papilloma virus. Changes have been made to official immunization recommendations. Appropriate vaccine use can reduce the pediatric disease burden further. Hyperbilirubinemia is the subject of ongoing study, which may lead to improved diagnosis and treatment protocols and reduce the incidence of acute bilirubin encephalopathy. The best tool for rabies prevention after an animal bite is prompt postexposure prophylaxis.

  9. Global efficiency of local immunization on complex networks.

    Science.gov (United States)

    Hébert-Dufresne, Laurent; Allard, Antoine; Young, Jean-Gabriel; Dubé, Louis J

    2013-01-01

    Epidemics occur in all shapes and forms: infections propagating in our sparse sexual networks, rumours and diseases spreading through our much denser social interactions, or viruses circulating on the Internet. With the advent of large databases and efficient analysis algorithms, these processes can be better predicted and controlled. In this study, we use different characteristics of network organization to identify the influential spreaders in 17 empirical networks of diverse nature using 2 epidemic models. We find that a judicious choice of local measures, based either on the network's connectivity at a microscopic scale or on its community structure at a mesoscopic scale, compares favorably to global measures, such as betweenness centrality, in terms of efficiency, practicality and robustness. We also develop an analytical framework that highlights a transition in the characteristic scale of different epidemic regimes. This allows to decide which local measure should govern immunization in a given scenario.

  10. Global efficiency of local immunization on complex networks

    Science.gov (United States)

    Hébert-Dufresne, Laurent; Allard, Antoine; Young, Jean-Gabriel; Dubé, Louis J.

    2013-07-01

    Epidemics occur in all shapes and forms: infections propagating in our sparse sexual networks, rumours and diseases spreading through our much denser social interactions, or viruses circulating on the Internet. With the advent of large databases and efficient analysis algorithms, these processes can be better predicted and controlled. In this study, we use different characteristics of network organization to identify the influential spreaders in 17 empirical networks of diverse nature using 2 epidemic models. We find that a judicious choice of local measures, based either on the network's connectivity at a microscopic scale or on its community structure at a mesoscopic scale, compares favorably to global measures, such as betweenness centrality, in terms of efficiency, practicality and robustness. We also develop an analytical framework that highlights a transition in the characteristic scale of different epidemic regimes. This allows to decide which local measure should govern immunization in a given scenario.

  11. Delivery route determines the presence of immune complexes on umbilical cord erythrocytes.

    Science.gov (United States)

    de Lima, Andrés; Franco, Luis C; Sarmiento, Andrés; González, John M

    2017-11-01

    Umbilical cord blood offers a unique opportunity to study the basal level of immunoglobulin complexes. This study aims to determine the presence of immune complexes and complement deposition on erythrocytes from umbilical cord blood from normal, full-term pregnancies. In vitro pre-formed IgA, IgG, and IgM complexes were used as positive control for flow cytometry detection, and for C3d deposition. Blood samples (34) of umbilical cord blood taken from vaginal and cesarean deliveries were tested for the presence of immunoglobulin complexes. Fourteen samples from vaginal deliveries and 20 samples from cesarean deliveries were assessed. IgG and IgM complexes were detected on erythrocytes, whereas no IgA complexes or complement deposition was observed. Interestingly, the percentage of IgG complexes was higher on erythrocytes from vaginal delivery samples compared to those from cesarean deliveries. No other associations between immune complexes and other maternal or newborn variables were found. IgG and IgM complexes seem to be normally present on umbilical cord erythrocytes. Erythrocytes from vaginal deliveries have a higher percentage of IgG complexes present compared to that from cesarean deliveries. Since no C3d activity was detected, these complexes are non-pathological and should be part of the newborn's initial innate immune response.

  12. Steric-electronic effects in malarial peptides inducing sterile immunity

    Energy Technology Data Exchange (ETDEWEB)

    Moreno-Vranich, Armando [Fundacion Instituto de Inmunologia de Colombia (FIDIC), Bogota (Colombia); Patarroyo, Manuel E., E-mail: mepatarr@mail.com [Fundacion Instituto de Inmunologia de Colombia (FIDIC), Bogota (Colombia); Universidad Nacional de Colombia, Bogota (Colombia)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer Is it evident that the residues position are relevant regarding of {phi} angular value. Black-Right-Pointing-Pointer The geometry considered for detailing the alterations undergone by HABPs. Black-Right-Pointing-Pointer The inter planar interactions ruled by clashes between the atoms making them up. -- Abstract: Conserved Plasmodium falciparum high activity binding peptides' (HABPs) most relevant proteins involved in malaria parasite invasion are immunologically silent; critical binding residues must therefore be specifically replaced to render them highly immunogenic and protection-inducing. Such changes have a tremendous impact on these peptides' steric-electronic effects, such as modifications to peptide length peptide bonds and electronic orbitals' disposition, to allow a better fit into immune system MHCII molecules and better interaction with the TCR which might account for the final immunological outcome.

  13. Immunizations with hepatitis B viral antigens and a TLR7/8 agonist adjuvant induce antigen-specific immune responses in HBV-transgenic mice

    Directory of Open Access Journals (Sweden)

    Ying Wang

    2014-12-01

    Conclusions: Immunization with CL097-conjugated HBV-Ag reversed immune tolerance in HBV-Tg mice and induced antigen-specific immune responses. TLR7/8 agonists appear to be potent adjuvants for the induction of antigen-specific Th1 responses in an immune tolerant state.

  14. Polar lipids of Burkholderia pseudomallei induce different host immune responses.

    Directory of Open Access Journals (Sweden)

    Mercedes Gonzalez-Juarrero

    Full Text Available Melioidosis is a disease in tropical and subtropical regions of the world that is caused by Burkholderia pseudomallei. In endemic regions the disease occurs primarily in humans and goats. In the present study, we used the goat as a model to dissect the polar lipids of B. pseudomallei to identify lipid molecules that could be used for adjuvants/vaccines or as diagnostic tools. We showed that the lipidome of B. pseudomallei and its fractions contain several polar lipids with the capacity to elicit different immune responses in goats, namely rhamnolipids and ornithine lipids which induced IFN-γ, whereas phospholipids and an undefined polar lipid induced strong IL-10 secretion in CD4(+ T cells. Autologous T cells co-cultured with caprine dendritic cells (cDCs and polar lipids of B. pseudomallei proliferated and up-regulated the expression of CD25 (IL-2 receptor molecules. Furthermore, we demonstrated that polar lipids were able to up-regulate CD1w2 antigen expression in cDCs derived from peripheral blood monocytes. Interestingly, the same polar lipids had only little effect on the expression of MHC class II DR antigens in the same caprine dendritic cells. Finally, antibody blocking of the CD1w2 molecules on cDCs resulted in decreased expression for IFN-γ by CD4(+ T cells. Altogether, these results showed that polar lipids of B. pseudomallei are recognized by the caprine immune system and that their recognition is primarily mediated by the CD1 antigen cluster.

  15. Polar Lipids of Burkholderia pseudomallei Induce Different Host Immune Responses

    Science.gov (United States)

    Gonzalez-Juarrero, Mercedes; Mima, Naoko; Trunck, Lily A.; Schweizer, Herbert P.; Bowen, Richard A.; Dascher, Kyle; Mwangi, Waithaka; Eckstein, Torsten M.

    2013-01-01

    Melioidosis is a disease in tropical and subtropical regions of the world that is caused by Burkholderia pseudomallei. In endemic regions the disease occurs primarily in humans and goats. In the present study, we used the goat as a model to dissect the polar lipids of B. pseudomallei to identify lipid molecules that could be used for adjuvants/vaccines or as diagnostic tools. We showed that the lipidome of B. pseudomallei and its fractions contain several polar lipids with the capacity to elicit different immune responses in goats, namely rhamnolipids and ornithine lipids which induced IFN-γ, whereas phospholipids and an undefined polar lipid induced strong IL-10 secretion in CD4+ T cells. Autologous T cells co-cultured with caprine dendritic cells (cDCs) and polar lipids of B. pseudomallei proliferated and up-regulated the expression of CD25 (IL-2 receptor) molecules. Furthermore, we demonstrated that polar lipids were able to up-regulate CD1w2 antigen expression in cDCs derived from peripheral blood monocytes. Interestingly, the same polar lipids had only little effect on the expression of MHC class II DR antigens in the same caprine dendritic cells. Finally, antibody blocking of the CD1w2 molecules on cDCs resulted in decreased expression for IFN-γ by CD4+ T cells. Altogether, these results showed that polar lipids of B. pseudomallei are recognized by the caprine immune system and that their recognition is primarily mediated by the CD1 antigen cluster. PMID:24260378

  16. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression.

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Barilla, Rocky; Daley, Donnele; Greco, Stephanie H; Torres-Hernandez, Alejandro; Pergamo, Matthew; Ochi, Atsuo; Zambirinis, Constantinos P; Pansari, Mridul; Rendon, Mauricio; Tippens, Daniel; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Engle, Dannielle; Miller, George

    2016-04-14

    Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle--its cognate receptor--was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells

  17. Immunization

    Science.gov (United States)

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  18. Hantavirus Gc induces long-term immune protection via LAMP-targeting DNA vaccine strategy.

    Science.gov (United States)

    Jiang, Dong-Bo; Zhang, Jin-Peng; Cheng, Lin-Feng; Zhang, Guan-Wen; Li, Yun; Li, Zi-Chao; Lu, Zhen-Hua; Zhang, Zi-Xin; Lu, Yu-Chen; Zheng, Lian-He; Zhang, Fang-Lin; Yang, Kun

    2018-02-01

    Hemorrhagic fever with renal syndrome (HFRS) occurs widely throughout Eurasia. Unfortunately, there is no effective treatment, and prophylaxis remains the best option against the major pathogenic agent, hantaan virus (HTNV), which is an Old World hantavirus. However, the absence of cellular immune responses and immunological memory hampers acceptance of the current inactivated HFRS vaccine. Previous studies revealed that a lysosome-associated membrane protein 1 (LAMP1)-targeting strategy involving a DNA vaccine based on the HTNV glycoprotein Gn successfully conferred long-term immunity, and indicated that further research on Gc, another HTNV antigen, was warranted. Plasmids encoding Gc and lysosome-targeted Gc, designated pVAX-Gc and pVAX-LAMP/Gc, respectively, were constructed. Proteins of interest were identified by fluorescence microscopy following cell line transfection. Five groups of 20 female BALB/c mice were subjected to the following inoculations: inactivated HTNV vaccine, pVAX-LAMP/Gc, pVAX-Gc, and, as the negative controls, pVAX-LAMP or the blank vector pVAX1. Humoral and cellular immunity were assessed by enzyme-linked immunosorbent assays (ELISAs) and 15-mer peptide enzyme-linked immunospot (ELISpot) epitope mapping assays. Repeated immunization with pVAX-LAMP/Gc enhanced adaptive immune responses, as demonstrated by the specific and neutralizing antibody titers and increased IFN-γ production. The inactivated vaccine induced a comparable humoral reaction, but the negative controls only elicited insignificant responses. Using a mouse model of HTNV challenge, the in vivo protection conferred by the inactivated vaccine and Gc-based constructs (with/without LAMP recombination) was confirmed. Evidence of pan-epitope reactions highlighted the long-term cellular response to the LAMP-targeting strategy, and histological observations indicated the safety of the LAMP-targeting vaccines. The long-term protective immune responses induced by pVAX-LAMP/Gc may be

  19. Circulating immune complexes and complement concentrations in patients with alcoholic liver disease

    DEFF Research Database (Denmark)

    Gluud, C; Jans, H

    1982-01-01

    A prospective evaluation of circulating immune complexes (CIC) and the activity of the complement system was undertaken in 53 alcoholic patients just before diagnostic liver biopsy. Circulating immune complexes were detected in 39% of patients with alcoholic steatosis (n = 26), 58% of patients...... with alcoholic hepatitis (n = 12), and 60% of patients with alcoholic cirrhosis (n = 15). No significant difference was found between the three group of patients. The activity of the complement system was within reference limits in the majority of patients and only slight differences were detected between...

  20. [Effect of vitamine A on mice immune response induced by specific periodontal pathogenic bacteria-immunization].

    Science.gov (United States)

    Lin, Xiao-Ping; Zhou, Xiao-Jia; Liu, Hong-Li; DU, Li-Li; Toshihisa, Kawai

    2010-12-01

    The aim of this study was to investigate the effect of vitamine-A deficiency on the induction of specific periodontal pathogenic bacteria A. actinomycetetemcomitans(Aa) immunization. BALB/c mice were fed with vitamine A-depleted diet or control regular diet throughout the whole experiment period. After 2 weeks, immunized formalin-killed Aa to build immunized models, 6 weeks later, sacrificed to determine specific antibody-IgG, IgM and sub-class IgG antibody titers in serum, and concentration of IL-10, IFN-γ, TNF-α and RANKL in T cell supernatant were measured by ELISA and T cell proliferation was measured by cintilography. SPSS 11.5 software package was used for statistical analysis. The levels of whole IgG and IgM antibody which were immunized by Aa significantly elevated, non-immune group was unable to produce any antibody. Compared with Aa immunized+RD group, the level of whole IgG in Aa immunized+VAD group was significantly higher (Pvitamin-A diet can increase the immunized mice's susceptibility to periodontal pathogenic bacteria and trigger or aggravate immune inflammatory response. Adequate vitamin A is an important factor in maintaining body health. Supported by Natural Science Foundation of Liaoning Province (Grant No.20092139) and Science and Technology Program of Shenyang Municipality (Grant No.F10-149-9-32).

  1. Activation of cutaneous immune responses in complex regional pain syndrome

    Science.gov (United States)

    Birklein, Frank; Drummond, Peter D.; Li, Wenwu; Schlereth, Tanja; Albrecht, Nahid; Finch, Philip M.; Dawson, Linda F.; Clark, J. David; Kingery, Wade S.

    2014-01-01

    The pathogenesis of complex regional pain syndrome (CRPS) is unresolved, but TNF-α and IL-6 are elevated in experimental skin blister fluid from CRPS affected limbs, as is tryptase, a marker for mast cells. In the rat fracture model of CRPS exaggerated sensory and sympathetic neural signaling stimulate keratinocyte and mast cell proliferation, causing the local production of high levels of inflammatory cytokines leading to pain behavior. The current investigation used CRPS patient skin biopsies to determine whether keratinocyte and mast cell proliferation occur in CRPS skin and to identify the cellular source of the up-regulated TNF-α, IL-6, and tryptase observed in CRPS experimental skin blister fluid. Skin biopsies were collected from the affected skin and the contralateral mirror site in 55 CRPS patients and the biopsy sections were immunostained for keratinocyte, cell proliferation, mast cell markers, TNF-α, and IL-6. In early CRPS keratinocytes were activated in the affected skin, resulting in proliferation, epidermal thickening, and up-regulated TNF-α and IL-6 expression. In chronic CRPS there was reduced keratinocyte proliferation with epidermal thinning in the affected skin. Acute CRPS patients also had increased mast cell accumulation in the affected skin, but there was no increase in mast cell numbers in chronic CRPS. PMID:24462502

  2. Induction of complex immune responses and strong protection against retrovirus challenge by adenovirus-based immunization depends on the order of vaccine delivery.

    Science.gov (United States)

    Kaulfuß, Meike; Wensing, Ina; Windmann, Sonja; Hrycak, Camilla Patrizia; Bayer, Wibke

    2017-02-06

    In the Friend retrovirus mouse model we developed potent adenovirus-based vaccines that were designed to induce either strong Friend virus GagL 85-93 -specific CD8 + T cell or antibody responses, respectively. To optimize the immunization outcome we evaluated vaccination strategies using combinations of these vaccines. While the vaccines on their own confer strong protection from a subsequent Friend virus challenge, the simple combination of the vaccines for the establishment of an optimized immunization protocol did not result in a further improvement of vaccine effectivity. We demonstrate that the co-immunization with GagL 85-93 /leader-gag encoding vectors together with envelope-encoding vectors abrogates the induction of GagL 85-93 -specific CD8 + T cells, and in successive immunization protocols the immunization with the GagL 85-93 /leader-gag encoding vector had to precede the immunization with an envelope encoding vector for the efficient induction of GagL 85-93 -specific CD8 + T cells. Importantly, the antibody response to envelope was in fact enhanced when the mice were adenovirus-experienced from a prior immunization, highlighting the expedience of this approach. To circumvent the immunosuppressive effect of envelope on immune responses to simultaneously or subsequently administered immunogens, we developed a two immunizations-based vaccination protocol that induces strong immune responses and confers robust protection of highly Friend virus-susceptible mice from a lethal Friend virus challenge.

  3. Canine Distemper Virus (CDV) immune-stimulating complexes (iscoms), but not measles virus iscoms, protect dogs against CDV infection.

    NARCIS (Netherlands)

    P. de Vries (Petra); F.G.C.M. Uytdehaag (Fons); A.D.M.E. Osterhaus (Albert)

    1988-01-01

    textabstractThe potential of immune-stimulating complexes (iscoms), a novel form of antigenic presentation, for the induction of protective immunity against morbillivirus infection was shown by immunizing dogs with canine distemper virus (CDV) iscoms, which contained the fusion (F) protein and a

  4. Immune Reconstitution Kinetics following Intentionally Induced Mixed Chimerism by Nonmyeloablative Transplantation.

    Directory of Open Access Journals (Sweden)

    Nayoun Kim

    Full Text Available Establishing mixed chimerism is a promising approach for inducing donor-specific transplant tolerance. The establishment and maintenance of mixed chimerism may enable long-term engraftment of organ transplants while minimizing the use of immunosuppressants. Several protocols for inducing mixed chimerism have been reported; however, the exact mechanism underlying the development of immune tolerance remains to be elucidated. Therefore, understanding the kinetics of engraftment during early post-transplant period may provide insight into establishing long-term mixed chimerism and permanent transplant tolerance. In this study, we intentionally induced allogeneic mixed chimerism using a nonmyeloablative regimen by host natural killer (NK cell depletion and T cell-depleted bone marrow (BM grafts in a major histocompatibility complex (MHC-mismatched murine model and analyzed the kinetics of donor (C57BL/6 and recipient (BALB/c engraftment in the weeks following transplantation. Donor BM cells were well engrafted and stabilized without graft-versus-host disease (GVHD as early as one week post-bone marrow transplantation (BMT. Donor-derived thymic T cells were reconstituted four weeks after BMT; however, the emergence of newly developed T cells was more obvious at the periphery as early as two weeks after BMT. Also, the emergence and changes in ratio of recipient- and donor-derived NKT cells and antigen presenting cells (APCs including dendritic cells (DCs and B cells were noted after BMT. Here, we report a longitudinal analysis of the development of donor- and recipient-originated hematopoietic cells in various lymphatic tissues of intentionally induced mixed chimerism mouse model during early post-transplant period. Through the understanding of immune reconstitution at early time points after nonmyeloablative BMT, we suggest guidelines on intentionally inducing durable mixed chimerism.

  5. UVB-induced immune suppression and infection with Schistosoma mansoni

    International Nuclear Information System (INIS)

    Noonan, F.P.; Lewis, F.A.

    1995-01-01

    Irradiation with ultraviolet B (UVB, 290-320 nm) causes a systematic immunosuppression of cell-mediated immunity. The question of whether UV immunosuppression modulates the course of infectious diseases is important because UVB levels in sunlight are sufficient to predict significant UV-induced immunosuppression at most latitudes. We have investigated the effect of immunosuppressive doses of UVB on the disease caused by the helminth parasite Schistosoma mansoni. C57BL/6 mice were irradiated once or three times weekly over 60-80 days with UV from a bank of FS40 sunlamps. Each UV treatment consisted of an immunosuppressive UV dose, as determined by suppression of contact hypersensitivity to trinitrochlorobenzene, corresponding to about 15-30 min of noonday tropical sunlight exposure under ideal clear sky conditions. Cumulative UV doses were between 80 and 170 kJ/m 2 . Worm and egg burdens, liver granuloma diameters and liver fibrosis showed minimal changes ( 2 administered in six treatments) did not impair the resistance to rechallenge conferred by vaccination with 60 Co-irradiated cercariae. We have observed a dichotomy between UV immnosuppression and both disease and vaccination in this helminth infection, in contrast to the effects of UVB shown in other infectious diseases. (author)

  6. Complement fixation by solid phase immune complexes. Reduced capacity in SLE sera

    DEFF Research Database (Denmark)

    Baatrup, G; Jonsson, H; Sjöholm, A

    1988-01-01

    We describe an ELISA for assessment of complement function based on the capacity of serum to support fixation of complement components to solid phase immune complexes (IC). Microplates were coated with aggregated bovine serum albumin (BSA) followed by rabbit anti-BSA IgG. The solid phase IC were...

  7. Detection of immune-complex-dissociated nonstructural-1 antigen in patients with acute dengue virus infections

    NARCIS (Netherlands)

    P. Koraka (Penelope); C.P. Burghoorn-Maas; A. Falconar; T.E. Setiati (Tatty); K. Djamiatun; J. Groen (Jan); A.D.M.E. Osterhaus (Albert)

    2003-01-01

    textabstractAccurate and timely diagnosis of dengue virus (DEN) infections is essential for the differential diagnosis of patients with febrile illness and hemorrhagic fever. In the present study, the diagnostic value of a newly developed immune-complex dissociated nonstructural-1 (NS-1) antigen dot

  8. Detection of immune-complex-dissociated nonstructural-1 antigen in patients with acute dengue virus infections.

    NARCIS (Netherlands)

    Koraka, P.; Burghoorn-Maas, C.P.; Falconar, A.; Setiati, T.E.; Djamiatun, K.; Groen, J.; Osterhaus, A.D.

    2003-01-01

    Accurate and timely diagnosis of dengue virus (DEN) infections is essential for the differential diagnosis of patients with febrile illness and hemorrhagic fever. In the present study, the diagnostic value of a newly developed immune-complex dissociated nonstructural-1 (NS-1) antigen dot blot

  9. Circulating immune complexes, immunoglobulin classes (IgG, IgA ...

    African Journals Online (AJOL)

    Objective:- To evaluate serum levels of circulating immune complexes (CICs), immunoglobulin classes (IgG, IgA and IgM) and Complement Components (C3c, C4 and Factor B) in Nigerians with Type 1 or Type 2 diabetes mellitus. Design:- Case control study. Setting:- University College Hospital, Ibadan, Oyo State, Nigeria.

  10. Complement-mediated solubilization of immune complexes. Solubilization inhibition and complement factor levels in SLE patients

    DEFF Research Database (Denmark)

    Baatrup, Gunnar; Petersen, Ivan; Kappelgaard, E

    1984-01-01

    Thirty-two of 36 serum samples from 19 SLE patients showed reduced capacity to mediate complement-dependent solubilization of immune complexes (IC). SLE patients with nephritis exerted the lowest complement-mediated solubilization capacity (CMSC) whereas sera from patients with inactive disease g...

  11. Detection of circulating immune complexes in breast cancer and melanoma by three different methods

    Energy Technology Data Exchange (ETDEWEB)

    Krapf, F; Renger, D; Fricke, M; Kemper, A; Schedel, I; Deicher, H

    1982-08-01

    By the simultaneous application of three methods, C1q-binding-test (C1q-BA), a two antibody conglutinin binding ELISA and a polyethylene-glycol 6000 precipitation with subsequent quantitative determination of immunoglobulins and complement factors in the redissolved precipitates (PPLaNT), circulating immune complexes could be demonstrated in the sera of 94% of patients with malignant melanoma and of 75% of breast cancer patients. The specific detection rates of the individual methods varied between 23% (C1q-BA) and 46% (PPLaNT), presumably due to the presence of qualitatively different immune complexes in the investigated sera. Accordingly, the simultaneous use of the afore mentioned assays resulted in an increased diagnostic sensitivity and a duplication of the predictive value. Nevertheless, because of the relatively low incidence of malignant diseases in the total population, and due to the fact that circulating immune complexes occur in other non-malignant diseases with considerable frequency, tests for circulating immune complexes must be regarded as less useful parameters in the early diagnostic of cancer.

  12. Antigen detection in vivo after immunization with different presentation forms of rabies virus antigen: Involvement of marginal metallophilic macrophages in the uptake of immune-stimulating complexes

    NARCIS (Netherlands)

    Claassen, I.J.T.M.; Osterhaus, A.D.M.E.; Claassen, E.

    1995-01-01

    Several mechanisms have been postulated to explain the relatively high immunogenicity of antigens presented in immune-stimulating complexes (iscom). Their potency can in part be explained by the specific targeting of these structures to cells presenting antigens to the immune system. However, until

  13. Antigen detection in vivo after immunization with different presentation forms of rabies virus antigen: involvement of marginal metallophilic macrophages in the uptake of immune-stimulating complexes.

    NARCIS (Netherlands)

    I.J.Th.M. Claassen (Ivo); A.D.M.E. Osterhaus (Albert); H.J.H.M. Claassen (Eric)

    1995-01-01

    textabstractSeveral mechanisms have been postulated to explain the relatively high immunogenicity of antigens presented in immune-stimulating complexes (iscom). Their potency can in part be explained by the specific targeting of these structures to cells presenting antigens to the immune system.

  14. [The humoral immune response in mice induced by recombinant Lactococcus lactis expressing HIV-1 gag].

    Science.gov (United States)

    Zhao, Xiaofei; Zhang, Cairong; Liu, Xiaojuan; Ma, Zhenghai

    2014-11-01

    To analyze the humoral immune response induced by recombinant Lactococcus lactis expressing HIV-1 gag in mice immunized orally, intranasally, subcutaneously or in the combined way of above three. Fifty BALB/c mice were randomly divided into 5 groups, 10 mice per group. The mice were immunized consecutively three times at two week intervals with 10(9) CFU of recombinant Lactococcus lactis expressing gag through oral, intranasal, subcutaneous administration or the mix of them. The mice that were immunized orally with Lactococcus lactis containing PMG36e served as a control group. The sera of mice were collected before primary immunization and 2 weeks after each immunization to detect the gag specific IgG by ELISA. Compared with the control group, the higher titer of serum gag specific IgG was detected in the four groups immunized with recombinant Lactococcus lactis expressing gag, and it was the highest in the mixed immunization group (PLactococcus lactis expressing gag can induce humoral immune response in mice by oral, intranasal, subcutaneous injection or the mix of them, and the mixed immunization can enhance the immune effects of Lactococcus lactis vector vaccine.

  15. Epidermal Langerhans' cell induction of immunity against an ultraviolet-induced skin tumour

    International Nuclear Information System (INIS)

    Cavanagh, L.L.; Sluyter, R.; Henderson, K.G.; Barnetson, R.St.C.; Halliday, G.M.

    1996-01-01

    Lanerghans' cells (LC) have been shown experimentally to induce immune response against many antigens; however, their role in the initiation of anti-tumour immunity has received little attention. This study examined the ability of murine epidermal LC to induce immunity to an ultraviolet radiation (UV)-induced skin tumour. Freshly prepared epidermal cells (EC) were cultured for 2 or 20 hr with granulocyte-macrophage colony-stimulating factor (GM-CSF), pulsed with an extract of the UV-13-1 tumour, then used to immunize naive syngeneic mice. Delayed type hypersensitivity (DTH) was elicited 10 days after immunization by injection of UV-13-1 tumour cells into the ear pinna, and measured 24 hr later. EC cultured with GM-CSF for 2 hr induced anti-tumour DTH, as did EC cultured for 20 hr without GM-CSF. Conversely, EC cultured for 2 hr without GM-CSF, or EC cultured for 20 hr with GM-CSF were unable to induce a DTH. Induction of immunity required active presentation of tumour antigens by Ia + EC and was tumour specific. Thus Ia + epidermal cells are capable of inducing anti-tumour immunity to UV-induced skin tumours, but only when they contact antigen in particular states of maturation. (author)

  16. Interaction Between 2 Nutraceutical Treatments and Host Immune Status in the Pediatric Critical Illness Stress-Induced Immune Suppression Comparative Effectiveness Trial.

    Science.gov (United States)

    Carcillo, Joseph A; Dean, J Michael; Holubkov, Richard; Berger, John; Meert, Kathleen L; Anand, Kanwaljeet J S; Zimmerman, Jerry J; Newth, Christopher J L; Harrison, Rick; Burr, Jeri; Willson, Douglas F; Nicholson, Carol; Bell, Michael J; Berg, Robert A; Shanley, Thomas P; Heidemann, Sabrina M; Dalton, Heidi; Jenkins, Tammara L; Doctor, Allan; Webster, Angie; Tamburro, Robert F

    2017-11-01

    The pediatric Critical Illness Stress-induced Immune Suppression (CRISIS) trial compared the effectiveness of 2 nutraceutical supplementation strategies and found no difference in the development of nosocomial infection and sepsis in the overall population. We performed an exploratory post hoc analysis of interaction between nutraceutical treatments and host immune status related to the development of nosocomial infection/sepsis. Children from the CRISIS trial were analyzed according to 3 admission immune status categories marked by decreasing immune competence: immune competent without lymphopenia, immune competent with lymphopenia, and previously immunocompromised. The comparative effectiveness of the 2 treatments was analyzed for interaction with immune status category. There were 134 immune-competent children without lymphopenia, 79 previously immune-competent children with lymphopenia, and 27 immunocompromised children who received 1 of the 2 treatments. A significant interaction was found between treatment arms and immune status on the time to development of nosocomial infection and sepsis ( P patient characteristic.

  17. The immune complex CTA1-DD/IgG adjuvant specifically targets connective tissue mast cells through FcγRIIIA and augments anti-HPV immunity after nasal immunization.

    Science.gov (United States)

    Fang, Y; Zhang, T; Lidell, L; Xu, X; Lycke, N; Xiang, Z

    2013-11-01

    We have previously reported that CTA1-DD/IgG immune complexes augment antibody responses in a mast cell-dependent manner following intranasal (IN) immunizations. However, from a safety perspective, mast cell activation could preclude clinical use. Therefore, we have extended these studies and demonstrate that CTA1-DD/IgG immune complexes administered IN did not trigger an anaphylactic reaction. Importantly, CTA1-DD/IgE immune complexes did not activate mast cells. Interestingly, only connective tissue, but not mucosal, mast cells could be activated by CTA1-DD/IgG immune complexes. This effect was mediated by FcγRIIIA, only expressed on connective tissue mast cells, and found in the nasal submucosa. FcγRIIIA-deficient mice had compromised responses to immunization adjuvanted by CTA1-DD/IgG. Proof-of-concept studies revealed that IN immunized mice with human papillomavirus (HPV) type 16 L1 virus-like particles (VLP) and CTA1-DD/IgG immune complexes demonstrated strong and sustained specific antibody titers in serum and vaginal secretions. From a mast cell perspective, CTA1-DD/IgG immune complexes appear to be safe and effective mucosal adjuvants.

  18. Massively Parallel RNA Sequencing Identifies a Complex Immune Gene Repertoire in the lophotrochozoan Mytilus edulis

    Science.gov (United States)

    Philipp, Eva E. R.; Kraemer, Lars; Melzner, Frank; Poustka, Albert J.; Thieme, Sebastian; Findeisen, Ulrike; Schreiber, Stefan; Rosenstiel, Philip

    2012-01-01

    The marine mussel Mytilus edulis and its closely related sister species are distributed world-wide and play an important role in coastal ecology and economy. The diversification in different species and their hybrids, broad ecological distribution, as well as the filter feeding mode of life has made this genus an attractive model to investigate physiological and molecular adaptations and responses to various biotic and abiotic environmental factors. In the present study we investigated the immune system of Mytilus, which may contribute to the ecological plasticity of this species. We generated a large Mytilus transcriptome database from different tissues of immune challenged and stress treated individuals from the Baltic Sea using 454 pyrosequencing. Phylogenetic comparison of orthologous groups of 23 species demonstrated the basal position of lophotrochozoans within protostomes. The investigation of immune related transcripts revealed a complex repertoire of innate recognition receptors and downstream pathway members including transcripts for 27 toll-like receptors and 524 C1q domain containing transcripts. NOD-like receptors on the other hand were absent. We also found evidence for sophisticated TNF, autophagy and apoptosis systems as well as for cytokines. Gill tissue and hemocytes showed highest expression of putative immune related contigs and are promising tissues for further functional studies. Our results partly contrast with findings of a less complex immune repertoire in ecdysozoan and other lophotrochozoan protostomes. We show that bivalves are interesting candidates to investigate the evolution of the immune system from basal metazoans to deuterostomes and protostomes and provide a basis for future molecular work directed to immune system functioning in Mytilus. PMID:22448234

  19. Immunometabolic Pathways in BCG-Induced Trained Immunity

    NARCIS (Netherlands)

    Arts, R.J.; Carvalho, A.; Rocca, C. La; Palma, C.; Rodrigues, F.; Silvestre, R.; Kleinnijenhuis, J.; Lachmandas, E.; Goncalves, L.G.; Belinha, A.; Cunha, C.; Oosting, M.; Joosten, L.A.; Matarese, G.; Crevel, R. van; Netea, M.G.

    2016-01-01

    The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity.

  20. The innate and adaptive immune response induced by alveolar macrophages exposed to ambient particulate matter

    International Nuclear Information System (INIS)

    Miyata, Ryohei; Eeden, Stephan F. van

    2011-01-01

    Emerging epidemiological evidence suggests that exposure to particulate matter (PM) air pollution increases the risk of cardiovascular events but the exact mechanism by which PM has adverse effects is still unclear. Alveolar macrophages (AM) play a major role in clearing and processing inhaled PM. This comprehensive review of research findings on immunological interactions between AM and PM provides potential pathophysiological pathways that interconnect PM exposure with adverse cardiovascular effects. Coarse particles (10 μm or less, PM 10 ) induce innate immune responses via endotoxin-toll-like receptor (TLR) 4 pathway while fine (2.5 μm or less, PM 2.5 ) and ultrafine particles (0.1 μm or less, UFP) induce via reactive oxygen species generation by transition metals and/or polyaromatic hydrocarbons. The innate immune responses are characterized by activation of transcription factors [nuclear factor (NF)-κB and activator protein-1] and the downstream proinflammatory cytokine [interleukin (IL)-1β, IL-6, and tumor necrosis factor-α] production. In addition to the conventional opsonin-dependent phagocytosis by AM, PM can also be endocytosed by an opsonin-independent pathway via scavenger receptors. Activation of scavenger receptors negatively regulates the TLR4-NF-κB pathway. Internalized particles are subsequently subjected to adaptive immunity involving major histocompatibility complex class II (MHC II) expression, recruitment of costimulatory molecules, and the modulation of the T helper (Th) responses. AM show atypical antigen presenting cell maturation in which phagocytic activity decreases while both MHC II and costimulatory molecules remain unaltered. PM drives AM towards a Th1 profile but secondary responses in a Th1- or Th-2 up-regulated milieu drive the response in favor of a Th2 profile.

  1. The innate and adaptive immune response induced by alveolar macrophages exposed to ambient particulate matter

    Energy Technology Data Exchange (ETDEWEB)

    Miyata, Ryohei; Eeden, Stephan F. van, E-mail: Stephan.vanEeden@hli.ubc.ca

    2011-12-15

    Emerging epidemiological evidence suggests that exposure to particulate matter (PM) air pollution increases the risk of cardiovascular events but the exact mechanism by which PM has adverse effects is still unclear. Alveolar macrophages (AM) play a major role in clearing and processing inhaled PM. This comprehensive review of research findings on immunological interactions between AM and PM provides potential pathophysiological pathways that interconnect PM exposure with adverse cardiovascular effects. Coarse particles (10 {mu}m or less, PM{sub 10}) induce innate immune responses via endotoxin-toll-like receptor (TLR) 4 pathway while fine (2.5 {mu}m or less, PM{sub 2.5}) and ultrafine particles (0.1 {mu}m or less, UFP) induce via reactive oxygen species generation by transition metals and/or polyaromatic hydrocarbons. The innate immune responses are characterized by activation of transcription factors [nuclear factor (NF)-{kappa}B and activator protein-1] and the downstream proinflammatory cytokine [interleukin (IL)-1{beta}, IL-6, and tumor necrosis factor-{alpha}] production. In addition to the conventional opsonin-dependent phagocytosis by AM, PM can also be endocytosed by an opsonin-independent pathway via scavenger receptors. Activation of scavenger receptors negatively regulates the TLR4-NF-{kappa}B pathway. Internalized particles are subsequently subjected to adaptive immunity involving major histocompatibility complex class II (MHC II) expression, recruitment of costimulatory molecules, and the modulation of the T helper (Th) responses. AM show atypical antigen presenting cell maturation in which phagocytic activity decreases while both MHC II and costimulatory molecules remain unaltered. PM drives AM towards a Th1 profile but secondary responses in a Th1- or Th-2 up-regulated milieu drive the response in favor of a Th2 profile.

  2. Epicutaneous Immunization with Type II Collagen Inhibits both Onset and Progression of Chronic Collagen-Induced Arthritis

    OpenAIRE

    Strid, Jessica; Tan, Lee Aun; Strobel, Stephan; Londei, Marco; Callard, Robin

    2007-01-01

    Epicutaneous immunization is a potential non-invasive technique for antigen-specific immune-modulation. Topical application of protein antigens to barrier-disrupted skin induces potent antigen-specific immunity with a strong Th2-bias. In this study, we investigate whether the autoimmune inflammatory response of chronic collagen-induced arthritis (CCIA) in DBA/1-TCR-beta Tg mice can be modified by epicutaneous immunization. We show that epicutaneous immunization with type II collagen (CII) inh...

  3. One Problem, Many Solutions : Simple Statistical Approaches Help Unravel the Complexity of the Immune System in an Ecological Context

    NARCIS (Netherlands)

    Buehler, Deborah M.; Versteegh, Maaike A.; Matson, Kevin D.; Tieleman, Irene

    2011-01-01

    The immune system is a complex collection of interrelated and overlapping solutions to the problem of disease. To deal with this complexity, researchers have devised multiple ways to measure immune function and to analyze the resulting data. In this way both organisms and researchers employ many

  4. Quantitative Multiplex Immunohistochemistry Reveals Myeloid-Inflamed Tumor-Immune Complexity Associated with Poor Prognosis

    Directory of Open Access Journals (Sweden)

    Takahiro Tsujikawa

    2017-04-01

    Full Text Available Here, we describe a multiplexed immunohistochemical platform with computational image processing workflows, including image cytometry, enabling simultaneous evaluation of 12 biomarkers in one formalin-fixed paraffin-embedded tissue section. To validate this platform, we used tissue microarrays containing 38 archival head and neck squamous cell carcinomas and revealed differential immune profiles based on lymphoid and myeloid cell densities, correlating with human papilloma virus status and prognosis. Based on these results, we investigated 24 pancreatic ductal adenocarcinomas from patients who received neoadjuvant GVAX vaccination and revealed that response to therapy correlated with degree of mono-myelocytic cell density and percentages of CD8+ T cells expressing T cell exhaustion markers. These data highlight the utility of in situ immune monitoring for patient stratification and provide digital image processing pipelines to the community for examining immune complexity in precious tissue sections, where phenotype and tissue architecture are preserved to improve biomarker discovery and assessment.

  5. Immunization with the recombinant antigen Ss-IR induces protective immunity to infection with Strongyloides stercoralis in mice.

    Science.gov (United States)

    Abraham, David; Hess, Jessica A; Mejia, Rojelio; Nolan, Thomas J; Lok, James B; Lustigman, Sara; Nutman, Thomas B

    2011-10-19

    Human intestinal infections with the nematode Strongyloides stercoralis remain a significant problem worldwide and a vaccine would be a useful addition to the tools available to prevent and control this infection. The goal of this study was to test single antigens for their efficacy in a vaccine against S. stercoralis larvae in mice. Alum was used as the adjuvant in these studies and antigens selected for analysis were either recognized by protective human IgG (Ss-TMY-1, Ss-EAT-6, and Ss-LEC-5) or were known to be highly immunogenic in humans (Ss-NIE-1 and Ss-IR). Only mice immunized with the Ss-IR antigen demonstrated a significant decrease of approximately 80% in the survival of larval parasites in the challenge infection. Antibodies, recovered from mice with protective immunity to S. stercoralis after immunization with Ss-IR, were used to locate the antigen in the larvae. Confocal microscopy revealed that IgG from mice immunized with Ss-IR bound to the surface of the parasites and observations by electron microscopy indicated that IgG bound to granules in the glandular esophagus. Serum collected from mice immunized with Ss-IR passively transferred immunity to naïve mice. These studies demonstrate that Ss-IR, in combination with alum, induces high levels of protective immunity through an antibody dependent mechanism and may therefore be suitable for further development as a vaccine against human strongyloidiasis. Copyright © 2011 Elsevier Ltd. All rights reserved.

  6. Oral Methylated N-Aryl Chitosan Derivatives for Inducing Immune ...

    African Journals Online (AJOL)

    received OVA in TM65CM50CS were significantly (p < 0.05) higher than those that ... enhancing paracellular permeability but showed no immune responses, while ... However, poor immunogenicity ... soluble in dilute acidic solutions below pH.

  7. Immunity to transplantable nitrosourea-induced neurogenic tumors. III. Systemic adoptive transfer of immunity

    International Nuclear Information System (INIS)

    Shibuya, N.; Hochgeschwender, U.; Kida, Y.; Hochwald, G.M.; Thorbecke, G.J.; Cravioto, H.

    1984-01-01

    The effect of intravenously injected tumor immune spleen cells on growth of 3 X 10 5 gliosarcoma T 9 cells injected intradermally (ID) or intracerebrally (IC) into sublethally irradiated CDF rats was evaluated. Spleen cells from donor rats with sufficient immunity to reject 5 X 10 5 T 9 cells inhibited the growth of T 9 cells mixed with spleen cells in a ratio of 1:25 and injected ID, but could not act after intravenous transfer. However, donor rats which had rejected increasing T 9 challenge doses up to 1 X 10 7 cells produced immune spleen cells which, upon IV transfer, could inhibit growth of ID T 9 challenge but not of EB-679, an unrelated glioma, in recipient rats. Rejection of IC T 9 challenge was also obtained after IV transfer, in recipients of such ''hyperimmune'' spleen cells, but was less (60% maximum) than that noted after ID T 9 challenge (100% maximum). The removal of B cells from the transferred spleen cells did not affect the results, suggesting that the specific immunity was mediated by T cells. The authors conclude that the special immunological circumstances of tumors growing in the brain renders them less accessible to rejection by systemically transferred immune cells, but it is nevertheless possible to effect a significant incidence of rejection of syngeneic tumor growth in the brain by the intravenous transfer of hyperimmune spleen cells

  8. Circulating immune complexes and complement concentrations in patients with alcoholic liver disease

    DEFF Research Database (Denmark)

    Gluud, C; Jans, H

    1982-01-01

    A prospective evaluation of circulating immune complexes (CIC) and the activity of the complement system was undertaken in 53 alcoholic patients just before diagnostic liver biopsy. Circulating immune complexes were detected in 39% of patients with alcoholic steatosis (n = 26), 58% of patients...... with alcoholic hepatitis (n = 12), and 60% of patients with alcoholic cirrhosis (n = 15). No significant difference was found between the three group of patients. The activity of the complement system was within reference limits in the majority of patients and only slight differences were detected between...... the three groups. No significant differences were observed in liver biochemistry and complement concentrations in CIC-positive and CIC-negative patients. Detection of CIC in patients with alcoholic liver disease does not seem to be of any diagnostic value or play any pathogenic role. The high prevalence...

  9. Complement-mediated solubilization of immune complexes and their interaction with complement C3 receptors

    DEFF Research Database (Denmark)

    Petersen, Ivan; Baatrup, Gunnar; Jepsen, H H

    1985-01-01

    Some of the molecular events in the complement (C)-mediated solubilization of immune complexes (IC) have been clarified in recent years. The solubilization is primarily mediated by alternative C pathway proteins whereas factors in the classical pathway accelerate the process. Components of the me......Some of the molecular events in the complement (C)-mediated solubilization of immune complexes (IC) have been clarified in recent years. The solubilization is primarily mediated by alternative C pathway proteins whereas factors in the classical pathway accelerate the process. Components...... of the cellular localization, expression and structure of the C3 receptors, especially the C3b (CR1) receptor, has been considerably extended in the last few years, whereas our understanding of the physiological role of these receptors is still fragmentary. However, it is becoming increasingly evident...

  10. CLINICAL CASE OF TREATMENT WITH RIBOSOMAL COMPLEX IN CHILD WITH COMPROMISED IMMUNITY

    Directory of Open Access Journals (Sweden)

    A.A. Alekseeva

    2011-01-01

    Full Text Available The leading pathology in children is acute respiratory infections (ARI according to the expert data of WHO. The incidence of prolonged and recurrent types of ARI increases during recent years. Patients with these diseases subsequently form the group of children with compromised immunity. Immunogens and immunomodulators are the drugs of nonspecific prophylaxis which are used for the prevention of ARI. The group of bacterial immunomodulators is big but most well-studied systemic drug from this group is Ribomunyl. Ribosomal complex is effective and safe in pediatric practice. The article presents the clinical case of treatment with ribosomal complex in immunocompronised child with allergic pathology.Key words: children with compromised immunity, allergy, acute respiratory infections, treatment.(Voprosy sovremennoi pediatrii — Current Pediatrics. 2011; 10 (2: 211–215

  11. Do entheogen-induced mystical experiences boost the immune system? Psychedelics, peak experiences, and wellness.

    Science.gov (United States)

    Roberts, T B

    1999-01-01

    Daily events that boost the immune system (as indicated by levels of salivary immunoglobulin A), some instances of spontaneous remission, and mystical experiences seem to share a similar cluster of thoughts, feelings, moods, perceptions, and behaviors. Entheogens--psychedelic drugs used in a religious context--can also produce mystical experiences (peak experiences, states of unitive consciousness, intense primary religious experiences) with the same cluster of effects. When this happens, is it also possible that such entheogen-induced mystical experiences strengthen the immune system? Might spontaneous remissions occur more frequently under such conditions? This article advances the so called "Emxis hypothesis"--that entheogen-induced mystical experiences influence the immune system.

  12. Endoplasmic reticulum chaperone glucose regulated protein 170-Pokemon complexes elicit a robust antitumor immune response in vivo.

    Science.gov (United States)

    Yuan, Bangqing; Xian, Ronghua; Wu, Xianqu; Jing, Junjie; Chen, Kangning; Liu, Guojun; Zhou, Zhenhua

    2012-07-01

    Previous evidence suggested that the stress protein grp170 can function as a highly efficient molecular chaperone, binding to large protein substrates and acting as a potent vaccine against specific tumors when purified from the same tumor. In addition, Pokemon can be found in almost all malignant tumor cells and is regarded to be a promising candidate for the treatment of tumors. However, the potential of the grp170-Pokemon chaperone complex has not been well described. In the present study, the natural chaperone complex between grp170 and the Pokemon was formed by heat shock, and its immunogenicity was detected by ELISPOT and (51)Cr-release assays in vitro and by tumor bearing models in vivo. Our results demonstrated that the grp170-Pokemon chaperone complex could elicit T cell responses as determined by ELISPOT and (51)Cr-release assays. In addition, immunized C57BL/6 mice were challenged with subcutaneous (s.c.) injection of Lewis cancer cells to induce primary tumors. Treatment of mice with the grp170-Pokemon chaperone complex also significantly inhibited tumor growth and prolonged the life span of tumor-bearing mice. Our results indicated that the grp170-Pokemon chaperone complex might represent a powerful approach to tumor immunotherapy and have significant potential for clinical application. Copyright © 2012 Elsevier GmbH. All rights reserved.

  13. Application of fluorescent monocytes for probing immune complexes on antigen microarrays.

    Directory of Open Access Journals (Sweden)

    Zoltán Szittner

    Full Text Available Microarrayed antigens are used for identifying serum antibodies with given specificities and for generating binding profiles. Antibodies bind to these arrayed antigens forming immune complexes and are conventionally identified by secondary labelled antibodies.In the body immune complexes are identified by bone marrow derived phagocytic cells, such as monocytes. In our work we were looking into the possibility of replacing secondary antibodies with monocytoid cells for the generation of antibody profiles. Using the human monocytoid cell line U937, which expresses cell surface receptors for immune complex components, we show that cell adhesion is completely dependent on the interaction of IgG heavy chains and Fcγ receptors, and this recognition is susceptible to differences between heavy chain structures and their glycosylation. We also report data on a possible application of this system in autoimmune diagnostics.Compared to secondary antibodies, fluorescent monocytesas biosensors are superior in reflecting biological functions of microarray-bound antibodies and represent an easy and robust alternative for profiling interactions between serum proteins and antigens.

  14. The alternative complement pathway control protein H binds to immune complexes and serves their detection

    International Nuclear Information System (INIS)

    Nydegger, U.E.; Corvetta, A.; Spaeth, P.J.; Spycher, M.

    1983-01-01

    During solubilization of immune complexes C3b becomes fixed to the immunoglobulin part and serves as a receptor for the alternative complement pathway control protein H. The H-C3b immune complex interaction can be made detectable using 4% polyethyleneglycol to separate free from bound 125 I-H. Tetanus toxoid (Te)/anti-Te complexes kept soluble with fresh serum and containing 125 IU of specific antibody bound 18% of 125 I-H; when fresh serum was chelated with 10 mM EDTA, 125 I-H binding was only 5%. On sucrose density gradients, the H-binding material sedimented in the range of 12 to 30 S. In 36 serum samples from rheumatoid arthritis (RA) patients and in 12 serum samples from patients with systemic lupus erythematosus (SLE), 125 I-H binding was significantly elevated to 9.5 +/- 4.7% (mean +/- 1 SD) and 13.3 +/- 5.6%, respectively, while 125 I-H binding by 36 normal human sera was 4 +/- 2%. RA samples (17/36, 47%) and SLE samples (9/12, 75%) had H-binding values increased by more than 2 SD above the normal mean. The serum samples were also assessed for conglutinin- and C1q-binding activities; a significant correlation between H and C1q binding was observed (P less than 0.001); there was no correlation between H and conglutinin binding. Although binding to immune complexes through its interaction with C3b, H clearly detects a population of complexes other than conglutinin, thus expanding the possibilities of further characterizing pathological complexes

  15. Immunity and Tolerance Induced by Intestinal Mucosal Dendritic Cells

    Directory of Open Access Journals (Sweden)

    Julio Aliberti

    2016-01-01

    Full Text Available Dendritic cells present in the digestive tract are constantly exposed to environmental antigens, commensal flora, and invading pathogens. Under steady-state conditions, these cells have high tolerogenic potential, triggering differentiation of regulatory T cells to protect the host from unwanted proinflammatory immune responses to innocuous antigens or commensals. On the other hand, these cells must discriminate between commensal flora and invading pathogens and mount powerful immune response against pathogens. A potential result of unbalanced tolerogenic versus proinflammatory responses mediated by dendritic cells is associated with chronic inflammatory conditions, such as Crohn’s disease, ulcerative colitis, food allergies, and celiac disease. Herein, we review the dendritic cell population involved in mediating tolerance and immunity in mucosal surfaces, the progress in unveiling their development in vivo, and factors that can influence their functions.

  16. Modification of glomerular immune complex deposition in mice by activation of the reticuloendothelial system.

    OpenAIRE

    Barcelli, U; Rademacher, R; Ooi, Y M; Ooi, B S

    1981-01-01

    To determine the effect of activation of the reticuloendothelial system on the localization of immune complexes in the kidney, a model of passive serum sickness nephritis in the mouse was used, with activation of the reticuloendothelial system with Corynebacterium parvum. Groups of mice, control and C. parvum-treated animals, were injected with BSA-125I-anti-BSA complexes containing 3 mg 125I-anti-BSA. Blood was obtained at 5 min, at 3 h, and at 12 h, when the animals were killed. Blood conce...

  17. The Value of a Comparative Approach to Understand the Complex Interplay between Microbiota and Host Immunity

    Directory of Open Access Journals (Sweden)

    Norma M. Morella

    2017-09-01

    Full Text Available The eukaryote immune system evolved and continues to evolve within a microbial world, and as such is critically shaped by—and in some cases even reliant upon—the presence of host-associated microbial species. There are clear examples of adaptations that allow the host to simultaneously tolerate and/or promote growth of symbiotic microbiota while protecting itself against pathogens, but the relationship between immunity and the microbiome reaches far beyond simple recognition and includes complex cross talk between host and microbe as well as direct microbiome-mediated protection against pathogens. Here, we present a broad but brief overview of how the microbiome is controlled by and interacts with diverse immune systems, with the goal of identifying questions that can be better addressed by taking a comparative approach across plants and animals and different types of immunity. As two key examples of such an approach, we focus on data examining the importance of early exposure on microbiome tolerance and immune system development and function, and the importance of transmission among hosts in shaping the potential coevolution between, and long-term stability of, host–microbiome associations. Then, by comparing existing evidence across short-lived plants, mouse model systems and humans, and insects, we highlight areas of microbiome research that are strong in some systems and absent in others with the hope of guiding future research that will allow for broad-scale comparisons moving forward. We argue that such an approach will not only help with identification of generalities in host–microbiome–immune interactions but also improve our understanding of the role of the microbiome in host health.

  18. Sperm storage induces an immunity cost in ants

    DEFF Research Database (Denmark)

    Baer, Boris; Armitage, Sophie A O; Boomsma, Jacobus J

    2006-01-01

    Ant queens are among the most long-lived insects known. They mate early in adult life and maintain millions of viable sperm in their sperm storage organ until they die many years later. Because they never re-mate, the reproductive success of queens is ultimately sperm-limited, but it is not known...... what selective forces determine the upper limit to sperm storage. Here we show that sperm storage carries a significant cost of reduced immunity during colony founding. Newly mated queens of the leaf-cutting ant Atta colombica upregulate their immune response shortly after completing their nest burrow...

  19. Immunogenicity to Biotherapeutics – the role of Anti-drug Immune complexes

    Directory of Open Access Journals (Sweden)

    Murli eKrishna

    2016-02-01

    Full Text Available AbstractBiologic molecules are increasingly becoming a part of the therapeutics portfolio that has been either recently approved for marketing or those that are in the pipeline of several biotech and pharmaceutical companies. This is largely based on their ability to be highly specific relative to small molecules. However by virtue of being a large protein, and having a complex structure with structural variability arising from production using recombinant gene technology in cell lines, such therapeutics run the risk of being recognized as foreign by a host immune system. Given the range of immune mediated adverse effects that have been documented to biologic drugs thus far, including infusion reactions, and the evolving therapeutic platforms in the pipeline that engineer different functional modules in a biotherapeutic, it is critical to understand the interplay of the adaptive and innate immune responses, the pathophysiology of immunogenicity to biologic drugs in instances where there have been immune mediated adverse clinical sequelae and address technical approaches for their laboratory evaluation. The current paradigm in immunogenicity evaluation has a tiered approach to the detection and characterization of anti-drug antibodies (ADAs elicited in vivo to a biotherapeutic; alongside with the structural, biophysical and molecular information of the therapeutic, these analytical assessments form the core of the immunogenicity risk assessment. However many of the immune mediated adverse effects attributed to ADAs require the formation of a drug/ADA immune complex intermediate (ICs that can have a variety of downstream effects. This review will focus on the activation of potential immunopathological pathways arising as a consequence of circulating as well as cell surface bound drug bearing-ICs, risk factors that are either intrinsic to the therapeutic molecule or to the host which might predispose to IC mediated effects, and review the recent

  20. Metabolic and adaptive immune responses induced in mice infected ...

    African Journals Online (AJOL)

    This study investigated metabolic and immuno-inflammatory responses of mice infected with tissue-dwelling larvae of Trichinella zimbabwensis and explored the relationship between infection, metabolic parameters and Th1/Th17 immune responses. Sixty (60) female BALB/c mice aged between 6 to 8 weeks old were ...

  1. Platelet activating factor receptor binding plays a critical role in jet fuel-induced immune suppression

    International Nuclear Information System (INIS)

    Ramos, Gerardo; Kazimi, Nasser; Nghiem, Dat X.; Walterscheid, Jeffrey P.; Ullrich, Stephen E.

    2004-01-01

    Applying military jet fuel (JP-8) or commercial jet fuel (Jet-A) to the skin of mice suppresses the immune response in a dose-dependant manner. The release of biological response modifiers, particularly prostaglandin E 2 (PGE 2 ), is a critical step in activating immune suppression. Previous studies have shown that injecting selective cyclooxygenase-2 inhibitors into jet fuel-treated mice blocks immune suppression. Because the inflammatory phospholipid mediator, platelet-activating factor (PAF), up-regulates cyclooxygenase-2 production and PGE 2 synthesis by keratinocytes, we tested the hypothesis that PAF-receptor binding plays a role in jet fuel-induced immune suppression. Treating keratinocyte cultures with PAF and/or jet fuel (JP-8 and Jet-A) stimulates PGE 2 secretion. Jet fuel-induced PGE 2 production was suppressed by treating the keratinocytes with specific PAF-receptor antagonists. Injecting mice with PAF, or treating the skin of the mice with JP-8, or Jet-A, induced immune suppression. Jet fuel-induced immune suppression was blocked when the jet fuel-treated mice were injected with PAF-receptor antagonists before treatment. Jet fuel treatment has been reported to activate oxidative stress and treating the mice with anti-oxidants (Vitamins C, or E or beta-hydroxy toluene), before jet fuel application, interfered with immune suppression. These findings confirm previous studies showing that PAF-receptor binding can modulate immune function. Furthermore, they suggest that PAF-receptor binding may be an early event in the induction of immune suppression by immunotoxic environmental agents that target the skin

  2. Perillyl alcohol suppresses antigen-induced immune responses in the lung

    International Nuclear Information System (INIS)

    Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide; Nakagome, Kazuyuki; Harada, Hiroaki; Kawahata, Kimito; Tanaka, Ryoichi; Yamamoto, Kazuhiko; Dohi, Makoto

    2014-01-01

    Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4 + T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4 + T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects

  3. Application of human erythrocytes to a radioimmune assay of immune complexes in serum. [Lupus erythematosus, type B hepatitis

    Energy Technology Data Exchange (ETDEWEB)

    Tsuda, F; Miyakawa, Y; Mayumi, M [Tokyo Metropolitan Lab. of Public Health (Japan)

    1979-07-01

    An immune adherence receptor exists on the surface of primate erythrocytes, and has been characterized as a receptor for the activated third component of complement (C3b). Human red blood cells (RCBs, blood group O) were applied to a sensitive determination of complement-fixing, soluble immune complexes in serum. The method involved the binding of immune complexes with RBCs in the presence of complement and the detection of cell-bound IgG molecules by radiolabelled anti-human IgG antibodies. Since the binding of RBCs with monomeric IgG was minimal, cell bound IgG molecules were taken as representing immune complexes. When aggregated human gammaglobulin (AHG) was used as a model of immune complexes, as little as 5 ..mu..g dissolved in 1 ml of normal human serum were detected. The binding of RBCs with AHG was inhibited in EDTA solution where the classical complement pathway could not be activated. The RBC radioimmune assay was successfully applied to the determination of soluble immune complexes in pathological serum samples obtained from the patients with systemic lupus erythematosus and those with fulminant Type B hepatitis. False-positive results by autoantibodies against RBCs could be excluded by a Coombs test and by comparing the binding in the presence of complement with that in EDTA solution. The ubiquitous availability of RBCs coupled with a high sensitivity would allow the RBC radioimmune assay to be used as a further method of determining immune complexes in the serum.

  4. Nanovectorized radiotherapy: a new strategy to induce anti-tumor immunity

    International Nuclear Information System (INIS)

    Vanpouille-Box, Claire; Hindré, François

    2012-01-01

    Recent experimental findings show that activation of the host immune system is required for the success of chemo- and radiotherapy. However, clinically apparent tumors have already developed multiple mechanisms to escape anti-tumor immunity. The fact that tumors are able to induce a state of tolerance and immunosuppression is a major obstacle in immunotherapy. Hence, there is an overwhelming need to develop new strategies that overcome this state of immune tolerance and induce an anti-tumor immune response both at primary and metastatic sites. Nanovectorized radiotherapy that combines ionizing radiation and nanodevices, is one strategy that could boost the quality and magnitude of an immune response in a predictable and designable fashion. The potential benefits of this emerging treatment may be based on the unique combination of immunostimulatory properties of nanoparticles with the ability of ionizing radiation to induce immunogenic tumor cell death. In this review, we will discuss available data and propose that the nanovectorized radiotherapy could be a powerful new strategy to induce anti-tumor immunity required for positive patient outcome.

  5. Nanovectorized radiotherapy, a new strategy to induce anti-tumor immunity

    Directory of Open Access Journals (Sweden)

    Claire eVanpouille-Box

    2012-10-01

    Full Text Available Recent experimental findings show that activation of the host immune system is required for the success of chemo- and radio-therapy. However, clinically-apparent tumors have already developed multiple mechanisms to escape anti-tumor immunity. The fact that tumors are able to induce a state of tolerance and immunosuppression is a major obstacle in immunotherapy. Hence, there is an overwhelming need to develop new strategies that overcome this state of immune tolerance and induce an anti-tumor immune response both at primary and metastatic sites. Nanovectorized radiotherapy that combines ionizing radiation and nano-devices, is one strategy that could boost the quality and magnitude of an immune response in a predictable and designable fashion. The potential benefits of this emerging treatment may be based on the unique combination of immuno-stimulatory properties of nanoparticles with the ability of ionizing radiation to induce immunogenic tumor cell death. In this review, we will discuss available data and propose that the nanovectorized radiotherapy could be a powerful new strategy to induce anti-tumor immunity required for positive patient outcome.

  6. Radiation induced ligand loss from cobalt complexes

    International Nuclear Information System (INIS)

    Funston, A. M.; McFadyen, W.D.; Tregloan, P.A.

    2000-01-01

    Full text: Due to the rapid nature of ligand dissociation from cobalt(II) complexes the study of the rate of ligand dissociation necessitates the use of a technique such as pulse radiolysis. This allows the rapid reduction of the corresponding cobalt(III) complex by a reducing radical, such as the aquated electron, to form the cobalt(II) complex. However, to date, no systematic study of either the mechanism of reduction or the influence of the electronic structure on the rate of ligand dissociation has been carried out. In order to understand these processes more fully the mechanism of reduction of a range of related cobalt(III) complexes by the aquated electron and the subsequent rate of ligand dissociation from the resulting cobalt(II) complexes is being investigated. It has been found that a number of processes are observed following the initial rapid reaction of the cobalt(III) complex with the aquated electron. Ultimately ligand loss is observed. Depending upon the complex, the initial processes observed may include the formation of coordinated radicals and electron transfer within the complex. For complexes containing aromatic ligands such as 2,2'-bipyridine, 1,10-phenanthroline and dipyrido[3,2-a:2',3'-c]phenazine the formation of a coordinated radical is observed as the initial reduction step. The kinetics of ligand dissociation of these complexes has been determined. The loss of monodentate ligands is fast and has been indistinguishable from the reduction processes when aromatic ligands are also present in the complex. However, for diamine chelates and diimine chelates spectra of the transient species can be resolved

  7. Role of MicroRNAs in Obesity-Induced Metabolic Disorder and Immune Response

    Directory of Open Access Journals (Sweden)

    Hong Zhong

    2018-01-01

    Full Text Available In all living organisms, metabolic homeostasis and the immune system are the most fundamental requirements for survival. Recently, obesity has become a global public health issue, which is the cardinal risk factor for metabolic disorder. Many diseases emanating from obesity-induced metabolic dysfunction are responsible for the activated immune system, including innate and adaptive responses. Of note, inflammation is the manifest accountant signal. Deeply studied microRNAs (miRNAs have participated in many pathways involved in metabolism and immune responses to protect cells from multiple harmful stimulants, and they play an important role in determining the progress through targeting different inflammatory pathways. Thus, immune response and metabolic regulation are highly integrated with miRNAs. Collectively, miRNAs are the new targets for therapy in immune dysfunction.

  8. Role of MicroRNAs in Obesity-Induced Metabolic Disorder and Immune Response.

    Science.gov (United States)

    Zhong, Hong; Ma, Minjuan; Liang, Tingming; Guo, Li

    2018-01-01

    In all living organisms, metabolic homeostasis and the immune system are the most fundamental requirements for survival. Recently, obesity has become a global public health issue, which is the cardinal risk factor for metabolic disorder. Many diseases emanating from obesity-induced metabolic dysfunction are responsible for the activated immune system, including innate and adaptive responses. Of note, inflammation is the manifest accountant signal. Deeply studied microRNAs (miRNAs) have participated in many pathways involved in metabolism and immune responses to protect cells from multiple harmful stimulants, and they play an important role in determining the progress through targeting different inflammatory pathways. Thus, immune response and metabolic regulation are highly integrated with miRNAs. Collectively, miRNAs are the new targets for therapy in immune dysfunction.

  9. FAM26F: An Enigmatic Protein Having a Complex Role in the Immune System.

    Science.gov (United States)

    Malik, Uzma; Javed, Aneela

    2016-09-19

    Mammalian immune system is a complex amalgam of diverse cellular and noncellular components such as cytokines, receptors and co-receptors. FAM26F (family with sequence similarity 26, member F) is a recently identified tetraspanin-like membrane glycoprotein which is predicted to make homophilic interactions and potential synapses between several immune cells including CD4 + , CD8 + , NK, dendritic cells and macrophages. Various whole transcriptome analyses have demonstrated the differential expression of FAM26F in several bacterial, viral and parasitic infections, in certain pathophysiological conditions such as liver and heart transplantation, and in various cancers. The complete understanding of transcriptional regulation of FAM26F is in its infancy however it is up regulated by various stimulants such as polyI:C, LPS, INF gamma and TNF alpha, and via various proposed pathways including TLR3, TLR4 IFN-β and Dectin-1. These pathways can merge in STAT1 activation. The synergistic expression of FAM26F on both NK-cells and myeloid dendritic cells is required to activate NK-cells against tumors via its cytoplasmic tail, thus emphasizing therapeutic potential of FAM26F for NK sensitive tumors. Current review provides a comprehensive basis to propose that FAM26F expression level is at least a hallmark for IFN-γ-lead immune responses and thus can proficiently be regarded as an early diagnostic marker. Future investigation dissecting the role of FAM26F in activation of various immune cell populations in local amplification by cell-cell contact is crucial to provide the missing link imperative for elucidating the relevance of this protein in immune responses.

  10. HIV-induced immune activation - pathogenesis and clinical relevance

    Directory of Open Access Journals (Sweden)

    Stellbrink HJ

    2010-01-01

    Full Text Available Abstract This manuscript is communicated by the German AIDS Society (DAIG http://www.daignet.de. It summarizes a series of presentations and discussions during a workshop on immune activation due to HIV infection. The workshop was held on November 22nd 2008 in Hamburg, Germany. It was organized by the ICH Hamburg under the auspices of the German AIDS Society (DAIG e.V..

  11. Genome complexity in the coelacanth is reflected in its adaptive immune system

    Science.gov (United States)

    Saha, Nil Ratan; Ota, Tatsuya; Litman, Gary W.; Hansen, John; Parra, Zuly; Hsu, Ellen; Buonocore, Francesco; Canapa, Adriana; Cheng, Jan-Fang; Amemiya, Chris T.

    2014-01-01

    We have analyzed the available genome and transcriptome resources from the coelacanth in order to characterize genes involved in adaptive immunity. Two highly distinctive IgW-encoding loci have been identified that exhibit a unique genomic organization, including a multiplicity of tandemly repeated constant region exons. The overall organization of the IgW loci precludes typical heavy chain class switching. A locus encoding IgM could not be identified either computationally or by using several different experimental strategies. Four distinct sets of genes encoding Ig light chains were identified. This includes a variant sigma-type Ig light chain previously identified only in cartilaginous fishes and which is now provisionally denoted sigma-2. Genes encoding α/β and γ/δ T-cell receptors, and CD3, CD4, and CD8 co-receptors also were characterized. Ig heavy chain variable region genes and TCR components are interspersed within the TCR α/δ locus; this organization previously was reported only in tetrapods and raises questions regarding evolution and functional cooption of genes encoding variable regions. The composition, organization and syntenic conservation of the major histocompatibility complex locus have been characterized. We also identified large numbers of genes encoding cytokines and their receptors, and other genes associated with adaptive immunity. In terms of sequence identity and organization, the adaptive immune genes of the coelacanth more closely resemble orthologous genes in tetrapods than those in teleost fishes, consistent with current phylogenomic interpretations. Overall, the work reported described herein highlights the complexity inherent in the coelacanth genome and provides a rich catalog of immune genes for future investigations.

  12. Scrapie affects the maturation cycle and immune complex trapping by follicular dendritic cells in mice.

    Directory of Open Access Journals (Sweden)

    Gillian McGovern

    2009-12-01

    Full Text Available Transmissible spongiform encephalopathies (TSEs or prion diseases are infectious neurological disorders of man and animals, characterised by abnormal disease-associated prion protein (PrP(d accumulations in the brain and lymphoreticular system (LRS. Prior to neuroinvasion, TSE agents often accumulate to high levels within the LRS, apparently without affecting immune function. However, our analysis of scrapie-affected sheep shows that PrP(d accumulations within the LRS are associated with morphological changes to follicular dendritic cells (FDCs and tingible body macrophages (TBMs. Here we examined FDCs and TBMs in the mesenteric lymph nodes (MLNs of scrapie-affected mice by light and electron microscopy. In MLNs from uninfected mice, FDCs could be morphologically categorised into immature, mature and regressing forms. However, in scrapie-affected MLNs this maturation cycle was adversely affected. FDCs characteristically trap and retain immune complexes on their surfaces, which they display to B-lymphocytes. In scrapie-affected MLNs, some FDCs were found where areas of normal and abnormal immune complex retention occurred side by side. The latter co-localised with PrP(d plasmalemmal accumulations. Our data suggest this previously unrecognised morphology represents the initial stage of an abnormal FDC maturation cycle. Alterations to the FDCs included PrP(d accumulation, abnormal cell membrane ubiquitin and excess immunoglobulin accumulation. Regressing FDCs, in contrast, appeared to lose their membrane-attached PrP(d. Together, these data suggest that TSE infection adversely affects the maturation and regression cycle of FDCs, and that PrP(d accumulation is causally linked to the abnormal pathology observed. We therefore support the hypothesis that TSEs cause an abnormality in immune function.

  13. Experimentally induced spermatophore production and immune responses reveal a trade-off in crickets

    OpenAIRE

    Angela M. Kerr; Susan N. Gershman; Scott K. Sakaluk

    2010-01-01

    The energetic demands of the immune system and reproduction are often high and can lead to trade-offs between these 2 life-history traits. In decorated crickets, Gryllodes sigillatus, much of a male's reproductive effort is devoted to calling, and to the synthesis of a spermatophylax, a large, gelatinous, non--sperm-containing mass forming part of the spermatophore and consumed by the female after mating. We employed a reciprocal design in which we experimentally induced an immune response in...

  14. Immunity booster

    International Nuclear Information System (INIS)

    Stefanescu, Ioan; Titescu, Gheorghe; Tamaian, Radu; Haulica, Ion; Bild, Walther

    2002-01-01

    The immunity booster is, according to its patent description, microbiologically pure water with an D/(D+H) isotopic concentration of 100 ppm, with physical-chemical characteristics similar to those of distilled water. It is obtained by sterilization of a mixture of deuterium depleted water, with a 25 ppm isotopic concentration, with distilled water in a volume ratio of 4:6. Unlike natural immunity boosters (bacterial agents as Bacillus Chalmette-Guerin, Corynebacterium parvum; lipopolysaccharides; human immunoglobulin) or synthetical products (levamysol; isoprinosyne with immunostimulating action), which cause hypersensitivity and shocks, thrill, fever, sickness and the immunity complex disease, the water of 100 ppm D/(D + H) isotopic concentration is a toxicity free product. The testing for immune reaction of the immunity booster led to the following results: - an increase of cell action capacity in the first immunity shielding stage (macrophages), as evidenced by stimulation of a number of essential characterizing parameters, as well as of the phagocytosis capacity, bactericide capacity, and opsonic capacity of serum; - an increase of the number of leucocyte particularly of the granulocyte in peripheral blood, produced especially when medullar toxic agents like caryolysine are used; - it hinders the effect of lowering the number of erythrocytes in peripheral blood produced by experimentally induced chronic inflammation; - an increase of nonspecific immunity defence capacity against specific bacterial aggression of both Gram-positive bacteria (Streptococcus pneumoniae 558 ) and of the Gram-negative ones (Klebsiella pneumoniae 507 ); - an increase of immunity - stimulating activity (proinflamatory), like that of levamisole as evidenced by the test of stimulation of experimentally induced inflammation by means of carrageenan. The following advantages of the immunity booster are stressed: - it is toxicity free and side effect free; - can be orally administrated as

  15. HPV-16 L1 genes with inactivated negative RNA elements induce potent immune responses

    International Nuclear Information System (INIS)

    Rollman, Erik; Arnheim, Lisen; Collier, Brian; Oeberg, Daniel; Hall, Haakan; Klingstroem, Jonas; Dillner, Joakim; Pastrana, Diana V.; Buck, Chris B.; Hinkula, Jorma; Wahren, Britta; Schwartz, Stefan

    2004-01-01

    Introduction of point mutations in the 5' end of the human papillomavirus type 16 (HPV-16) L1 gene specifically inactivates negative regulatory RNA processing elements. DNA vaccination of C57Bl/6 mice with the mutated L1 gene resulted in improved immunogenicity for both neutralizing antibodies as well as for broad cellular immune responses. Previous reports on the activation of L1 by codon optimization may be explained by inactivation of the regulatory RNA elements. The modified HPV-16 L1 DNA that induced anti-HPV-16 immunity may be seen as a complementary approach to protein subunit immunization against papillomavirus

  16. Adoptively transferred immune T cells eradicate established tumors in spite of cancer-induced immune suppression

    Science.gov (United States)

    Arina, Ainhoa; Schreiber, Karin; Binder, David C.; Karrison, Theodore; Liu, Rebecca B.; Schreiber, Hans

    2014-01-01

    Myeloid-derived CD11b+Gr1+ suppressor cells (MDSC) and tumor-associated macrophages (TAM) are considered a major obstacle for effective adoptive T cell therapy. Myeloid cells suppress naive T cell proliferation ex vivo and can prevent the generation of T cell responses in vivo. We find, however, that immune T cells adoptively transferred eradicate well-established tumors in the presence of MDSC and TAM which are strongly immunosuppressive ex vivo. These MDSC and TAM were comparable in levels and immunosuppression among different tumor models. Longitudinal microscopy of tumors in vivo revealed that after T cell transfer tumor vasculature and cancer cells disappeared simultaneously. During T-cell mediated tumor destruction, the tumor stroma contained abundant myeloid cells (mainly TAM) that retained their suppressive properties. Preimmunized but not naive mice resisted immune suppression caused by an unrelated tumor-burden supporting the idea that in vivo, myeloid immunosuppressive cells can suppress naive but not memory T cell responses. PMID:24367029

  17. Serum and mucosal immune responses to an inactivated influenza virus vaccine induced by epidermal powder immunization.

    Science.gov (United States)

    Chen, D; Periwal, S B; Larrivee, K; Zuleger, C; Erickson, C A; Endres, R L; Payne, L G

    2001-09-01

    Both circulating and mucosal antibodies are considered important for protection against infection by influenza virus in humans and animals. However, current inactivated vaccines administered by intramuscular injection using a syringe and needle elicit primarily circulating antibodies. In this study, we report that epidermal powder immunization (EPI) via a unique powder delivery system elicits both serum and mucosal antibodies to an inactivated influenza virus vaccine. Serum antibody responses to influenza vaccine following EPI were enhanced by codelivery of cholera toxin (CT), a synthetic oligodeoxynucleotide containing immunostimulatory CpG motifs (CpG DNA), or the combination of these two adjuvants. In addition, secretory immunoglobulin A (sIgA) antibodies were detected in the saliva and mucosal lavages of the small intestine, trachea, and vaginal tract, although the titers were much lower than the IgG titers. The local origin of the sIgA antibodies was further shown by measuring antibodies released from cultured tracheal and small intestinal fragments and by detecting antigen-specific IgA-secreting cells in the lamina propria using ELISPOT assays. EPI with a single dose of influenza vaccine containing CT or CT and CpG DNA conferred complete protection against lethal challenges with an influenza virus isolated 30 years ago, whereas a prime and boost immunizations were required for protection in the absence of an adjuvant. The ability to elicit augmented circulating antibody and mucosal antibody responses makes EPI a promising alternative to needle injection for administering vaccines against influenza and other diseases.

  18. The Skin Microbiome: Is It Affected by UV-induced Immune Suppression?

    Science.gov (United States)

    Patra, VijayKumar; Byrne, Scott N.; Wolf, Peter

    2016-01-01

    Human skin apart from functioning as a physical barricade to stop the entry of pathogens, also hosts innumerable commensal organisms. The skin cells and the immune system constantly interact with microbes, to maintain cutaneous homeostasis, despite the challenges offered by various environmental factors. A major environmental factor affecting the skin is ultraviolet radiation (UV-R) from sunlight. UV-R is well known to modulate the immune system, which can be both beneficial and deleterious. By targeting the cells and molecules within skin, UV-R can trigger the production and release of antimicrobial peptides, affect the innate immune system and ultimately suppress the adaptive cellular immune response. This can contribute to skin carcinogenesis and the promotion of infectious agents such as herpes simplex virus and possibly others. On the other hand, a UV-established immunosuppressive environment may protect against the induction of immunologically mediated skin diseases including some of photodermatoses such as polymorphic light eruption. In this article, we share our perspective about the possibility that UV-induced immune suppression may alter the landscape of the skin’s microbiome and its components. Alternatively, or in concert with this, direct UV-induced DNA and membrane damage to the microbiome may result in pathogen associated molecular patterns (PAMPs) that interfere with UV-induced immune suppression. PMID:27559331

  19. The skin microbiome: Is it affected by UV-induced immune suppression?

    Directory of Open Access Journals (Sweden)

    Vijaykumar Patra

    2016-08-01

    Full Text Available Human skin apart from functioning as a physical barricade to stop the entry of pathogens, also hosts innumerable commensal organisms. The skin cells and the immune system constantly interact with microbes, to maintain cutaneous homeostasis, despite the challenges offered by various environmental factors. A major environmental factor affecting the skin is ultraviolet radiation UV-R from sunlight. UV-R is well known to modulate the immune system, which can be both beneficial and deleterious. By targeting the cells and molecules within skin, UV-R can trigger the production and release of antimicrobial peptides (AMPs, affect the innate immune system and ultimately suppress the adaptive cellular immune response. This can contribute to skin carcinogenesis and the promotion of infectious agents such as herpes simplex virus and possibly others. On the other hand, a UV-established immunosuppressive environment may protect against the induction of immunologically mediated skin diseases including some of photodermatoses such as polymorphic light eruption. In this article, we share our perspective about the possibility that UV-induced immune suppression may alter the landscape of the skin's microbiome and its components. Alternatively, or in concert with this, direct UV-induced DNA and membrane damage to the microbiome may result in pathogen associated molecular patterns (PAMPs that interfere with UV-induced immune suppression.

  20. Differential trafficking of oxidized LDL and oxidized LDL immune complexes in macrophages: impact on oxidative stress.

    Directory of Open Access Journals (Sweden)

    Mohammed M Al Gadban

    2010-09-01

    Full Text Available Oxidized low-density lipoproteins (oxLDL and oxLDL-containing immune complexes (oxLDL-IC contribute to formation of lipid-laden macrophages (foam cells. It has been shown that oxLDL-IC are considerably more efficient than oxLDL in induction of foam cell formation, inflammatory cytokines secretion, and cell survival promotion. Whereas oxLDL is taken up by several scavenger receptors, oxLDL-IC are predominantly internalized through the FCgamma receptor I (FCgamma RI. This study examined differences in intracellular trafficking of lipid and apolipoprotein moieties of oxLDL and oxLDL-IC and the impact on oxidative stress.Fluorescently labeled lipid and protein moieties of oxLDL co-localized within endosomal and lysosomal compartments in U937 human monocytic cells. In contrast, the lipid moiety of oxLDL-IC was detected in the endosomal compartment, whereas its apolipoprotein moiety advanced to the lysosomal compartment. Cells treated with oxLDL-IC prior to oxLDL demonstrated co-localization of internalized lipid moieties from both oxLDL and oxLDL-IC in the endosomal compartment. This sequential treatment likely inhibited oxLDL lipid moieties from trafficking to the lysosomal compartment. In RAW 264.7 macrophages, oxLDL-IC but not oxLDL induced GFP-tagged heat shock protein 70 (HSP70 and HSP70B', which co-localized with the lipid moiety of oxLDL-IC in the endosomal compartment. This suggests that HSP70 family members might prevent the degradation of the internalized lipid moiety of oxLDL-IC by delaying its advancement to the lysosome. The data also showed that mitochondrial membrane potential was decreased and generation of reactive oxygen and nitrogen species was increased in U937 cell treated with oxLDL compared to oxLDL-IC.Findings suggest that lipid and apolipoprotein moieties of oxLDL-IC traffic to separate cellular compartments, and that HSP70/70B' might sequester the lipid moiety of oxLDL-IC in the endosomal compartment. This mechanism could

  1. Reconstructing an ancestral mammalian immune supercomplex from a marsupial major histocompatibility complex.

    Directory of Open Access Journals (Sweden)

    Katherine Belov

    2006-03-01

    Full Text Available The first sequenced marsupial genome promises to reveal unparalleled insights into mammalian evolution. We have used the Monodelphis domestica (gray short-tailed opossum sequence to construct the first map of a marsupial major histocompatibility complex (MHC. The MHC is the most gene-dense region of the mammalian genome and is critical to immunity and reproductive success. The marsupial MHC bridges the phylogenetic gap between the complex MHC of eutherian mammals and the minimal essential MHC of birds. Here we show that the opossum MHC is gene dense and complex, as in humans, but shares more organizational features with non-mammals. The Class I genes have amplified within the Class II region, resulting in a unique Class I/II region. We present a model of the organization of the MHC in ancestral mammals and its elaboration during mammalian evolution. The opossum genome, together with other extant genomes, reveals the existence of an ancestral "immune supercomplex" that contained genes of both types of natural killer receptors together with antigen processing genes and MHC genes.

  2. Significance of Lipid-Derived Reactive Aldehyde-Specific Immune Complexes in Systemic Lupus Erythematosus.

    Directory of Open Access Journals (Sweden)

    Gangduo Wang

    Full Text Available Even though systemic lupus erythematosus (SLE is associated with high morbidity and mortality rates among young and middle-aged women, the molecular mechanisms of disease pathogenesis are not fully understood. Previous studies from our laboratory suggested an association between oxidative stress and SLE disease activity (SLEDAI. To further assess the role of reactive oxygen species (ROS in SLE, we examined the contribution of lipid-derived reactive aldehydes (LDRAs-specific immune complexes in SLE. Sera from 60 SLE patients with varying SLEDAI and 32 age- and gender- matched healthy controls were analyzed for oxidative stress and related markers. Patients were divided into two groups based on their SLEDAI scores (<6 and ≥ 6. Both SLEDAI groups showed higher serum 4-hydroxynonenal (HNE-/malondialdehyde (MDA-protein adducts and their specific immune complexes (HNE-/MDA-specific ICs together with IL-17 than the controls, but the levels were significantly greater in the high SLEDAI (≥ 6 group. Moreover, the serum levels of anti-oxidant enzymes Cu/Zn superoxide dismutase (SOD and catalase (CAT were significantly reduced in both patient groups compared to controls. Remarkably, for the first time, our data show that increased HNE-/MDA-specific ICs are positively associated with SLEDAI and elevated circulating immune complexes (CICs, suggesting a possible causal relationship among oxidative stress, LDRA-specific ICs and the development of SLE. Our findings, apart from providing firm support to an association between oxidative stress and SLE, also suggest that these oxidative stress markers, especially the HNE-/MDA-specific ICs, may be useful in evaluating the prognosis of SLE as well as in elucidating the mechanisms of disease pathogenesis.

  3. Immune Cells and Molecular Networks in Experimentally Induced Pulpitis.

    Science.gov (United States)

    Renard, E; Gaudin, A; Bienvenu, G; Amiaud, J; Farges, J C; Cuturi, M C; Moreau, A; Alliot-Licht, B

    2016-02-01

    Dental pulp is a dynamic tissue able to resist external irritation during tooth decay by using immunocompetent cells involved in innate and adaptive responses. To better understand the immune response of pulp toward gram-negative bacteria, we analyzed biological mediators and immunocompetent cells in rat incisor pulp experimentally inflamed by either lipopolysaccharide (LPS) or saline solution (phosphate-buffered saline [PBS]). Untreated teeth were used as control. Expression of pro- and anti-inflammatory cytokines, chemokine ligands, growth factors, and enzymes were evaluated at the transcript level, and the recruitment of the different leukocytes in pulp was measured by fluorescence-activated cell-sorting analysis after 3 h, 9 h, and 3 d post-PBS or post-LPS treatment. After 3 d, injured rat incisors showed pulp wound healing and production of reparative dentin in both LPS and PBS conditions, testifying to the reversible pulpitis status of this model. IL6, IL1-β, TNF-α, CCL2, CXCL1, CXCL2, MMP9, and iNOS gene expression were significantly upregulated after 3 h of LPS stimulation as compared with PBS. The immunoregulatory cytokine IL10 was also upregulated after 3 h, suggesting that LPS stimulates not only inflammation but also immunoregulation. Fluorescence-activated cell-sorting analysis revealed a significant, rapid, and transient increase in leukocyte levels 9 h after PBS and LPS stimulation. The quantity of dendritic cells was significantly upregulated with LPS versus PBS. Interestingly, we identified a myeloid-derived suppressor cell-enriched cell population in noninjured rodent incisor dental pulp. The percentage of this population, known to regulate immune response, was higher 9 h after inflammation triggered with PBS and LPS as compared with the control. Taken together, these data offer a better understanding of the mechanisms involved in the regulation of dental pulp immunity that may be elicited by gram-negative bacteria. © International & American

  4. A microplate adaptation of the solid-phase C1q immune complex assay

    International Nuclear Information System (INIS)

    Hunt, J.S.; Kennedy, M.P.; Barber, K.E.; McGiven, A.R.

    1980-01-01

    A method has been developed for the detection of C1q binding immune complexes in serum in which microculture plates are used as the solid-phase matrix for adsorption of C1q. This micromethod used only one-tenth of the amount of both C1q and [ 125 I]antihuman immunoglobulin per test and enabled 7 times as many samples to be tested in triplicate in comparison with the number performed in duplicate by the standard tube assay. (Auth.)

  5. Recombinant TgHSP70 Immunization Protects against Toxoplasma gondii Brain Cyst Formation by Enhancing Inducible Nitric Oxide Expression

    Directory of Open Access Journals (Sweden)

    Neide M. Silva

    2017-04-01

    Full Text Available Toxoplasma gondii is known to cause congenital infection in humans and animals and severe disease in immunocompromised individuals; consequently development of vaccines against the parasite is highly necessary. Under stress conditions, T. gondii expresses the highly immunogenic heat shock protein 70 (TgHSP70. Here, we assessed the protective efficacy of rTgHSP70 immunization combined with Alum in oral ME-49 T. gondii infection and the mechanisms involved on it. It was observed that immunized mice with rTgHSP70 or rTgHSP70 adsorbed in Alum presented a significantly reduced number of cysts in the brain that was associated with increased iNOS+ cell numbers in the organ, irrespective the use of the adjuvant. Indeed, ex vivo experiments showed that peritoneal macrophages pre-stimulated with rTgHSP70 presented increased NO production and enhanced parasite killing, and the protein was able to directly stimulate B cells toward antibody producing profile. In addition, rTgHSP70 immunization leads to high specific antibody titters systemically and a mixed IgG1/IgG2a response, with predominance of IgG1 production. Nonetheless, it was observed that the pretreatment of the parasite with rTgHSP70 immune sera was not able to control T. gondii internalization and replication by NIH fibroblast neither peritoneal murine macrophages, nor anti-rTgHSP70 antibodies were able to kill T. gondii by complement-mediated lysis, suggesting that these mechanisms are not crucial to resistance. Interestingly, when in combination with Alum, rTgHSP70 immunization was able to reduce inflammation in the brain of infected mice and in parallel anti-rTgHSP70 immune complexes in the serum. In conclusion, immunization with rTgHSP70 induces massive amounts of iNOS expression and reduced brain parasitism, suggesting that iNOS expression and consequently NO production in the brain is a protective mechanism induced by TgHSP70 immunization, therefore rTgHSP70 can be a good candidate for

  6. Captive and free-living red knots Calidris canutus exhibit differences in non-induced immunity that suggest different immune strategies in different environments

    NARCIS (Netherlands)

    Buehler, Deborah M.; Piersma, Theunis; Tieleman, B. Irene

    Experiments on captive animals, in which conditions can be controlled, are useful for examining complex biological phenomena such as immune function. Such experiments have increased our understanding of immune responses in the context of trade-offs and pathogen pressure. However, few studies have

  7. Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration.

    Science.gov (United States)

    Cloutier, Nathalie; Allaeys, Isabelle; Marcoux, Genevieve; Machlus, Kellie R; Mailhot, Benoit; Zufferey, Anne; Levesque, Tania; Becker, Yann; Tessandier, Nicolas; Melki, Imene; Zhi, Huiying; Poirier, Guy; Rondina, Matthew T; Italiano, Joseph E; Flamand, Louis; McKenzie, Steven E; Cote, Francine; Nieswandt, Bernhard; Khan, Waliul I; Flick, Matthew J; Newman, Peter J; Lacroix, Steve; Fortin, Paul R; Boilard, Eric

    2018-02-13

    There is a growing appreciation for the contribution of platelets to immunity; however, our knowledge mostly relies on platelet functions associated with vascular injury and the prevention of bleeding. Circulating immune complexes (ICs) contribute to both chronic and acute inflammation in a multitude of clinical conditions. Herein, we scrutinized platelet responses to systemic ICs in the absence of tissue and endothelial wall injury. Platelet activation by circulating ICs through a mechanism requiring expression of platelet Fcγ receptor IIA resulted in the induction of systemic shock. IC-driven shock was dependent on release of serotonin from platelet-dense granules secondary to platelet outside-in signaling by αIIbβ3 and its ligand fibrinogen. While activated platelets sequestered in the lungs and leaky vasculature of the blood-brain barrier, platelets also sequestered in the absence of shock in mice lacking peripheral serotonin. Unexpectedly, platelets returned to the blood circulation with emptied granules and were thereby ineffective at promoting subsequent systemic shock, although they still underwent sequestration. We propose that in response to circulating ICs, platelets are a crucial mediator of the inflammatory response highly relevant to sepsis, viremia, and anaphylaxis. In addition, platelets recirculate after degranulation and sequestration, demonstrating that in adaptive immunity implicating antibody responses, activated platelets are longer lived than anticipated and may explain platelet count fluctuations in IC-driven diseases.

  8. Inducible defenses stay up late: temporal patterns of immune gene expression in Tenebrio molitor.

    Science.gov (United States)

    Johnston, Paul R; Makarova, Olga; Rolff, Jens

    2013-12-06

    The course of microbial infection in insects is shaped by a two-stage process of immune defense. Constitutive defenses, such as engulfment and melanization, act immediately and are followed by inducible defenses, archetypically the production of antimicrobial peptides, which eliminate or suppress the remaining microbes. By applying RNAseq across a 7-day time course, we sought to characterize the long-lasting immune response to bacterial challenge in the mealworm beetle Tenebrio molitor, a model for the biochemistry of insect immunity and persistent bacterial infection. By annotating a hybrid de novo assembly of RNAseq data, we were able to identify putative orthologs for the majority of components of the conserved insect immune system. Compared with Tribolium castaneum, the most closely related species with a reference genome sequence and a manually curated immune system annotation, the T. molitor immune gene count was lower, with lineage-specific expansions of genes encoding serine proteases and their countervailing inhibitors accounting for the majority of the deficit. Quantitative mapping of RNAseq reads to the reference assembly showed that expression of genes with predicted functions in cellular immunity, wound healing, melanization, and the production of reactive oxygen species was transiently induced immediately after immune challenge. In contrast, expression of genes encoding antimicrobial peptides or components of the Toll signaling pathway and iron sequestration response remained elevated for at least 7 days. Numerous genes involved in metabolism and nutrient storage were repressed, indicating a possible cost of immune induction. Strikingly, the expression of almost all antibacterial peptides followed the same pattern of long-lasting induction, regardless of their spectra of activity, signaling possible interactive roles in vivo. Copyright © 2014 Johnston et al.

  9. Different immunization routes induce protection against Aeromonas salmonicida through different immune mechanisms in rainbow trout

    DEFF Research Database (Denmark)

    Villumsen, Kasper Rømer; Raida, Martin Kristian

    in fish immunology and vaccinology, resulting in the development of both oral, immersion and injectable vaccine strategies over time. Applying mineral oil adjuvants, injectable vaccines inducing high levels of protection in salmon (Salmo salar) rose to prominence in the 1990’s. In general injectable......, adjuvanted vaccines have been shown to induce long-lasting increases in specific antibody levels. In general the majority of the published work concerning vaccination against A. salmonicida has been conducted on salmon. Using injectable oil-adjuvanted vaccines, we have previously shown that the induced level...... against A. salmonicida. The effect of immersion vaccination against A. salmonicida has been questioned over time. While some have presented excellent protection as a result of immersion vaccines, others have reported limited or absent protective effects. We have performed experiments on the protection...

  10. Ebola Virus Glycoprotein Induces an Innate Immune Response In vivo via TLR4

    Directory of Open Access Journals (Sweden)

    Chih-Yun Lai

    2017-08-01

    Full Text Available Ebola virus (EBOV, a member of the Filoviridae family, causes the most severe form of viral hemorrhagic fever. Although no FDA licensed vaccine or treatment against Ebola virus disease (EVD is currently available, Ebola virus glycoprotein (GP is the major antigen used in all candidate Ebola vaccines. Recent reports of protection as quickly as within 6 days of administration of the rVSV-based vaccine expressing EBOV GP before robust humoral responses were generated suggests that the innate immune responses elicited early after vaccination may contribute to the protection. However, the innate immune responses induced by EBOV GP in the absence of viral vectors or adjuvants have not been fully characterized in vivo. Our recent studies demonstrated that immunization with highly purified recombinant GP in the absence of adjuvants induced a robust IgG response and partial protection against EBOV infection suggesting that GP alone can induce protective immunity. In this study we investigated the early immune response to purified EBOV GP alone in vitro and in vivo. We show that GP was efficiently internalized by antigen presenting cells and subsequently induced production of key inflammatory cytokines. In vivo, immunization of mice with EBOV GP triggered the production of key Th1 and Th2 innate immune cytokines and chemokines, which directly governed the recruitment of CD11b+ macrophages and CD11c+ dendritic cells to the draining lymph nodes (DLNs. Pre-treatment of mice with a TLR4 antagonist inhibited GP-induced cytokine production and recruitment of immune cells to the DLN. EBOV GP also upregulated the expression of costimulatory molecules in bone marrow derived macrophages suggesting its ability to enhance APC stimulatory capacity, which is critical for the induction of effective antigen-specific adaptive immunity. Collectively, these results provide the first in vivo evidence that early innate immune responses to EBOV GP are mediated via the TLR4

  11. Hydralazine-induced pauci-immune glomerulonephritis: intriguing case series with misleading diagnoses

    Directory of Open Access Journals (Sweden)

    Faizan Babar

    2016-04-01

    Full Text Available Hydralazine has been used since the 1950s for the management of hypertension. Evidence for hydralazine-associated vasculitis dates to pre-ANCA (antineutrophil cytoplasmic antibodies era. This abstract describes two cases of ANCA-positive pauci-immune glomerulonephritis (GN in challenging scenarios where diagnosis was misconstrued. A comprehensive literature review was done to understand the pathogenesis of drug-induced pauci-immune GN. We have described key diagnostic features that are helpful in distinguishing idiopathic ANCA vasculitis from drug-induced vasculitis. Additionally, we have also described different treatments meant to provide therapy options with the least side effects.

  12. A cell wall protein-based vaccine candidate induce protective immune response against Sporothrix schenckii infection.

    Science.gov (United States)

    Portuondo, Deivys Leandro; Batista-Duharte, Alexander; Ferreira, Lucas Souza; Martínez, Damiana Téllez; Polesi, Marisa Campos; Duarte, Roberta Aparecida; de Paula E Silva, Ana Carolina Alves; Marcos, Caroline Maria; Almeida, Ana Marisa Fusco de; Carlos, Iracilda Zeppone

    2016-02-01

    Sporotrichosis is a subcutaneous mycosis caused by several closely related thermo-dimorphic fungi of the Sporothrix schenckii species complex, affecting humans and other mammals. In the last few years, new strategies have been proposed for controlling sporotrichosis owning to concerns about its growing incidence in humans, cats, and dogs in Brazil, as well as the toxicity and limited efficacy of conventional antifungal drugs. In this study, we assessed the immunogenicity and protective properties of two aluminum hydroxide (AH)-adsorbed S. schenckii cell wall protein (ssCWP)-based vaccine formulations in a mouse model of systemic S. schenckii infection. Fractioning by SDS-PAGE revealed nine protein bands, two of which were functionally characterized: a 44kDa peptide hydrolase and a 47kDa enolase, which was predicted to be an adhesin. Sera from immunized mice recognized the 47kDa enolase and another unidentified 71kDa protein, whereas serum from S. schenckii-infected mice recognized both these proteins plus another unidentified 9.4kDa protein. Furthermore, opsonization with the anti-ssCWP sera led to markedly increased phagocytosis and was able to strongly inhibit the fungus' adhesion to fibroblasts. Immunization with the higher-dose AH-adjuvanted formulation led to increased ex vivo release of IL-12, IFN-γ, IL-4, and IL-17, whereas only IL-12 and IFN-γ were induced by the higher-dose non-adjuvanted formulation. Lastly, passive transference of the higher-dose AH-adjuvanted formulation's anti-ssCWP serum was able to afford in vivo protection in a subsequent challenge with S. schenckii, becoming a viable vaccine candidate for further testing. Copyright © 2015 Elsevier GmbH. All rights reserved.

  13. Manganese induced immune suppression of the lobster, Nephrops norvegicus

    International Nuclear Information System (INIS)

    Hernroth, Bodil; Baden, Susanne P.; Holm, Kristina; Andre, Tove; Soederhaell, Irene

    2004-01-01

    Manganese (Mn) is one of the most abundant elements on earth, particularly in the soft bottom sediments of the oceans. As a micronutrient Mn is essential in the metabolic processes of organisms. However, at high concentrations the metal becomes a neurotoxin with well-documented effects. As a consequence of euthrophication, manganese is released from bottom sediments of coastal areas and the Norway lobsters, Nephrops norvegicus, can experience high levels of bioavailable Mn 2+ . Here, we present the first report showing that Mn also affects several fundamental processes in the mobilisation and activation of immunoactive haemocytes. When N. norvegicus was exposed to a realistic [Mn 2+ ] of 20 mg l -1 for 10 days 24.1 μg ml -1 was recorded in the haemolymph. At this concentration the total haemocyte count was reduced by ca. 60%. By using BrdU as a tracer for cell division, it was shown that the proliferation rate in the haematopoietic tissue did not increase, despite the haemocytepenia. A gene coding for a Runt-domain protein, known to be involved in maturation of immune active haemocytes in a variety of organisms, was identified also in haemocytes of N. norvegicus. The expression of this gene was >40% lower in the Mn-exposed lobsters as judged by using a cDNA probe and the in situ hybridisation technique. In response to non-self molecules, like lipopolysaccharide (LPS), the granular haemocytes of arthropods are known to degranulate and thereby release and activate the prophenoloxidase system, necessary for their immune defence. A degranulation assay, tested on isolated granular haemocytes, showed about 75% lower activity in the Mn-exposed lobsters than that for the unexposed. Furthermore, using an enzymatic assay, the activation per se of prophenoloxidase by LPS was found blocked in the Mn-exposed lobsters. Taken together, these results show that Mn exposure suppressed fundamental immune mechanisms of Norway lobsters. This identifies a potential harm that also

  14. Manganese induced immune suppression of the lobster, Nephrops norvegicus

    Energy Technology Data Exchange (ETDEWEB)

    Hernroth, Bodil [Department of Marine Ecology, Goeteborg University, Kristineberg Marine Research Station, SE-450 34 Fiskebaeckskil (Sweden)]. E-mail: bodil.hernroth@kmf.gu.se; Baden, Susanne P. [Department of Marine Ecology, Goeteborg University, Kristineberg Marine Research Station, SE-450 34 Fiskebaeckskil (Sweden); Holm, Kristina [Department of Marine Ecology, Goeteborg University, Kristineberg Marine Research Station, SE-450 34 Fiskebaeckskil (Sweden); Andre, Tove [Department of Comparative Physiology, Evolutionary Biology Centre, Uppsala University, Norbyvaegen 18A, SE-752 36 Uppsala (Sweden); Soederhaell, Irene [Department of Comparative Physiology, Evolutionary Biology Centre, Uppsala University, Norbyvaegen 18A, SE-752 36 Uppsala (Sweden)

    2004-12-10

    Manganese (Mn) is one of the most abundant elements on earth, particularly in the soft bottom sediments of the oceans. As a micronutrient Mn is essential in the metabolic processes of organisms. However, at high concentrations the metal becomes a neurotoxin with well-documented effects. As a consequence of euthrophication, manganese is released from bottom sediments of coastal areas and the Norway lobsters, Nephrops norvegicus, can experience high levels of bioavailable Mn{sup 2+}. Here, we present the first report showing that Mn also affects several fundamental processes in the mobilisation and activation of immunoactive haemocytes. When N. norvegicus was exposed to a realistic [Mn{sup 2+}] of 20 mg l{sup -1} for 10 days 24.1 {mu}g ml{sup -1} was recorded in the haemolymph. At this concentration the total haemocyte count was reduced by ca. 60%. By using BrdU as a tracer for cell division, it was shown that the proliferation rate in the haematopoietic tissue did not increase, despite the haemocytepenia. A gene coding for a Runt-domain protein, known to be involved in maturation of immune active haemocytes in a variety of organisms, was identified also in haemocytes of N. norvegicus. The expression of this gene was >40% lower in the Mn-exposed lobsters as judged by using a cDNA probe and the in situ hybridisation technique. In response to non-self molecules, like lipopolysaccharide (LPS), the granular haemocytes of arthropods are known to degranulate and thereby release and activate the prophenoloxidase system, necessary for their immune defence. A degranulation assay, tested on isolated granular haemocytes, showed about 75% lower activity in the Mn-exposed lobsters than that for the unexposed. Furthermore, using an enzymatic assay, the activation per se of prophenoloxidase by LPS was found blocked in the Mn-exposed lobsters. Taken together, these results show that Mn exposure suppressed fundamental immune mechanisms of Norway lobsters. This identifies a potential

  15. Immune complex modulation by plasma proteins. With special reference to the complement system and autoimmune diseases

    DEFF Research Database (Denmark)

    Baatrup, G

    1989-01-01

    The complement (C) system consists of two activation pathways, the classical and the alternative, which may both be activated by immune complexes (IC). C activation products become attached to the IC during activation leading to profound changes in the properties of the complexes. The common...... inflammation. 5) Tissue damage by activation and/or lysis of bystanding cells. 6) Modulation of B-cell proliferation and differentiation. Activation of the C system by IC is an essential normal component in the clearance of invading foreign material. However, in conditions with a persistent high concentration...... preformed, fluid phase IC (CMS assay). The CMS was found to be dependent upon the alternative pathway of C and facilitated by the classical. Further studies concerning the influence of C deficiencies or depletion of C factors, the concentration of divalent metallions, the temperature and the ionic strength...

  16. CRISPR-based immune systems of the Sulfolobales: complexity and diversity

    DEFF Research Database (Denmark)

    Garrett, Roger Antony; Shah, Shiraz Ali; Vestergaard, Gisle Alberg

    2011-01-01

    CRISPR (cluster of regularly interspaced palindromic repeats)/Cas and CRISPR/Cmr systems of Sulfolobus, targeting DNA and RNA respectively of invading viruses or plasmids are complex and diverse. We address their classification and functional diversity, and the wide sequence diversity of RAMP...... (repeat-associated mysterious protein)-motif containing proteins encoded in Cmr modules. Factors influencing maintenance of partially impaired CRISPR-based systems are discussed. The capacity for whole CRISPR transcripts to be generated despite the uptake of transcription signals within spacer sequences...... is considered. Targeting of protospacer regions of invading elements by Cas protein-crRNA (CRISPR RNA) complexes exhibit relatively low sequence stringency, but the integrity of protospacer-associated motifs appears to be important. Different mechanisms for circumventing or inactivating the immune systems...

  17. Complex structure of type VI peptidoglycan muramidase effector and a cognate immunity protein

    International Nuclear Information System (INIS)

    Wang, Tianyu; Ding, Jinjing; Zhang, Ying; Wang, Da-Cheng; Liu, Wei

    2013-01-01

    The structure of the Tse3–Tsi3 complex associated with the bacterial type VI secretion system of P. aeruginosa has been solved and refined at 1.9 Å resolution. The structural basis of the recognition of the muramidase effector and its inactivation by its cognate immunity protein is revealed. The type VI secretion system (T6SS) is a bacterial protein-export machine that is capable of delivering virulence effectors between Gram-negative bacteria. The T6SS of Pseudomonas aeruginosa transports two lytic enzymes, Tse1 and Tse3, to degrade cell-wall peptidoglycan in the periplasm of rival bacteria that are competing for niches via amidase and muramidase activities, respectively. Two cognate immunity proteins, Tsi1 and Tsi3, are produced by the bacterium to inactivate the two antibacterial effectors, thereby protecting its siblings from self-intoxication. Recently, Tse1–Tsi1 has been structurally characterized. Here, the structure of the Tse3–Tsi3 complex is reported at 1.9 Å resolution. The results reveal that Tse3 contains a C-terminal catalytic domain that adopts a soluble lytic transglycosylase (SLT) fold in which three calcium-binding sites were surprisingly observed close to the catalytic Glu residue. The electrostatic properties of the substrate-binding groove are also distinctive from those of known structures with a similar fold. All of these features imply that a unique catalytic mechanism is utilized by Tse3 in cleaving glycosidic bonds. Tsi3 comprises a single domain showing a β-sandwich architecture that is reminiscent of the immunoglobulin fold. Three loops of Tsi3 insert deeply into the groove of Tse3 and completely occlude its active site, which forms the structural basis of Tse3 inactivation. This work is the first crystallographic report describing the three-dimensional structure of the Tse3–Tsi3 effector–immunity pair

  18. Complex structure of type VI peptidoglycan muramidase effector and a cognate immunity protein

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Tianyu [Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Ding, Jinjing; Zhang, Ying; Wang, Da-Cheng, E-mail: dcwang@ibp.ac.cn [Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101 (China); Liu, Wei, E-mail: dcwang@ibp.ac.cn [The Third Military Medical University, Chongqing 400038 (China); Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101 (China)

    2013-10-01

    The structure of the Tse3–Tsi3 complex associated with the bacterial type VI secretion system of P. aeruginosa has been solved and refined at 1.9 Å resolution. The structural basis of the recognition of the muramidase effector and its inactivation by its cognate immunity protein is revealed. The type VI secretion system (T6SS) is a bacterial protein-export machine that is capable of delivering virulence effectors between Gram-negative bacteria. The T6SS of Pseudomonas aeruginosa transports two lytic enzymes, Tse1 and Tse3, to degrade cell-wall peptidoglycan in the periplasm of rival bacteria that are competing for niches via amidase and muramidase activities, respectively. Two cognate immunity proteins, Tsi1 and Tsi3, are produced by the bacterium to inactivate the two antibacterial effectors, thereby protecting its siblings from self-intoxication. Recently, Tse1–Tsi1 has been structurally characterized. Here, the structure of the Tse3–Tsi3 complex is reported at 1.9 Å resolution. The results reveal that Tse3 contains a C-terminal catalytic domain that adopts a soluble lytic transglycosylase (SLT) fold in which three calcium-binding sites were surprisingly observed close to the catalytic Glu residue. The electrostatic properties of the substrate-binding groove are also distinctive from those of known structures with a similar fold. All of these features imply that a unique catalytic mechanism is utilized by Tse3 in cleaving glycosidic bonds. Tsi3 comprises a single domain showing a β-sandwich architecture that is reminiscent of the immunoglobulin fold. Three loops of Tsi3 insert deeply into the groove of Tse3 and completely occlude its active site, which forms the structural basis of Tse3 inactivation. This work is the first crystallographic report describing the three-dimensional structure of the Tse3–Tsi3 effector–immunity pair.

  19. Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism.

    Science.gov (United States)

    Win, Myint Aung; Thein, Kyaw Zin; Qdaisat, Aiham; Yeung, Sai-Ching Jim

    2017-07-01

    Ipilimumab (a monoclonal antibody against CTLA-4) and nivolumab (a humanized antibody against PD-1) target these immune checkpoint pathways and are used for treatment of melanoma and an increasing number of other cancers. However, they may cause immune-related adverse effects (IRAEs). Although many endocrinopathies are known to be IRAEs, primary hypoparathyroidism with severe hypocalcemia has never been reported. This is the first case of hypoparathyroidism as an IRAE presenting to an Emergency Department with acute hypocalcemia. A 73-year-old man with metastatic melanoma presented to the Emergency Department for the chief complaints of imbalance, general muscle weakness, abdominal pain and tingling in extremities. He had wide spread metastasis, and begun immunotherapy with concurrent ipilimumab and nivolumab 1.5months ago. At presentation, he had ataxia, paresthesia in the hands and feet, and abdominal cramping. Magnetic resonance imaging of the brain was unremarkable. He was found to be hypocalcemic with undetectable plasma parathyroid hormone. He was admitted for treatment of symptomatic hypocalcemia and was diagnosed with primary hypoparathyroidism. Shortly afterwards, he had thyrotoxicosis manifesting as tachycardia and anxiety, followed by development of primary hypothyroidism. At 4months after the Emergency Department visit, his parathyroid function and thyroid function had not recovered, and required continued thyroid hormone replacement and calcium and vitamin D treatment for hypocalcemia. Primary hypoparathyroidism caused by ipilimumab and nivolumab may acute manifest with severe symptomatic hypocalcemia. Emergency care providers should be aware of hypoparathyroidism as a new IRAE in this new era of immuno-oncology. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Nucleic acid-induced antiviral immunity in invertebrates: an evolutionary perspective.

    Science.gov (United States)

    Wang, Pei-Hui; Weng, Shao-Ping; He, Jian-Guo

    2015-02-01

    Nucleic acids derived from viral pathogens are typical pathogen associated molecular patterns (PAMPs). In mammals, the recognition of viral nucleic acids by pattern recognition receptors (PRRs), which include Toll-like receptors (TLRs) and retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), induces the release of inflammatory cytokines and type I interferons (IFNs) through the activation of nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) 3/7 pathways, triggering the host antiviral state. However, whether nucleic acids can induce similar antiviral immunity in invertebrates remains ambiguous. Several studies have reported that nucleic acid mimics, especially dsRNA mimic poly(I:C), can strongly induce non-specific antiviral immune responses in insects, shrimp, and oyster. This behavior shows multiple similarities to the hallmarks of mammalian IFN responses. In this review, we highlight the current understanding of nucleic acid-induced antiviral immunity in invertebrates. We also discuss the potential recognition and regulatory mechanisms that confer non-specific antiviral immunity on invertebrate hosts. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Proliferative, necrotizing and crescentic immune complex-mediated glomerulonephritis in a cat

    Directory of Open Access Journals (Sweden)

    Carolyn Gross

    2015-09-01

    Full Text Available Case Summary A 5-year-old cat was examined for vomiting and anorexia of 2 days’ duration. Azotemia, hyperphosphatemia and hypoalbuminemia were the main biochemical findings. Serial analyses of the urine revealed isosthenuria, proteinuria and eventual glucosuria. Hyperechoic perirenal fat was detected surrounding the right kidney by ultrasonography. Histopathologic evaluation of ante-mortem ultrasound-guided needle biopsies of the right kidney was consistent with proliferative, necrotizing and crescentic glomerulonephritis with fibrin thrombi, proteinaceous and red blood cell casts, and moderate multifocal chronic-active interstitial nephritis. Owing to a lack of clinical improvement, the cat was eventually euthanized. Post-mortem renal biopsies were processed for light microscopy, transmission electron microscopy and immunofluorescence. This revealed severe focal proliferative and necrotizing glomerulonephritis with cellular crescent formation, podocyte injury and secondary segmental sclerosis. Ultrastructural analysis revealed scattered electron-dense deposits in the mesangium, and immunofluorescence demonstrated positive granular staining for λ light chains, consistent with immune complex-mediated glomerulonephritis. Severe diffuse acute tubular epithelial injury and numerous red blood cell casts were also seen. Relevance and novel information To our knowledge, this is the first report of naturally occurring proliferative, necrotizing and crescentic immune complex glomerulonephritis in a cat.

  2. Skin cancer induced by ultraviolet radiation and immunity

    International Nuclear Information System (INIS)

    Sado, Toshihiko

    1977-01-01

    It was clarified that an immunological mechanism, in which the resistance against ultraviolet radiation (UV)-induced neoplasm with strong antigenicity in the body disappeared, was introduced, when the mouse was exposed to UV for two to five weeks. It was also suggested that the immunological mechanism was an induction of T lymphocyte (inhibitive T cells) which had a function to specifically inhibit proliferation of lymphocyte clone which had anti-UV-induced neoplasm activity contained in lymphocyte mass of normal mouse. It can be thought that the action mechanism of this cells may inhibit a process of differentiation of T precursor cells of cell damage, which has anti-UV-induced neoplasm activity, into cell damage T cells. As a mechanism in which such inhibitive T cells are induced, the possibility that specific inhibitive T cells against antigens which are changed by UV would be induced after proteins, which receives some changes in consequence of skin injuries due to UV, are separated from cells as soluble antigens, is thought. Reports of experiments on these problems performed by many researchers were also described. (Tsunoda, M.)

  3. Formation of infectious dengue virus-antibody immune complex in vivo in marmosets (Callithrix jacchus) after passive transfer of anti-dengue virus monoclonal antibodies and infection with dengue virus.

    Science.gov (United States)

    Moi, Meng Ling; Ami, Yasushi; Shirai, Kenji; Lim, Chang-Kweng; Suzaki, Yuriko; Saito, Yuka; Kitaura, Kazutaka; Saijo, Masayuki; Suzuki, Ryuji; Kurane, Ichiro; Takasaki, Tomohiko

    2015-02-01

    Infection with a dengue virus (DENV) serotype induces cross-reactive, weakly neutralizing antibodies to different dengue serotypes. It has been postulated that cross-reactive antibodies form a virus-antibody immune complex and enhance DENV infection of Fc gamma receptor (FcγR)-bearing cells. We determined whether infectious DENV-antibody immune complex is formed in vivo in marmosets after passive transfer of DENV-specific monoclonal antibody (mAb) and DENV inoculation and whether infectious DENV-antibody immune complex is detectable using FcγR-expressing cells. Marmosets showed that DENV-antibody immune complex was exclusively infectious to FcγR-expressing cells on days 2, 4, and 7 after passive transfer of each of the mAbs (mAb 4G2 and mAb 6B6C) and DENV inoculation. Although DENV-antibody immune complex was detected, contribution of the passively transferred antibody to overall viremia levels was limited in this study. The results indicate that DENV cross-reactive antibodies form DENV-antibody immune complex in vivo, which is infectious to FcγR-bearing cells but not FcγR-negative cells. © The American Society of Tropical Medicine and Hygiene.

  4. Intranasal immunization with protective antigen of Bacillus anthracis induces a long-term immunological memory response.

    Science.gov (United States)

    Woo, Sun-Je; Kang, Seok-Seong; Park, Sung-Moo; Yang, Jae Seung; Song, Man Ki; Yun, Cheol-Heui; Han, Seung Hyun

    2015-10-01

    Although intranasal vaccination has been shown to be effective for the protection against inhalational anthrax, establishment of long-term immunity has yet to be achieved. Here, we investigated whether intranasal immunization with recombinant protective antigen (rPA) of Bacillus anthracis induces immunological memory responses in the mucosal and systemic compartments. Intranasal immunization with rPA plus cholera toxin (CT) sustained PA-specific antibody responses for 6 months in lung, nasal washes, and vaginal washes as well as serum. A significant induction of PA-specific memory B cells was observed in spleen, cervical lymph nodes (CLNs) and lung after booster immunization. Furthermore, intranasal immunization with rPA plus CT remarkably generated effector memory CD4(+) T cells in the lung. PA-specific CD4(+) T cells preferentially increased the expression of Th1- and Th17-type cytokines in lung, but not in spleen or CLNs. Collectively, the intranasal immunization with rPA plus CT promoted immunologic memory responses in the mucosal and systemic compartments, providing long-term immunity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Suppressed neural complexity during ketamine- and propofol-induced unconsciousness.

    Science.gov (United States)

    Wang, Jisung; Noh, Gyu-Jeong; Choi, Byung-Moon; Ku, Seung-Woo; Joo, Pangyu; Jung, Woo-Sung; Kim, Seunghwan; Lee, Heonsoo

    2017-07-13

    Ketamine and propofol have distinctively different molecular mechanisms of action and neurophysiological features, although both induce loss of consciousness. Therefore, identifying a common feature of ketamine- and propofol-induced unconsciousness would provide insight into the underlying mechanism of losing consciousness. In this study we search for a common feature by applying the concept of type-II complexity, and argue that neural complexity is essential for a brain to maintain consciousness. To test this hypothesis, we show that complexity is suppressed during loss of consciousness induced by ketamine or propofol. We analyzed the randomness (type-I complexity) and complexity (type-II complexity) of electroencephalogram (EEG) signals before and after bolus injection of ketamine or propofol. For the analysis, we use Mean Information Gain (MIG) and Fluctuation Complexity (FC), which are information-theory-based measures that quantify disorder and complexity of dynamics respectively. Both ketamine and propofol reduced the complexity of the EEG signal, but ketamine increased the randomness of the signal and propofol decreased it. The finding supports our claim and suggests EEG complexity as a candidate for a consciousness indicator. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Downmodulation of Vaccine-Induced Immunity and Protection against the Intracellular Bacterium Francisella tularensis by the Inhibitory Receptor FcγRIIB

    Directory of Open Access Journals (Sweden)

    Brian J. Franz

    2015-01-01

    Full Text Available Fc gamma receptor IIB (FcγRIIB is the only Fc gamma receptor (FcγR which negatively regulates the immune response, when engaged by antigen- (Ag- antibody (Ab complexes. Thus, the generation of Ag-specific IgG in response to infection or immunization has the potential to downmodulate immune protection against infection. Therefore, we sought to determine the impact of FcγRIIB on immune protection against Francisella tularensis (Ft, a Category A biothreat agent. We utilized inactivated Ft (iFt as an immunogen. Naïve and iFt-immunized FcγRIIB knockout (KO or wildtype (WT mice were challenged with Ft-live vaccine strain (LVS. While no significant difference in survival between naïve FcγRIIB KO versus WT mice was observed, iFt-immunized FcγRIIB KO mice were significantly better protected than iFt-immunized WT mice. Ft-specific IgA in serum and bronchial alveolar lavage, as well as IFN-γ, IL-10, and TNF-α production by splenocytes harvested from iFt-immunized FcγRIIB KO, were also significantly elevated. In addition, iFt-immunized FcγRIIB KO mice exhibited a reduction in proinflammatory cytokine levels in vivo at 5 days after challenge, which correlates with increased survival following Ft-LVS challenge in published studies. Thus, these studies demonstrate for the first time the ability of FcγRIIB to regulate vaccine-induced IgA production and downmodulate immunity and protection. The immune mechanisms behind the above observations and their potential impact on vaccine development are discussed.

  7. Perillyl alcohol suppresses antigen-induced immune responses in the lung

    Energy Technology Data Exchange (ETDEWEB)

    Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide; Nakagome, Kazuyuki; Harada, Hiroaki; Kawahata, Kimito; Tanaka, Ryoichi; Yamamoto, Kazuhiko [Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Dohi, Makoto, E-mail: mdohi-tky@umin.ac.jp [Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Institute of Respiratory Immunology, Shibuya Clinic for Respiratory Diseases and Allergology, Tokyo (Japan)

    2014-01-03

    Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4{sup +} T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4{sup +} T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.

  8. Odorant cues linked to social immunity induce lateralized antenna stimulation in honey bees (Apis mellifera L.).

    Science.gov (United States)

    McAfee, Alison; Collins, Troy F; Madilao, Lufiani L; Foster, Leonard J

    2017-04-07

    Hygienic behaviour (HB) is a social immunity trait in honey bees (Apis mellifera L.) whereby workers detect, uncap and remove unhealthy brood, improving disease resistance in the colony. This is clearly economically valuable; however, the molecular mechanism behind it is not well understood. The freeze-killed brood (FKB) assay is the conventional method of HB selection, so we compared odour profiles of FKB and live brood to find candidate HB-inducing odours. Surprisingly, we found that significantly more brood pheromone (β-ocimene) was released from FKB. β-ocimene abundance also positively correlated with HB, suggesting there could be a brood effect contributing to overall hygiene. Furthermore, we found that β-ocimene stimulated worker antennae in a dose-dependent manner, with the left antennae responding significantly stronger than right antennae in hygienic bees, but not in non-hygienic bees. Five other unidentifiable compounds were differentially emitted from FKB which could also be important for HB. We also compared odour profiles of Varroa-infested brood to healthy brood and found an overall interactive effect between developmental stage and infestation, but specific odours did not drive these differences. Overall, the data we present here is an important foundation on which to build our understanding the molecular mechanism behind this complex behaviour.

  9. Oil price induced gas acquisition contracts. Immune to price changes; Oelpreisindizierte Gasbezugsvertraege. Immun gegen Preisaenderungen

    Energy Technology Data Exchange (ETDEWEB)

    Verhoeven, Meike [Soptim AG, Aachen (Germany)

    2012-10-15

    The gas price continues to be linked to the oil price. Gas utilities that must buy gas in these conditions and sell it at a fixed price incur considerable financial risk. Especially with long-term buying contracts, and especially for gas from Russia, producers insist on linking to the oil price. Gas utilities, on the other hand, had to stop to sell gas at a price linked to the oil price two years ago. Utilities attempt to protect themselves, e.g. via oil swaps. Professional portfolio management is necessary to cope with the risks and the highly complex processes involved.

  10. Nickel-induced hypersensitivity: etiology, immune reactions, prevention and therapy.

    Science.gov (United States)

    Hostýnek, Jurij J

    2002-08-01

    As a contact allergen causing type I and type IV hypersensitivity, mediated by reagins and allergen-specific T lymphocytes, expressed in a wide range of cutaneous eruptions following dermal or systemic exposure, nickel has acquired the distinction of being among the most frequent causes of hypersensitivity, occupationally as well as among the general population. In synoptic form the many effects that nickel has on the organism are presented, to provide a comprehensive picture of the aspects of that metal with many biologically noxious, but metallurgically indispensable characteristics. This paper reviews the epidemiology, the prognosis for occupational and non-occupational nickel allergic hypersensitivity (NAH), the many types of exposure and the resulting immune responses, immunotoxicity and rate of diffusion through the skin. Alternatives towards prevention and remediation, topical and systemic, for this pervasive and increasing form of morbidity resulting from multiple types of exposure are discussed. Merits and limitations of preventive measures in industry and private life are considered, as well as the effectiveness of topical and systemic therapy in treating NAH.

  11. Does exposure to UV radiation induce a shift to a Th-2-like immune reaction?

    International Nuclear Information System (INIS)

    Ullrich, S.E.

    1996-01-01

    In addition to being the primary cause of skin cancer, UV radiation is immune suppressive and there appears to be a link between the ability of UV to suppress the immune response and induce skin cancer. Cytokines made by UV-irradiated keratinocytes play an essential role in activating immune suppression. In particular, we have found that keratinocyte-derived interleukin (IL)-10 is responsible for the systemic impairment of antigen presenting cell function and the UV-induced suppression of delayed-type hypersenstivity (DTH). Antigen presentation by splenic adherent cells isolated from UV-irradiated mice to T helper-1 type T (Th1) cells is suppressed, whereas antigen presentation to T helper-2 type T (Th2) cells is enhanced. The enhanced antigen presentation to Th2 cells and the impaired presentation to Th1 cells can be reversed in vivo by injecting the UV-irradiated mice with monoclonal anti-IL-10 antibody. Furthermore, immune suppression can be transferred from UV-irradiated mice to normal recipients by adoptive transfer of T cells. Injecting the recipient mice with anti-IL-4 or anti-IL-10 prevents the transfer of immune suppression, suggesting the suppressor cells are Th2 cells. In addition, injecting UV-irradiated mice with IL-12, a cytokine that has been shown to be the primary inducer of Th1 cells, and one that prevents the differentiation of Th2 cells in vivo, reverses UV-induced immune suppression. These findings support the hypothesis that UV exposure activates IL-10 secretion, which depresses the function of Th1 cells, while enhancing the activity of Th2 cells. (Author)

  12. DNA-protein complexes induced by chromate and other carcinogens

    International Nuclear Information System (INIS)

    Costa, M.

    1991-01-01

    DNA-protein complexes induced in intact Chinese hamster ovary cells by chromate have been isolated, analyzed, and compared with those induced by cis-platinum, ultraviolet light, and formaldehyde. Actin has been identified as one of the major proteins complexed to DNA by chromate based upon its molecular weight, isoelectric point, positive reaction with an actin polyclonal antibody, and proteolytic mapping. Chromate and cis-platinum both complex proteins of similar molecular weight and isoelectric point, positive reaction with an actin polyclonal antibody, and proteolytic mapping. Chromate and cis-platinum both complex proteins of similar molecular weight and isoelectric points, and these complexes can be disrupted by chelating agents and sulfhydryl reducing agents, suggesting that the metal itself is participating in binding rather than having a catalytic or indirect role (i.e., oxygen radicals). In contrast, formaldehyde complexed histones to the DNA, and these complexes were not disrupted by chelating or reducing agents. An antiserum raised to chromate-induced DNA-protein complexes reacted primarily with 97,000 kDa protein that did not silver stain. Slot blots, as well as Western blots, were used to detect formation of p97 DNA crosslinks. This protein was complexed to the DNA by all four agents studied

  13. Fungal innate immunity induced by bacterial microbe-associated molecular patterns (MAMPs)

    DEFF Research Database (Denmark)

    Ip Cho, Simon; Sundelin, Thomas; Erbs, Gitte

    2016-01-01

    Plants and animals detect bacterial presence through Microbe-Associated Molecular Patterns (MAMPs) which induce an innate immune response. The field of fungal-bacterial interaction at the molecular level is still in its infancy and little is known about MAMPs and their detection by fungi. Exposin...

  14. Relish2 mediates bursicon homodimer-induced prophylactic immunity in the mosquito Aedes aegypti

    Science.gov (United States)

    Bursicon is a neuropeptide hormone consisting of two cystine-knot proteins (burs a and burs ß), responsible for cuticle tanning and other developmental processes in insects. Recent studies show that each bursicon subunit forms homodimers that induce prophylactic immunity in Drosophila melanogaster. ...

  15. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens

    Science.gov (United States)

    Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte...

  16. Immunity induced by a broad class of inorganic crystalline materials is directly controlled by their chemistry

    NARCIS (Netherlands)

    G.R. Williams (Gareth); K. Fierens (Kaat); S.G. Preston (Stephen); A.C. Lunn; O. Rysnik (Oliwia); S. de Prijck (Sofie); M. Kool (Mirjam); H.C. Buckley (Hannah); B.N.M. Lambrecht (Bart); D. O'Hare (Dermot); J.M. Austyn (Jonathan)

    2014-01-01

    textabstractThere is currently no paradigm in immunology that enables an accurate prediction of how the immune system will respond to any given agent. Here we show that the immunological responses induced by members of a broad class of inorganic crystalline materials are controlled purely by their

  17. Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites.

    Directory of Open Access Journals (Sweden)

    Jayanthi Santhanam

    2014-01-01

    Full Text Available Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS by a virulent clone (AJ in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs, background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter μ, the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, μ was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but

  18. Immune response to UV-induced tumors: mediation of progressor tumor rejection by natural killer cells

    International Nuclear Information System (INIS)

    Streeter, P.R.; Fortner, G.W.

    1986-01-01

    Skin tumors induced in mice by chronic ultraviolet (UV) irradiation are highly antigenic and can induce a state of transplantation immunity in syngeneic animals. In the present study, the authors compared the in vitro cytolytic activity of splenic lymphocytes from mice immunized with either regressor or progressor UV-tumors. The results of this comparison implicated tumor-specific cytolytic T (Tc) lymphocytes in rejection of regressor UV-tumors, and revealed that immunization with the progressor UV-tumor 2237 failed to elicit detectable levels of progressor tumor-specific Tc cells even as the tumors rejected. Following in vitro resensitization of spleen cells from either regressor or progressor tumor immune animals, the authors found NK-like lymphocytes with anti-tumor activity. As the authors had not detected cells with this activity in splenic lymphocyte preparations prior to in vitro resensitization, the authors examined lymphocytes from the local tumor environment during the course of progressor tumor rejection for this activity. This analysis revealed NK lymphocytes exhibiting significant levels of cytolytic activity against UV-tumors. These results implicate NK cells as potential effector cells in the rejection of progressor UV-tumors by immune animals, and suggests that these cells may be regulated by T lymphocytes

  19. Inactivated rotavirus vaccine induces protective immunity in gnotobiotic piglets.

    Science.gov (United States)

    Wang, Yuhuan; Azevedo, Marli; Saif, Linda J; Gentsch, Jon R; Glass, Roger I; Jiang, Baoming

    2010-07-26

    Live oral rotavirus vaccines that are effective in middle and high income countries have been much less immunogenic and effective among infants in resource-limited settings. Several hypotheses might explain this difference, including neutralization of the vaccine by high levels of maternal antibody in serum and breast milk, severe malnutrition, and interference by other flora and viruses in the gut. We have pursued development of an alternative parenteral rotavirus vaccine with the goal of inducing comparable levels of immunogenicity and efficacy in populations throughout the world regardless of their income levels. In the present study, we assessed the immunogenicity and protection of a candidate inactivated rotavirus vaccine (IRV), the human strain CDC-9 (G1P[8]) formulated with aluminum phosphate, against rotavirus infection in gnotobiotic piglets. Three doses of IRV induced high titers of rotavirus-specific IgG and neutralizing activity in the sera of gnotobiotic piglets and protection against shedding of rotavirus antigen following oral challenge with a homologous virulent human strain Wa (G1P[8]). Our findings demonstrate the proof of concept for an IRV in a large animal model and provide evidence and justification for further clinical development as an alternative candidate vaccine. Published by Elsevier Ltd.

  20. Outer membrane vesicles of Gallibacterium anatis induce protective immunity in egg-laying hens.

    Science.gov (United States)

    Pors, Susanne E; Pedersen, Ida J; Skjerning, Ragnhild Bager; Thøfner, Ida C N; Persson, Gry; Bojesen, Anders M

    2016-11-15

    Gallibacterium anatis causes infections in the reproductive tract of egg-laying hens and induce increased mortality and decreased egg production. New prophylactic measures are needed in order to improve animal welfare and production efficiency. Bacterial outer membrane vesicles (OMVs) have previously shown promising results in protection against infections and we hypothesized that OMVs could serve as an immunogen to protect egg-laying hens against G. anatis. To investigate the immunogenic potential of G. anatis OMVs, two in vivo studies in egg-laying hens were made. The trials assessedthe degree of protection provided by immunization with G. anatis OMV against challenge and the IgY responses in serum after immunization and challenge, respectively. A total of 64 egg-laying hens were included in the trials. OMVs for immunization were produced and purified from a high-producing G. anatis ΔtolR mutant. Challenge was done with G. anatis 12656-12 and evaluated by scoring lesions and bacterial re-isolation rates from peritoneum. Finally, levels of OMV-specific IgY in sera were assayed by ELISA. Immunization with OMVs decreased the lesions scores significantly, while the bacterial re-isolation remained unchanged. Furthermore, a high OMV-specific IgY response was induced by immunization and subsequent challenge of the hens. The results strongly indicate that immunization with G. anatis OMVs provides significant protection against G. anatis challenge and induces specific antibody responses with high titers of OMV-specific IgY in serum. The results therefore show great promise for OMV based vaccines aiming at providing protecting against G. anatis in egg-laying hens. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Trivalent combination vaccine induces broad heterologous immune responses to norovirus and rotavirus in mice.

    Directory of Open Access Journals (Sweden)

    Kirsi Tamminen

    Full Text Available Rotavirus (RV and norovirus (NoV are the two major causes of viral gastroenteritis (GE in children worldwide. We have developed an injectable vaccine design to prevent infection or GE induced with these enteric viruses. The trivalent combination vaccine consists of NoV capsid (VP1 derived virus-like particles (VLPs of GI-3 and GII-4 representing the two major NoV genogroups and tubular RV recombinant VP6 (rVP6, the most conserved and abundant RV protein. Each component was produced in insect cells by a recombinant baculovirus expression system and combined in vitro. The vaccine components were administered intramuscularly to BALB/c mice either separately or in the trivalent combination. High levels of NoV and RV type specific serum IgGs with high avidity (>50% as well as intestinal IgGs were detected in the immunized mice. Cross-reactive IgG antibodies were also elicited against heterologous NoV VLPs not used for immunization (GII-4 NO, GII-12 and GI-1 VLPs and to different RVs from cell cultures. NoV-specific serum antibodies blocked binding of homologous and heterologous VLPs to the putative receptors, histo-blood group antigens, suggesting broad NoV neutralizing activity of the sera. Mucosal antibodies of mice immunized with the trivalent combination vaccine inhibited RV infection in vitro. In addition, cross-reactive T cell immune responses to NoV and RV-specific antigens were detected. All the responses were sustained for up to six months. No mutual inhibition of the components in the trivalent vaccine combination was observed. In conclusion, the NoV GI and GII VLPs combination induced broader cross-reactive and potentially neutralizing immune responses than either of the VLPs alone. Therefore, trivalent vaccine might induce protective immune responses to the vast majority of circulating NoV and RV genotypes.

  2. Detection of circulating immune complexes by Raji cell assay: comparison of flow cytometric and radiometric methods

    International Nuclear Information System (INIS)

    Kingsmore, S.F.; Crockard, A.D.; Fay, A.C.; McNeill, T.A.; Roberts, S.D.; Thompson, J.M.

    1988-01-01

    Several flow cytometric methods for the measurement of circulating immune complexes (CIC) have recently become available. We report a Raji cell flow cytometric assay (FCMA) that uses aggregated human globulin (AHG) as primary calibrator. Technical advantages of the Raji cell flow cytometric assay are discussed, and its clinical usefulness is evaluated in a method comparison study with the widely used Raji cell immunoradiometric assay. FCMA is more precise and has greater analytic sensitivity for AHG. Diagnostic sensitivity by the flow cytometric method is superior in systemic lupus erythematosus (SLE), rheumatoid arthritis, and vasculitis patients: however, diagnostic specificity is similar for both assays, but the reference interval of FCMA is narrower. Significant correlations were found between CIC levels obtained with both methods in SLE, rheumatoid arthritis, and vasculitis patients and in longitudinal studies of two patients with cerebral SLE. The Raji cell FCMA is recommended for measurement of CIC levels to clinical laboratories with access to a flow cytometer

  3. Serum and plasma fibronectin binds to complement reacted immune complexes primarily via Clq

    DEFF Research Database (Denmark)

    Baatrup, G; Svehag, S E

    1986-01-01

    The binding of fibronectin to human Clq, C3b, and complement-reacted immune complexes (IC) was investigated by enzyme-linked immunosorbent assays. Microplates were coated with BSA followed by incubation with rabbit-anti-BSA IgG or F(ab')2 fragments of rabbit anti-BSA. Incubation of the solid phase...... with serum at 37 degrees C caused attachment of Clq and C3b. Addition of EDTA to the serum inhibited the binding of C3b, but not Clq, whereas substitution of the anti-BSA IgG on the solid phase with the F(ab')2 fragments abrogated the Clq, but not the C3b binding. Fibronectin binding was observed after...

  4. Polysaccharides isolated from Açaí fruit induce innate immune responses.

    Directory of Open Access Journals (Sweden)

    Jeff Holderness

    2011-02-01

    Full Text Available The Açaí (Acai fruit is a popular nutritional supplement that purportedly enhances immune system function. These anecdotal claims are supported by limited studies describing immune responses to the Acai polyphenol fraction. Previously, we characterized γδ T cell responses to both polyphenol and polysaccharide fractions from several plant-derived nutritional supplements. Similar polyphenol and polysaccharide fractions are found in Acai fruit. Thus, we hypothesized that one or both of these fractions could activate γδ T cells. Contrary to previous reports, we did not identify agonist activity in the polyphenol fraction; however, the Acai polysaccharide fraction induced robust γδ T cell stimulatory activity in human, mouse, and bovine PBMC cultures. To characterize the immune response to Acai polysaccharides, we fractionated the crude polysaccharide preparation and tested these fractions for activity in human PBMC cultures. The largest Acai polysaccharides were the most active in vitro as indicated by activation of myeloid and γδ T cells. When delivered in vivo, Acai polysaccharide induced myeloid cell recruitment and IL-12 production. These results define innate immune responses induced by the polysaccharide component of Acai and have implications for the treatment of asthma and infectious disease.

  5. Tyrosine kinase inhibitors induced immune thrombocytopenia in chronic myeloid leukemia?

    Directory of Open Access Journals (Sweden)

    Avital F. Barak

    2011-12-01

    Full Text Available The outcome and quality of life of chronic myeloid leukemia (CML patients has remarkably changed with the treatment of tyrosine kinase inhibitors (TKIs. Currently, hematopoietic stem cell transplantation (HSCT is considered mainly as a third line salvage therapy in cases of TKIs resistance or intolerance. Here we describe a patient with chronic phase CML who developed both resistance and late occurrence of s severe thrombocytopenia on first and second generation TKIs and eventually underwent HSCT. Although the mechanism of the myelosuppression is not fully understood, we showed for the first time the development of dose dependent platelet antibodies in the presence of TKIs, suggesting the possibility of TKIs induced thrombocytopenia. Our case emphasizes that late development of severe myelosuppression during imatinib treatment is probably an important indication for consideration of early HSCT.

  6. Ultraviolet light-denatured DNA/anti-ultraviolet light-denatured DNA immune-complex nephritis in rabbits

    International Nuclear Information System (INIS)

    Sweny, P.

    1980-01-01

    Two groups of preimmunized rabbits were studied during a 3-month course of daily intravenous injections of uv DNA in amounts sufficient to neuralize circulating antibody. One group was given high-molecular-weight uv DNA, and the other group, US uv DNA. Rabbits receiving US uv DNA formed potentially more damaging immune complexes, since this group of animals developed greater rises in blood urea and greater falls in C3. Both groups of animals developed evidence of immune complex-mediated glomerular nephritis as evidenced by heavy granular deposits of IgG and C3 in the glomeruli. The results suggest that immune complexes formed with US uv DNA may be more nephrotoxic

  7. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level.

    Science.gov (United States)

    Brommer, Benedikt; Engel, Odilo; Kopp, Marcel A; Watzlawick, Ralf; Müller, Susanne; Prüss, Harald; Chen, Yuying; DeVivo, Michael J; Finkenstaedt, Felix W; Dirnagl, Ulrich; Liebscher, Thomas; Meisel, Andreas; Schwab, Jan M

    2016-03-01

    Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS ('immune paralysis'), sufficient to propagate clinically relevant infection in an injury level dependent manner. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Beryllium-induced immune response in C3H mice

    Energy Technology Data Exchange (ETDEWEB)

    Benson, J.M.; Bice, D.E.; Nikula, K.J. [and others

    1995-12-01

    Studies conducted at ITRI over the past several years have investigated whether Beagle dogs, monkeys, and mice are suitable models for human chronic beryllium-induced lung disease (CBD). Recent studies have focused on the histopathological and immunopathological changes occurring in A/J and C3H/HeJ mice acutely exposed by inhalation to Be metal. Lung lesions in both strains of mice included focal lymphocyte aggregates comprised primarily of B lymphocytes and lesser amounts of T-helper lymphocytes and microgranulomas consisting chiefly of macrophages and T-helper lymphocytes. The distribution of proliferating cells within the microgranulomas was similar to the distribution of T-helper cells. These results strongly suggested that A/J and C3H/HeJ mice responded to inhaled Be metal in a fashion similar to humans in terms of pulmonary lesions and the apparent in situ proliferation of T-helper cells. Results of these studies confirm lymphocyte involvement in the pulmonary response to inhaled Be metal.

  9. Immune-mediated steroid-responsive epileptic spasms and epileptic encephalopathy associated with VGKC-complex antibodies.

    Science.gov (United States)

    Suleiman, Jehan; Brenner, Tanja; Gill, Deepak; Troedson, Christopher; Sinclair, Adriane J; Brilot, Fabienne; Vincent, Angela; Lang, Bethan; Dale, Russell C

    2011-11-01

    Autoantibodies that bind to voltage-gated potassium-channel complex proteins (VGKC-complex antibodies) occur frequently in adults with limbic encephalitis presenting with cognitive impairment and seizures. Recently, VGKC-complex antibodies have been described in a few children with limbic encephalitis, and children with unexplained encephalitis presenting with status epilepticus. We report a case of infantile-onset epileptic spasms and developmental delay compatible with epileptic encephalopathy. Our patient was a female infant, aged 4 months at presentation. She had evidence of immune activation in the central nervous system with elevated cerebrospinal fluid neopterin and mirrored oligoclonal bands, which prompted testing for autoantibodies. VGKC-complex antibodies were elevated (201 pmol/L, normalVGKC-complex antibodies might represent a marker of immune therapy responsiveness in a subgroup of patients with infantile epileptic encephalopathy. © The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.

  10. Investigations of immunoglobulins, circulating immune complexes and plasma free hemoglobin in cancer patients on 60Co gamma-ray therapy

    International Nuclear Information System (INIS)

    Horvath, M.; Rode, I.L.; Fekete, B.; Kiss, B.; Ringwald, G.

    1981-01-01

    32 patients with different tumours were irradiated by 60 Co gamma-rays. During therapy lasting for several weeks, changes in the content of immunoglobulin and of some other serum proteins, circulating immune complexes and plasma free hemoglobin were determined. Immunosuppression according to immunoglobulin content in serum was not produced by this type of radiation. Decrease in immune complex levels was a good prognostic sign. Low values of plasma hemoglobin content during treatment indicated that no erythrocyte membrane damage had been effected. (orig.) [de

  11. Low-dose radiation induces drosophila innate immunity through toll pathway activation

    International Nuclear Information System (INIS)

    Seong, Ki Moon; Kim, Cha Soon; Lee, Byung-Sub; Nam, Seon Young; Yang, Kwang Hee; Kim, Ji-Young; Jin, Young-Woo; Park, Joong-Jean; Min, Kyung-Jin

    2012-01-01

    Numerous studies report that exposing certain organisms to low-dose radiation induces beneficial effects on lifespan, tumorigenesis, and immunity. By analyzing survival after bacterial infection and antimicrobial peptide gene expression in irradiated flies, we demonstrate that low-dose irradiation of Drosophila enhances innate immunity. Low-dose irradiation of flies significantly increased resistance against gram-positive and gram-negative bacterial infections, as well as expression of several antimicrobial peptide genes. Additionally, low-dose irradiation also resulted in a specific increase in expression of key proteins of the Toll signaling pathway and phosphorylated forms of p38 and N-terminal kinase (JNK). These results indicate that innate immunity is activated after low-dose irradiation through Toll signaling pathway in Drosophila. (author)

  12. Can VHS virus bypass the protective immunity induced by DNA vaccination in rainbow trout?

    DEFF Research Database (Denmark)

    Sepúlveda, Dagoberto; Lorenzen, Niels

    2016-01-01

    DNA vaccines encoding viral glycoproteins have been very successful for induction of protective immunity against diseases caused by rhabdoviruses in cultured fish species. However, the vaccine concept is based on a single viral gene and since RNA viruses are known to possess high variability...... and adaptation capacity, this work aimed at evaluating whether viral haemorrhagic septicaemia virus (VHSV), an RNA virus and member of Rhabdoviridae family, was able to evade the protective immune response induced by the DNA vaccination of rainbow trout. The experiments comprised repeated passages of a highly...... pathogenic VHSV isolate in a fish cell line in the presence of neutralizing fish serum (in vitro approach), and in rainbow trout immunized with the VHS DNA vaccine (in vivo approach). For the in vitro approach, the virus collected from the last passage (passaged virus) was as sensitive as the parental virus...

  13. Evidence of a Redox-Dependent Regulation of Immune Responses to Exercise-Induced Inflammation

    Directory of Open Access Journals (Sweden)

    Alexandra Sakelliou

    2016-01-01

    Full Text Available We used thiol-based antioxidant supplementation (n-acetylcysteine, NAC to determine whether immune mobilisation following skeletal muscle microtrauma induced by exercise is redox-sensitive in healthy humans. According to a two-trial, double-blind, crossover, repeated measures design, 10 young men received either placebo or NAC (20 mg/kg/day immediately after a muscle-damaging exercise protocol (300 eccentric contractions and for eight consecutive days. Blood sampling and performance assessments were performed before exercise, after exercise, and daily throughout recovery. NAC reduced the decline of reduced glutathione in erythrocytes and the increase of plasma protein carbonyls, serum TAC and erythrocyte oxidized glutathione, and TBARS and catalase activity during recovery thereby altering postexercise redox status. The rise of muscle damage and inflammatory markers (muscle strength, creatine kinase activity, CRP, proinflammatory cytokines, and adhesion molecules was less pronounced in NAC during the first phase of recovery. The rise of leukocyte and neutrophil count was decreased by NAC after exercise. Results on immune cell subpopulations obtained by flow cytometry indicated that NAC ingestion reduced the exercise-induced rise of total macrophages, HLA+ macrophages, and 11B+ macrophages and abolished the exercise-induced upregulation of B lymphocytes. Natural killer cells declined only in PLA immediately after exercise. These results indicate that thiol-based antioxidant supplementation blunts immune cell mobilisation in response to exercise-induced inflammation suggesting that leukocyte mobilization may be under redox-dependent regulation.

  14. Isolation and Purification of an Antibacterial Protein from Immune Induced Haemolymph of American Cockroach, Periplaneta americana

    Directory of Open Access Journals (Sweden)

    Hamid Reza Basseri

    2016-10-01

    Full Text Available Background: Antimicrobial peptides play a role as effectors substances in the immunity of vertebrate and inverte­brate hosts. In the current study, antimicrobial peptide was isolated from the haemolymph of the American cock­roach, Periplaneta americana.Methods: Micrococcus luteus as Gram-positive bacteria and Escherichia coli as Gram-negative bacteria were candi­date for injection. Induction was done by injecting both bacteria into the abdominal cavity of two groups of cock­roaches separately. The haemolymphs were collected 24 hours after post injection and initially tested against both bacteria. Subsequently, the immune induced haemolymph was purified by high performance liquid chromatography (HPLC to separate the proteins responsible for the antibacterial activity.Results: The non-induced haemolymph did not show any activity against both bacteria whereas induced haemo­lymph exhibited high activity against M. luteus but did less against E. coli. Two fractions showed antibacterial activ­ity against M. luteus. Finally the molecular weight of the isolated antibacterial proteins were determined as 72 kDa and 62 kDa using SDS-PAGE.Conclusion: Induced haemolymph of American cockroaches has the ability to produce peptides to combat against Gram-positive bacteria when an immune challenge is mounted. Further work has to be done to sequence of the pro­tein, which it would be advantageous.

  15. Inflammation promotes oral squamous carcinoma immune evasion via induced programmed death ligand-1 surface expression.

    Science.gov (United States)

    Lu, Wanlu; Lu, Libing; Feng, Yun; Chen, Jiao; Li, Yan; Kong, Xiangli; Chen, Sixiu; Li, Xiaoyu; Chen, Qianming; Zhang, Ping

    2013-05-01

    The association between inflammation and cancer provides a new target for tumor biotherapy. The inflammatory cells and molecules within the tumor microenvironment have decisive dual roles in antitumor immunity and immune evasion. In the present study, phytohemagglutinin (PHA) was used to stimulate peripheral blood mononuclear cells (PBMCs) to simulate the tumor inflammatory microenvironment. The effect of immune cells and inflammatory cytokines on the surface expression of programmed cell death-1 ligand 1 (PD-L1) and tumor immune evasion was investigated using flow cytometry (FCM) and an in vivo xenotransplantation model. Based on the data, PHA-activated, but not resting, immune cells were able to promote the surface expression of PD-L1 in Tca8113 oral squamous carcinoma cells via the secretion of inflammatory cytokines, but not by cell-cell contact. The majority of the inflammatory cytokines had no significant effect on the proliferation, cell cycle progression and apoptosis of the Tca8113 cells, although they each induced the expression of PD-L1 in a dose-dependent manner. In total, 99% of the Tca8113 cells expressed PD-L1 following treatment with the supernatant of PHA-stimulated PBMCs. The PHA-supernatant pretreated Tca8113 cells unusually induced Tca8113 antigen-specific CD8 + T cell apoptosis in vitro and the evasion of antigen-specific T cell attraction in a nude mouse tumor-bearing model. These results indicate a new mechanism for the promotion of tumor immune evasion by the tumor inflammatory microenvironment.

  16. Hepatitis B circulating immune complexes. Characterization by radioimmunoprecipitation - PEG assay (ripega)

    Energy Technology Data Exchange (ETDEWEB)

    Santoro, F; Wattre, P; Dessaint, J P; Capron, A [Institut Pasteur de Lille, 59 - Villeneuve d' Ascq (France)

    1977-04-01

    Incidence of circulating immune complexes (IC) was investigated in carriers of hepatitis B antigen (HBAg) and/or anti-HB antibodies (anti-HBAb). Three methods were used: radiolabelled C1q binding test (C1qBT), complement fixation test (CFT), and optical density (OD) measurement after dissolution of 3% polyethylene glycol (PEG) precipitate of serum. A highly significant correlation was obtained between these three techniques. The level of IC was higher in carriers of HBAg without anti-HBAb than in others. The characterization of HBAg and anti-HBAb in IC was carried out by a new procedure, the radioimmunoprecipitation-PEG assay (RIPEGA). This sensitive and reproducible test was performed by incubation of /sup 125/I-HBAg or /sup 125/I-HBAg with 3% precipitate of the carriers' sera. Separation of free from complexed /sup 125/I-HBAg or /sup 125/I-HBAb was achieved by PEG precipitation. A highly significant correlation was found between the levels of circulating IC evaluated by the C1q-BT and the quantities of HBAg or anti HBAb measured by RIPEGA. RIPEGA was used to quantify HBAg and anti-HBAb present in serum from HBAg and/or anti-HBAb carriers, confirmed by a radioimmunoassay. In preliminary results, RIGPEGA was shown to be more sensitive than classical radioimmunoassay.

  17. Structure of insoluble immune complexes as studied by spectroturbidimetry and dynamic light scattering

    Science.gov (United States)

    Khlebtsov, Boris N.; Burygin, Gennadii L.; Matora, Larisa Y.; Shchyogolev, Sergei Y.; Khlebtsov, Nikolai G.

    2004-07-01

    We describe two variants of a method for determining the average composition of insoluble immune complex particles (IICP). The first variant is based on measuring the specific turbidity (the turbidity per unit mass concentration of the dispersed substance) and the average size of IICP determined from dynamic light scattering (DLS). In the second variant, the wavelength exponent (i.e., the slope of the logarithmic turbidity spectrum) is used in combination with specific turbidity measurements. Both variants allow the average biopolymer volume fraction to be determined in terms of the average refractive index of IICP. The method is exemplified by two experimental antigen+antibody systems: (i) lipopolysaccharide-protein complex (LPPC) of Azospirillum brasilense Sp245+rabbit anti-LPPC; and (ii) human IgG (hIgG)+sheep anti-hIgG. Our measurements by the two methods for both types of systems gave, on the average, the same result: the volume fraction of the IICP biopolymers is about 30%; accordingly, the volume fraction of buffer solvent is 70%.

  18. Tetranychus urticae mites do not mount an induced immune response against bacteria.

    Science.gov (United States)

    Santos-Matos, Gonçalo; Wybouw, Nicky; Martins, Nelson E; Zélé, Flore; Riga, Maria; Leitão, Alexandre B; Vontas, John; Grbić, Miodrag; Van Leeuwen, Thomas; Magalhães, Sara; Sucena, Élio

    2017-06-14

    The genome of the spider mite Tetranychus urticae , a herbivore, is missing important elements of the canonical Drosophila immune pathways necessary to fight bacterial infections. However, it is not known whether spider mites can mount an immune response and survive bacterial infection. In other chelicerates, bacterial infection elicits a response mediated by immune effectors leading to the survival of infected organisms. In T. urticae , infection by either Escherichia coli or Bacillus megaterium did not elicit a response as assessed through genome-wide transcriptomic analysis. In line with this, spider mites died within days even upon injection with low doses of bacteria that are non-pathogenic to Drosophila Moreover, bacterial populations grew exponentially inside the infected spider mites. By contrast, Sancassania berlesei , a litter-dwelling mite, controlled bacterial proliferation and resisted infections with both Gram-negative and Gram-positive bacteria lethal to T. urticae This differential mortality between mite species was absent when mites were infected with heat-killed bacteria. Also, we found that spider mites harbour in their gut 1000-fold less bacteria than S. berlesei We show that T. urticae has lost the capacity to mount an induced immune response against bacteria, in contrast to other mites and chelicerates but similarly to the phloem feeding aphid Acyrthosiphon pisum Hence, our results reinforce the putative evolutionary link between ecological conditions regarding exposure to bacteria and the architecture of the immune response. © 2017 The Authors.

  19. Exploratory study on Th1 epitope-induced protective immunity against Coxiella burnetii infection.

    Directory of Open Access Journals (Sweden)

    Xiaolu Xiong

    Full Text Available Coxiella burnetii is a Gram-negative bacterium that causes Q fever in humans. In the present study, 131 candidate peptides were selected from the major immunodominant proteins (MIPs of C. burnetii due to their high-affinity binding capacity for the MHC class II molecule H2 I-A(b based on bioinformatic analyses. Twenty-two of the candidate peptides with distinct MIP epitopes were well recognized by the IFN-γ recall responses of CD4(+ T cells from mice immunized with parental proteins in an ELISPOT assay. In addition, 7 of the 22 peptides could efficiently induce CD4(+ T cells from mice immunized with C. burnetii to rapidly proliferate and significantly increase IFN-γ production. Significantly higher levels of IL-2, IL-12p70, IFN-γ, and TNF-α were also detected in serum from mice immunized with a pool of the 7 peptides. Immunization with the pool of 7 peptides, but not the individual peptides, conferred a significant protection against C. burnetii infection in mice, suggesting that these Th1 peptides could work together to efficiently activate CD4(+ T cells to produce the Th1-type immune response against C. burnetii infection. These observations could contribute to the rational design of molecular vaccines for Q fever.

  20. Immune responses against SARS-coronavirus nucleocapsid protein induced by DNA vaccine

    International Nuclear Information System (INIS)

    Zhao Ping; Cao Jie; Zhao Lanjuan; Qin Zhaolin; Ke Jinshan; Pan Wei; Ren Hao; Yu Jianguo; Qi Zhongtian

    2005-01-01

    The nucleocapsid (N) protein of SARS-coronavirus (SARS-CoV) is the key protein for the formation of the helical nucleocapsid during virion assembly. This protein is believed to be more conserved than other proteins of the virus, such as spike and membrane glycoprotein. In this study, the N protein of SARS-CoV was expressed in Escherichia coli DH5α and identified with pooled sera from patients in the convalescence phase of SARS. A plasmid pCI-N, encoding the full-length N gene of SARS-CoV, was constructed. Expression of the N protein was observed in COS1 cells following transfection with pCI-N. The immune responses induced by intramuscular immunization with pCI-N were evaluated in a murine model. Serum anti-N immunoglobulins and splenocytes proliferative responses against N protein were observed in immunized BALB/c mice. The major immunoglobulin G subclass recognizing N protein was immunoglobulin G2a, and stimulated splenocytes secreted high levels of gamma interferon and IL-2 in response to N protein. More importantly, the immunized mice produced strong delayed-type hypersensitivity (DTH) and CD8 + CTL responses to N protein. The study shows that N protein of SARS-CoV not only is an important B cell immunogen, but also can elicit broad-based cellular immune responses. The results indicate that the N protein may be of potential value in vaccine development for specific prophylaxis and treatment against SARS

  1. Tumor necrosis factor-α-induced protein 1 and immunity to hepatitis B virus

    Science.gov (United States)

    Lin, Marie C; Lee, Nikki P; Zheng, Ning; Yang, Pai-Hao; Wong, Oscar G; Kung, Hsiang-Fu; Hui, Chee-Kin; Luk, John M; Lau, George Ka-Kit

    2005-01-01

    AIM: To compare the gene expression profile in a pair of HBV-infected twins. METHODS: The gene expression profile was compared in a pair of HBV-infected twins. RESULTS: The twins displayed different disease outcomes. One acquired natural immunity against HBV, whereas the other became a chronic HBV carrier. Eighty-eight and forty-six genes were found to be up- or down-regulated in their PBMCs, respectively. Tumor necrosis factor-alpha-induced protein 1 (TNF-αIP1) that expressed at a higher level in the HBV-immune twins was identified and four pairs of siblings with HBV immunity by RT-PCR. However, upon HBV core antigen stimulation, TNF-αIP1 was downregulated in PBMCs from subjects with immunity, whereas it was slightly upregulated in HBV carriers. Bioinformatics analysis revealed a K+ channel tetramerization domain in TNF-αIP1 that shares a significant homology with some human, mouse, and C elegan proteins. CONCLUSION: TNF-αIP1 may play a role in the innate immunity against HBV. PMID:16437679

  2. Chronic activation of the epithelial immune system of the fruit fly's salivary glands has a negative effect on organismal growth and induces a peculiar set of target genes

    Directory of Open Access Journals (Sweden)

    Abdelsadik Ahmed

    2010-04-01

    Full Text Available Abstract Background Epithelial and especially mucosal immunity represents the first line of defence against the plethora of potential pathogens trying to invade via the gastrointestinal tract. The salivary glands of the fruit fly are an indispensable part of the gastrointestinal tract, but their contribution to the mucosal immunity has almost completely been neglected. Our major goal was to elucidate if the fly's salivary glands are able to mount an immune response and what the major characteristics of this immune response are. Results Ectopic activation of the IMD-pathway within the salivary gland cells is able to induce an immune response, indicating that the salivary glands are indeed immune competent. This reaction is characterized by the concurrent expression of numerous antimicrobial peptide genes. In addition, ectopic activation of the salivary gland's immune response induces morphological changes such as dwarfism throughout all developmental stages and a significantly decreased length of the salivary glands themselves. DNA-microarray analyses of the reaction revealed a complex pattern of up- and downregulated genes. Gene ontology analyses of regulated genes revealed a significant increase in genes associated with ribosomal and proteasomal function. On the other hand, genes coding for peptide receptors and some potassium channels are downregulated. In addition, the comparison of the transcriptional events induced following IMD-activation in the trachea and the salivary glands shows also only a small overlap, indicating that the general IMD-activated core transcriptome is rather small and that the tissue specific component of this response is dominating. Among the regulated genes, those that code for signaling associated protease activity are significantly modulated. Conclusions The salivary glands are immune-competent and they contribute to the overall intestinal immune system. Although they produce antimicrobial peptides, their overall

  3. Allergen-containing immune complexes used for immunotherapy of allergic asthma. Preparation of complexes and evaluation of their clinical performance in guinea pigs

    DEFF Research Database (Denmark)

    Poulsen, L K; Lundberg, L; Søndergaard, I

    1989-01-01

    Guinea pigs inbred for their ability to develop respiratory anaphylaxis to experimental antigens have been used for comparison of different forms of immunotherapy (IT). Passive, active and combined (immune complexes between antigen and specific IgG) IT were compared with placebo. The bronchial re...... groups surprisingly recovered their original sensitivity to inhalation of the antigen....

  4. Club cells surviving influenza A virus infection induce temporary nonspecific antiviral immunity.

    Science.gov (United States)

    Hamilton, Jennifer R; Sachs, David; Lim, Jean K; Langlois, Ryan A; Palese, Peter; Heaton, Nicholas S

    2016-04-05

    A brief window of antigen-nonspecific protection has been observed after influenza A virus (IAV) infection. Although this temporary immunity has been assumed to be the result of residual nonspecific inflammation, this period of induced immunity has not been fully studied. Because IAV has long been characterized as a cytopathic virus (based on its ability to rapidly lyse most cell types in culture), it has been a forgone conclusion that directly infected cells could not be contributing to this effect. Using a Cre recombinase-expressing IAV, we have previously shown that club cells can survive direct viral infection. We show here not only that these cells can eliminate all traces of the virus and survive but also that they acquire a heightened antiviral response phenotype after surviving. Moreover, we experimentally demonstrate temporary nonspecific viral immunity after IAV infection and show that surviving cells are required for this phenotype. This work characterizes a virally induced modulation of the innate immune response that may represent a new mechanism to prevent viral diseases.

  5. Can VHS Virus Bypass the Protective Immunity Induced by DNA Vaccination in Rainbow Trout?

    Directory of Open Access Journals (Sweden)

    Dagoberto Sepúlveda

    Full Text Available DNA vaccines encoding viral glycoproteins have been very successful for induction of protective immunity against diseases caused by rhabdoviruses in cultured fish species. However, the vaccine concept is based on a single viral gene and since RNA viruses are known to possess high variability and adaptation capacity, this work aimed at evaluating whether viral haemorrhagic septicaemia virus (VHSV, an RNA virus and member of Rhabdoviridae family, was able to evade the protective immune response induced by the DNA vaccination of rainbow trout. The experiments comprised repeated passages of a highly pathogenic VHSV isolate in a fish cell line in the presence of neutralizing fish serum (in vitro approach, and in rainbow trout immunized with the VHS DNA vaccine (in vivo approach. For the in vitro approach, the virus collected from the last passage (passaged virus was as sensitive as the parental virus to serum neutralization, suggesting that the passaging did not promote the selection of virus populations able to bypass the neutralization by serum antibodies. Also, in the in vivo approach, where virus was passaged several times in vaccinated fish, no increased virulence nor increased persistence in vaccinated fish was observed in comparison with the parental virus. However, some of the vaccinated fish did get infected and could transmit the infection to naïve cohabitant fish. The results demonstrated that the DNA vaccine induced a robust protection, but also that the immunity was non-sterile. It is consequently important not to consider vaccinated fish as virus free in veterinary terms.

  6. Safety and immune regulatory properties of canine induced pluripotent stem cell-derived mesenchymal stem cells.

    Science.gov (United States)

    Chow, Lyndah; Johnson, Valerie; Regan, Dan; Wheat, William; Webb, Saiphone; Koch, Peter; Dow, Steven

    2017-12-01

    Mesenchymal stem cells (MSCs) exhibit broad immune modulatory activity in vivo and can suppress T cell proliferation and dendritic cell activation in vitro. Currently, most MSC for clinical usage are derived from younger donors, due to ease of procurement and to the superior immune modulatory activity. However, the use of MSC from multiple unrelated donors makes it difficult to standardize study results and compare outcomes between different clinical trials. One solution is the use of MSC derived from induced pluripotent stem cells (iPSC); as iPSC-derived MSC have nearly unlimited proliferative potential and exhibit in vitro phenotypic stability. Given the value of dogs as a spontaneous disease model for pre-clinical evaluation of stem cell therapeutics, we investigated the functional properties of canine iPSC-derived MSC (iMSC), including immune modulatory properties and potential for teratoma formation. We found that canine iMSC downregulated expression of pluripotency genes and appeared morphologically similar to conventional MSC. Importantly, iMSC retained a stable phenotype after multiple passages, did not form teratomas in immune deficient mice, and did not induce tumor formation in dogs following systemic injection. We concluded therefore that iMSC were phenotypically stable, immunologically potent, safe with respect to tumor formation, and represented an important new source of cells for therapeutic modulation of inflammatory disorders. Copyright © 2017. Published by Elsevier B.V.

  7. High-Altitude-Induced alterations in Gut-Immune Axis: A review.

    Science.gov (United States)

    Khanna, Kunjan; Mishra, K P; Ganju, Lilly; Kumar, Bhuvnesh; Singh, Shashi Bala

    2018-03-04

    High-altitude sojourn above 8000 ft is increasing day by day either for pilgrimage, mountaineering, holidaying or for strategic reasons. In India, soldiers are deployed to these high mountains for their duty or pilgrims visit to the holy places, which are located at very high altitude. A large population also resides permanently in high altitude regions. Every year thousands of pilgrims visit Holy cave of Shri Amarnath ji, which is above 15 000 ft. The poor acclimatization to high altitude may cause alteration in immunity. The low oxygen partial pressure may cause alterations in gut microbiota, which may cause changes in gut immunity. Effect of high altitude on gut-associated mucosal system is new area of research. Many studies have been carried out to understand the physiology and immunology behind the high-altitude-induced gut problems. Few interventions have also been discovered to circumvent the problems caused due to high-altitude conditions. In this review, we have discussed the effects of high-altitude-induced changes in gut immunity particularly peyer's patches, NK cells and inflammatory cytokines, secretary immunoglobulins and gut microbiota. The published articles from PubMed and Google scholar from year 1975 to 2017 on high-altitude hypoxia and gut immunity are cited in this review.

  8. Immune System Modifications Induced in a Mouse Model of Chronic Exposure to (90)Sr.

    Science.gov (United States)

    Synhaeve, Nicholas; Musilli, Stefania; Stefani, Johanna; Nicolas, Nour; Delissen, Olivia; Dublineau, Isabelle; Bertho, Jean-Marc

    2016-03-01

    Strontium 90 ((90)Sr) remains in the environment long after a major nuclear disaster occurs. As a result, populations living on contaminated land are potentially exposed to daily ingesting of low quantities of (90)Sr. The potential long-term health effects of such chronic contamination are unknown. In this study, we used a mouse model to evaluate the effects of (90)Sr ingestion on the immune system, the animals were chronically exposed to (90)Sr in drinking water at a concentration of 20 kBq/l, for a daily ingestion of 80-100 Bq/day. This resulted in a reduced number of CD19(+) B lymphocytes in the bone marrow and spleen in steady-state conditions. In contrast, the results from a vaccine experiment performed as a functional test of the immune system showed that in response to T-dependent antigens, there was a reduction in IgG specific to tetanus toxin (TT), a balanced Th1/Th2 response inducer antigen, but not to keyhole limpet hemocyanin (KLH), a strong Th2 response inducer antigen. This was accompanied by a reduction in Th1 cells in the spleen, consistent with the observed reduction in specific IgG concentration. The precise mechanisms by which (90)Sr acts on the immune system remain to be elucidated. However, our results suggest that (90)Sr ingestion may be responsible for some of the reported effects of internal contamination on the immune system in civilian populations exposed to the Chernobyl fallout.

  9. Innate Immune Complexity in the Purple Sea Urchin: Diversity of the Sp185/333 System

    Science.gov (United States)

    Smith, L. Courtney

    2012-01-01

    The California purple sea urchin, Strongylocentrotus purpuratus, is a long-lived echinoderm with a complex and sophisticated innate immune system. There are several large gene families that function in immunity in this species including the Sp185/333 gene family that has ∼50 (±10) members. The family shows intriguing sequence diversity and encodes a broad array of diverse yet similar proteins. The genes have two exons of which the second encodes the mature protein and has repeats and blocks of sequence called elements. Mosaics of element patterns plus single nucleotide polymorphisms-based variants of the elements result in significant sequence diversity among the genes yet maintains similar structure among the members of the family. Sequence of a bacterial artificial chromosome insert shows a cluster of six, tightly linked Sp185/333 genes that are flanked by GA microsatellites. The sequences between the GA microsatellites in which the Sp185/333 genes and flanking regions are located, are much more similar to each other than are the sequences outside the microsatellites suggesting processes such as gene conversion, recombination, or duplication. However, close linkage does not correspond with greater sequence similarity compared to randomly cloned and sequenced genes that are unlikely to be linked. There are three segmental duplications that are bounded by GAT microsatellites and include three almost identical genes plus flanking regions. RNA editing is detectible throughout the mRNAs based on comparisons to the genes, which, in combination with putative post-translational modifications to the proteins, results in broad arrays of Sp185/333 proteins that differ among individuals. The mature proteins have an N-terminal glycine-rich region, a central RGD motif, and a C-terminal histidine-rich region. The Sp185/333 proteins are localized to the cell surface and are found within vesicles in subsets of polygonal and small phagocytes. The coelomocyte proteome shows full

  10. Obesity-Associated Autoantibody Production Requires AIM to Retain the Immunoglobulin M Immune Complex on Follicular Dendritic Cells

    Directory of Open Access Journals (Sweden)

    Satoko Arai

    2013-04-01

    Full Text Available Natural immunoglobulin M (IgM is reactive to autoantigens and is believed to be important for autoimmunity. Blood pentameric IgM loaded with antigens forms a large immune complex (IC that contains various elements, including apoptosis inhibitor of macrophage (AIM. Here we demonstrate that this IgM-AIM association contributes to autoantibody production under obese conditions. In mice fed a high-fat diet, natural IgM increased through B cell TLR4 stimulation. AIM associated with IgM and protected AIM from renal excretion, increasing blood AIM levels along with the obesity-induced IgM augmentation. Meanwhile, the AIM association inhibited IgM binding to the Fcα/μ receptor on splenic follicular dendritic cells, thereby protecting the IgM IC from Fcα/μ receptor-mediated internalization. This supported IgM-dependent autoantigen presentation to B cells, stimulating IgG autoantibody production. Accordingly, in obese AIM-deficient (AIM−/− mice, the increase of multiple IgG autoantibodies observed in obese wild-type mice was abrogated. Thus, the AIM-IgM association plays a critical role in the obesity-associated autoimmune process.

  11. Exposure to low infective doses of HCV induces cellular immune responses without consistently detectable viremia or seroconversion in chimpanzees

    International Nuclear Information System (INIS)

    Shata, Mohamed Tarek; Tricoche, Nancy; Perkus, Marion; Tom, Darley; Brotman, Betsy; McCormack, Patricia; Pfahler, Wolfram; Lee, Dong-Hun; Tobler, Leslie H.; Busch, Michael; Prince, Alfred M.

    2003-01-01

    In hepatitis C virus (HCV) infection, there is accumulating data suggesting the presence of cellular immune responses to HCV in exposed but seemingly uninfected populations. Some studies have suggested cross-reactive antigens rather than prior HCV exposure as the main reason for the immune responses. In this study we address this question by analyzing the immune response of chimpanzees that have been sequentially exposed to increasing doses of HCV virions. The level of viremia, as well as the immune responses to HCV at different times after virus inoculation, were examined. Our data indicate that HCV infective doses as low as 1-10 RNA (+) virions induce detectable cellular immune responses in chimpanzees without consistently detectable viremia or persistent seroconversion. However, increasing the infective doses of HCV to 100 RNA (+) virions overcame the low-inoculum-induced immune response and produced high-level viremia followed by seroconversion

  12. Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment

    NARCIS (Netherlands)

    Mattei, D.; Ivanov, A.; Ferrai, C.; Jordan, P.; Guneykaya, D.; Buonfiglioli, A.; Schaafsma, W.; Przanowski, P.; Deuther-Conrad, W.; Brust, P.; Hesse, S.; Patt, M.; Sabri, O.; Ross, T. L.; Eggen, B. J. L.; Boddeke, E. W. G. M.; Kaminska, B.; Beule, D.; Pombo, A.; Kettenmann, H.; Wolf, S. A.

    2017-01-01

    Maternal immune activation (MIA) during pregnancy has been linked to an increased risk of developing psychiatric pathologies in later life. This link may be bridged by a defective microglial phenotype in the offspring induced by MIA, as microglia have key roles in the development and maintenance of

  13. Unanticipated Mycobacterium tuberculosis complex culture inhibition by immune modulators, immune suppressants, a growth enhancer, and vitamins A and D: clinical implications.

    Science.gov (United States)

    Greenstein, Robert J; Su, Liya; Shahidi, Azra; Brown, William D; Clifford, Anya; Brown, Sheldon T

    2014-09-01

    The development of novel antibiotics to treat multidrug-resistant (MDR) tuberculosis is time-consuming and expensive. Multiple immune modulators, immune suppressants, anti-inflammatories, and growth enhancers, and vitamins A and D, inhibit Mycobacterium avium subspecies paratuberculosis (MAP) in culture. We studied the culture inhibition of Mycobacterium tuberculosis complex by these agents. Biosafety level two M. tuberculosis complex (ATCC 19015 and ATCC 25177) was studied in radiometric Bactec or MGIT culture. Agents evaluated included clofazimine, methotrexate, 6-mercaptopurine, cyclosporine A, rapamycin, tacrolimus, monensin, and vitamins A and D. All the agents mentioned above caused dose-dependent inhibition of the M. tuberculosis complex. There was no inhibition by the anti-inflammatory 5-aminosalicylic acid, which causes bacteriostatic inhibition of MAP. We conclude that, at a minimum, studies with virulent M. tuberculosis are indicated with the agents mentioned above, as well as with the thioamide 5-propothiouricil, which has previously been shown to inhibit the M. tuberculosis complex in culture. Our data additionally emphasize the importance of vitamins A and D in treating mycobacterial diseases. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. Detection of Immune-Complex Dissociated Nonstructural-1 (NS-1) Antigen in Patients with Acute Dengue Virus Infections

    NARCIS (Netherlands)

    P. Koraka (Penelope); C.P. Burghoorn-Maas; A. Falconar; T.E. Setiati (Tatty); K. Djamiatun; J. Groen (Jan); A.D.M.E. Osterhaus (Albert)

    2003-01-01

    textabstractAccurate and timely diagnosis of dengue virus (DEN) infections is essential for the differential diagnosis of patients with febrile illness and hemorrhagic fever. In the present study, the diagnostic value of a newly developed immune-complex dissociated nonstructural-1 (NS-1) antigen dot

  15. Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells

    OpenAIRE

    Swaims, Alison Y.; Khani, Francesca; Zhang, Yingyu; Roberts, Arthur I.; Devadas, Satish; Shi, Yufang; Rabson, Arnold B.

    2010-01-01

    Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/lymphoma (ATL). Although the pathogenesis of these disorders is poorly understood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypothesis, we employed transgenic mice in which Tax is regulate...

  16. Maize Prolamins Could Induce a Gluten-Like Cellular Immune Response in Some Celiac Disease Patients

    Science.gov (United States)

    Ortiz-Sánchez, Juan P.; Cabrera-Chávez, Francisco; Calderón de la Barca, Ana M.

    2013-01-01

    Celiac disease (CD) is an autoimmune-mediated enteropathy triggered by dietary gluten in genetically prone individuals. The current treatment for CD is a strict lifelong gluten-free diet. However, in some CD patients following a strict gluten-free diet, the symptoms do not remit. These cases may be refractory CD or due to gluten contamination; however, the lack of response could be related to other dietary ingredients, such as maize, which is one of the most common alternatives to wheat used in the gluten-free diet. In some CD patients, as a rare event, peptides from maize prolamins could induce a celiac-like immune response by similar or alternative pathogenic mechanisms to those used by wheat gluten peptides. This is supported by several shared features between wheat and maize prolamins and by some experimental results. Given that gluten peptides induce an immune response of the intestinal mucosa both in vivo and in vitro, peptides from maize prolamins could also be tested to determine whether they also induce a cellular immune response. Hypothetically, maize prolamins could be harmful for a very limited subgroup of CD patients, especially those that are non-responsive, and if it is confirmed, they should follow, in addition to a gluten-free, a maize-free diet. PMID:24152750

  17. Escherichia coli O157:H7 induces stronger plant immunity than Salmonella enterica Typhimurium SL1344.

    Science.gov (United States)

    Roy, Debanjana; Panchal, Shweta; Rosa, Bruce A; Melotto, Maeli

    2013-04-01

    Consumption of fresh produce contaminated with bacterial human pathogens has resulted in various, sometimes deadly, disease outbreaks. In this study, we assessed plant defense responses induced by the fully pathogenic bacteria Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium SL1344 in both Arabidopsis thaliana and lettuce (Lactuca sativa). Unlike SL1344, O157:H7 induced strong plant immunity at both pre-invasion and post-invasion steps of infection. For instance, O157:H7 triggered stomatal closure even under high relative humidity, an environmental condition that generally weakens plant defenses against bacteria in the field and laboratory conditions. SL1344 instead induced a transient stomatal immunity. We also observed that PR1 gene expression was significantly higher in Arabidopsis leaves infected with O157:H7 compared with SL1344. These results suggest that plants may recognize and respond to some human pathogens more effectively than others. Furthermore, stomatal immunity can diminish the penetration of human pathogens through the leaf epidermis, resulting in low bacterial titers in the plant apoplast and suggesting that additional control measures can be employed to prevent food contamination. The understanding of how plant responses can diminish bacterial contamination is paramount in preventing outbreaks and improving the safety of food supplies.

  18. Hepatitis B virus infection and vaccine-induced immunity in Madrid (Spain).

    Science.gov (United States)

    Pedraza-Flechas, Ana María; García-Comas, Luis; Ordobás-Gavín, María; Sanz-Moreno, Juan Carlos; Ramos-Blázquez, Belén; Astray-Mochales, Jenaro; Moreno-Guillén, Santiago

    2014-01-01

    To estimate the prevalence of hepatitis B virus (HBV) infection and vaccine-induced immunity in the region of Madrid, and to analyze their evolution over time. An observational, analytical, cross-sectional study was carried out in the population aged 16-80 years between 2008 and 2009. This was the last of four seroprevalence surveys in the region of Madrid. The prevalence of HBV infection and vaccine-induced immunity was estimated using multivariate logistic models and were compared with the prevalences in the 1989, 1993 and 1999 surveys. In the population aged 16-80 years, the prevalence of HBV infection was 11.0% (95% CI: 9.8-12.3) and that of chronic infection was 0.7% (95% CI: 0.5-1.1). The prevalence of vaccine-induced immunity in the population aged 16-20 years was 73.0% (95% CI: 70.0-76.0). Compared with previous surveys, there was a decrease in the prevalence of HBV infection. Based on the prevalence of chronic infection (<1%), Madrid is a region with low HBV endemicity. Preventive strategies against HBV should especially target the immigrant population. Copyright © 2013. Published by Elsevier Espana.

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

    Science.gov (United States)

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

    2016-02-01

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

  20. Killer B Lymphocytes and their Fas Ligand Positive Exosomes as Inducers of Immune Tolerance

    Directory of Open Access Journals (Sweden)

    Steven Karl Lundy

    2015-03-01

    Full Text Available Induction of immune tolerance is a key process by which the immune system is educated to modulate reactions against benign stimuli such as self-antigens and commensal microbes. Understanding and harnessing the natural mechanisms of immune tolerance may become an increasingly useful strategy for treating many types of allergic and autoimmune diseases, as well as for improving the acceptance of solid organ transplants. Our laboratory and others have been interested in the natural ability of some B lymphocytes to express the death-inducing molecule Fas ligand (FasL, and their ability to kill T helper (TH lymphocytes. We have recently shown that experimental transformation of human B cells by a non-replicative variant of Epstein-Barr virus (EBV consistently resulted in high expression of functional FasL protein. The production and release of FasL+ exosomes that co-expressed MHC Class II molecules and had the capacity to kill antigen-specific TH cells was also observed. Several lines of evidence indicate that FasL+ B cells and FasL+MHCII+ exosomes have important roles in natural immune tolerance and have a great deal of therapeutic potential. Taken together, these findings suggest that EBV-immortalized human B lymphoblastoid cell lines could be used as cellular factories for FasL+ exosomes, which would be employed to therapeutically establish and/or regain immune tolerance toward specific antigens. The goals of this review are to summarize current knowledge of the roles of FasL+ B cells and exosomes in immune regulation, and to suggest methods of manipulating killer B cells and FasL+ exosomes for clinical purposes.

  1. Room Temperature Stable PspA-Based Nanovaccine Induces Protective Immunity

    Directory of Open Access Journals (Sweden)

    Danielle A. Wagner-Muñiz

    2018-03-01

    Full Text Available Streptococcus pneumoniae is a major causative agent of pneumonia, a debilitating disease particularly in young and elderly populations, and is the leading worldwide cause of death in children under the age of five. While there are existing vaccines against S. pneumoniae, none are protective across all serotypes. Pneumococcal surface protein A (PspA, a key virulence factor of S. pneumoniae, is an antigen that may be incorporated into future vaccines to address the immunological challenges presented by the diversity of capsular antigens. PspA has been shown to be immunogenic and capable of initiating a humoral immune response that is reactive across approximately 94% of pneumococcal strains. Biodegradable polyanhydrides have been studied as a nanoparticle-based vaccine (i.e., nanovaccine platform to stabilize labile proteins, to provide adjuvanticity, and enhance patient compliance by providing protective immunity in a single dose. In this study, we designed a room temperature stable PspA-based polyanhydride nanovaccine that eliminated the need for a free protein component (i.e., 100% encapsulated within the nanoparticles. Mice were immunized once with the lead nanovaccine and upon challenge, presented significantly higher survival rates than animals immunized with soluble protein alone, even with a 25-fold reduction in protein dose. This lead nanovaccine formulation performed similarly to protein adjuvanted with Alum, however, with much less tissue reactogenicity at the site of immunization. By eliminating the free PspA from the nanovaccine formulation, the lead nanovaccine was efficacious after being stored dry for 60 days at room temperature, breaking the need for maintaining the cold chain. Altogether, this study demonstrated that a single dose PspA-based nanovaccine against S. pneumoniae induced protective immunity and provided thermal stability when stored at room temperature for at least 60 days.

  2. [Effects of cell-mediated immunity induced by intramuscular chitosan-pJME/ GM-CSF nano-DNA vaccine in BAlb/c mice].

    Science.gov (United States)

    Zhai, Yong-Zhen; Zhou, Yan; Ma, Li; Feng, Guo-He

    2014-07-01

    This study aimed to investigate the immune adjuvant effect and mechanism induced by chitosan nanoparticles carrying pJME/GM-CSF. In this study, plasmid DNA (pJME/GM-CSF) was encapsulated in chitosan to prepare chitosan-pJME/GM-CSF nanoparticles using a complex coacervation process. Immunohistochemistry was used to detect the type of infiltrating cells at the site of intramuscular injection. The phenotype and functional changes of splenic DCs were measured by flow cytometry after different immunogens were injected intramuscularly. The killing activity of CTLs was assessed using the lactate dehydrogenase (LDH) release assay. The preparation of chitosan-pJME/GM-CSF nanoparticles matched the expected theoretical results. Our results also found that, after pJME/GM-CSF injection, the incoming cells were a mixture of macrophages, neutrophils, and immature DCs. Meanwhile, pJME/GM-CSF increased the expression of MHC class II molecules on splenic DCs, and enhanced their Ag capture and presentation functions. Cell-mediated immunity was induced by the vaccine. Furthermore, chitosan-pJME/GM-CSF nanoparticles outperformed the administration of standard pJME/GM-CSF in terms of DC recruitment, antigen processing and presentation, and vaccine enhancement. These findings reveal that chitosan could be used as delivery vector for DNA vaccine intramuscular immunizations, and enhance pJME/GM-CSF-induced cellular immune responses.

  3. An inducible transgenic mouse model for immune mediated hepatitis showing clearance of antigen expressing hepatocytes by CD8+ T cells.

    Directory of Open Access Journals (Sweden)

    Marcin Cebula

    Full Text Available The liver has the ability to prime immune responses against neo antigens provided upon infections. However, T cell immunity in liver is uniquely modulated by the complex tolerogenic property of this organ that has to also cope with foreign agents such as endotoxins or food antigens. In this respect, the nature of intrahepatic T cell responses remains to be fully characterized. To gain deeper insight into the mechanisms that regulate the CD8+ T cell responses in the liver, we established a novel OVA_X_CreER(T2 mouse model. Upon tamoxifen administration OVA antigen expression is observed in a fraction of hepatocytes, resulting in a mosaic expression pattern. To elucidate the cross-talk of CD8+ T cells with antigen-expressing hepatocytes, we adoptively transferred K(b/OVA257-264-specific OT-I T cells to OVA_X_CreER(T2 mice or generated triple transgenic OVA_X CreER(T2_X_OT-I mice. OT-I T cells become activated in OVA_X_CreER(T2 mice and induce an acute and transient hepatitis accompanied by liver damage. In OVA_X_CreER(T2_X_OT-I mice, OVA induction triggers an OT-I T cell mediated, fulminant hepatitis resulting in 50% mortality. Surviving mice manifest a long lasting hepatitis, and recover after 9 weeks. In these experimental settings, recovery from hepatitis correlates with a complete loss of OVA expression indicating efficient clearance of the antigen-expressing hepatocytes. Moreover, a relapse of hepatitis can be induced upon re-induction of cured OVA_X_CreER(T2_X_OT-I mice indicating absence of tolerogenic mechanisms. This pathogen-free, conditional mouse model has the advantage of tamoxifen inducible tissue specific antigen expression that reflects the heterogeneity of viral antigen expression and enables the study of intrahepatic immune responses to both de novo and persistent antigen. It allows following the course of intrahepatic immune responses: initiation, the acute phase and antigen clearance.

  4. MHC class II-associated invariant chain linkage of antigen dramatically improves cell-mediated immunity induced by adenovirus vaccines

    DEFF Research Database (Denmark)

    Holst, Peter Johannes; Mandrup Jensen, Camilla Maria; Orskov, Cathrine

    2008-01-01

    The ideal vaccine induces a potent protective immune response, which should be rapidly induced, long-standing, and of broad specificity. Recombinant adenoviral vectors induce potent Ab and CD8+ T cell responses against transgenic Ags within weeks of administration, and they are among the most...

  5. Formation, clearance, deposition, pathogenicity, and identification of biopharmaceutical-related immune complexes: review and case studies.

    Science.gov (United States)

    Rojko, Jennifer L; Evans, Mark G; Price, Shari A; Han, Bora; Waine, Gary; DeWitte, Mark; Haynes, Jill; Freimark, Bruce; Martin, Pauline; Raymond, James T; Evering, Winston; Rebelatto, Marlon C; Schenck, Emanuel; Horvath, Christopher

    2014-06-01

    Vascular inflammation, infusion reactions, glomerulopathies, and other potentially adverse effects may be observed in laboratory animals, including monkeys, on toxicity studies of therapeutic monoclonal antibodies and recombinant human protein drugs. Histopathologic and immunohistochemical (IHC) evaluation suggests these effects may be mediated by deposition of immune complexes (ICs) containing the drug, endogenous immunoglobulin, and/or complement components in the affected tissues. ICs may be observed in glomerulus, blood vessels, synovium, lung, liver, skin, eye, choroid plexus, or other tissues or bound to neutrophils, monocytes/macrophages, or platelets. IC deposition may activate complement, kinin, and/or coagulation/fibrinolytic pathways and result in a systemic proinflammatory response. IC clearance is biphasic in humans and monkeys (first from plasma to liver and/or spleen, second from liver or spleen). IC deposition/clearance is affected by IC composition, immunomodulation, and/or complement activation. Case studies are presented from toxicity study monkeys or rats and indicate IHC-IC deposition patterns similar to those predicted by experimental studies of IC-mediated reactions to heterologous protein administration to monkeys and other species. The IHC-staining patterns are consistent with findings associated with generalized and localized IC-associated pathology in humans. However, manifestations of immunogenicity in preclinical species are generally not considered predictive to humans. © 2014 by The Author(s).

  6. Human erythrocytes inhibit complement-mediated solubilization of immune complexes by human serum

    International Nuclear Information System (INIS)

    Dorval, B.L.

    1987-01-01

    The aim of this study was to develop an autologus human system to evaluate the effects of human erythrocytes on solubilization of immune complex precipitates (IC) by human serum. Incubation of IC with fresh human serum or guinea pig serum resulted in solubilization of IC. When packed erythrocytes were added to human serum or guinea pig serum binding of IC to the erythrocyte occurred and IC solubilization was inhibited significantly (p <.025). Sheep erythrocytes did not bind IC or inhibit IC solubilization. To evaluate the role of human erythrocyte complement receptor (CR1) on these findings, human erythrocytes were treated with trypsin or anti-CR1 antibodies. Both treatments abrogated IC binding to human erythrocytes but did not affect the ability of the human erythrocyte to inhibit IC solubilization. Radioimmunoassay was used to measure C3, C4 and C5 activation in human serum after incubation with IC, human erythrocytes, human erythrocytes plus IC, whole blood or in whole blood plus IC

  7. Mechanisms and kinetics for platelet and neutrophil localization in immune complex nephritis

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, R.J.; Alpers, C.E.; Pruchno, C.; Schulze, M.; Baker, P.J.; Pritzl, P.; Couser, W.G. (Univ. of Washington, Seattle (USA))

    1989-11-01

    We have previously reported that both neutrophils (PMNs) and platelets mediate proteinuria in a model of subendothelial immune complex (IC) nephritis (GN) in the rat. In order to understand the interaction of PMNs and platelets in this model, we quantitated the uptake of {sup 111}In-labelled platelets in glomeruli and correlated this with the number of PMNs observed histologically at 10 and 30 minutes, 1, 4 and 24 hours following induction of GN. Platelet accumulation was biphasic with a major peak at 10 minutes and a minor peak at four hours. Early platelet accumulation was complement dependent, and PMN-independent. PMN accumulation occurred after the initial platelet influx, peaking at one and four hours, was complement dependent, but was not affected by platelet depletion. Complement depletion significantly reduced proteinuria. This is the first documentation that platelet accumulation in glomeruli in IC GN is complement dependent. In addition, the enhancement of PMN-mediated injury by the platelet in this model does not involve effects of platelets on PMN localization, thus implying a functional interaction between these cells within the glomerulus.

  8. Uptake of apoptotic leukocytes by synovial lining macrophages inhibits immune complex-mediated arthritis.

    Science.gov (United States)

    van Lent, P L; Licht, R; Dijkman, H; Holthuysen, A E; Berden, J H; van den Berg, W B

    2001-11-01

    Previously we have shown that synovial lining macrophages (SLMs) determine the onset of experimental immune complex-mediated arthritis (ICA). During joint inflammation, many leukocytes undergo apoptosis, and removal of leukocytes by SLMs may regulate resolution of inflammation. In this study we investigated binding and uptake of apoptotic leukocytes by SLMs and its impact on the onset of murine experimental arthritis. We used an in vitro model to evaluate phagocytosis of apoptotic cells on chemotaxis. Phagocytosis of apoptotic thymocytes resulted in a significant decrease (58%) of chemotactic activity for polymorphonuclear neutrophils (PMNs). If apoptotic cells were injected directly into a normal murine knee joint, SLMs resulted in a prominent uptake of cells. After ICA induction, electron micrographs showed that apoptotic leukocytes were evidently present in SLMs on days 1 and 2. Injection of apoptotic leukocytes into the knee joint 1 h before induction of ICA significantly inhibited PMN infiltration into the knee joint at 24 h (61% decrease). This study indicates that uptake of apoptotic leukocytes by SLM reduces chemotactic activity and inhibits the onset of experimental arthritis. These findings indicate an important mechanism in the resolution of joint inflammation.

  9. Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes

    Science.gov (United States)

    Monsalvo, Ana Clara; Batalle, Juan P.; Lopez, M. Florencia; Krause, Jens C.; Klemenc, Jennifer; Zea, Johanna; Maskin, Bernardo; Bugna, Jimena; Rubinstein, Carlos; Aguilar, Leandro; Dalurzo, Liliana; Libster, Romina; Savy, Vilma; Baumeister, Elsa; Aguilar, Liliana; Cabral, Graciela; Font, Julia; Solari, Liliana; Weller, Kevin P.; Johnson, Joyce; Echavarria, Marcela; Edwards, Kathryn M.; Chappell, James D.; Crowe, James E.; Williams, John V.; Melendi, Guillermina A.; Polack, Fernando P.

    2010-01-01

    Pandemic influenza viruses often cause severe disease in middle-aged adults without preexistent co-morbidities. The mechanism of illness associated with severe disease in this age group is not well understood1–10. Here, we demonstrate preexisting serum antibody that cross-reacts with, but does not protect against 2009 H1N1 influenza virus in middle-aged adults. Non-protective antibody is associated with immune complex(IC)-mediated disease after infection. High titers of serum antibody of low avidity for H1-2009 antigen, and low avidity pulmonary ICs against the same protein were detected in severely ill patients. Moreover, C4d deposition - a sensitive marker of complement activation mediated by ICs- was present in lung sections of fatal cases. Archived lung sections from adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a novel biological mechanism for the unusual age distribution of severe cases during influenza pandemics. PMID:21131958

  10. DDA/TDB liposomes containing soluble Leishmania major antigens induced a mixed Th1/Th2 immune response in BALB/c mice

    Directory of Open Access Journals (Sweden)

    Mansure Hojatizade

    2017-04-01

    Full Text Available Objective(s: Leishmaniasis is a complex parasitic disease that represents a major public health problem. Despite numerous attempts over the past decades, yet there is no effective vaccine against human leishmaniasis probably due to the lack of suitable adjuvants. In this study, a first generation liposomal-based Leishmania vaccine was developed using soluble Leishmania major antigens (SLA and á, Ü-trehalose6, 6'-dibehenat (TDB as an immunostimulatory adjuvant. In this liposome structure, the cationic lipid Dimethyldioctadecylammonium (DDA provides intrinsic adjuvant activity and cholesterol was added as a membrane stabilizer. Liposomes containing SLA were prepared.Materials and Methods: BALB/c mice were subcutaneously (sc immunized with Lip (DDA/TDB/CHOL-SLA+, Lip (DDA/TDB-SLA+, Lip (DDA-SLA+, Lip (DDA/CHOL-SLA+, SLA or Tris-HCl buffer. Immunization was done every two weeks for three weeks. The immunized mice were then challenged sc in the left footpad with 1×106 stationary phase L. major promastigotes (50 ìl, at 2 weeks after last booster injection.Results: mice immunized with any of the liposomal formulations containing SLA (Lip-SLA+, substantially increased footpad swelling and parasite loads of foot and spleen with no significant difference compared to Tris-HCl buffer or SLA alone. Lip-SLA+ formulations induced a mixed Th1/Th2 immune response characterized by IFN-ã and IL-4 production as well as high levels of IgG1 anti-Leishmania antibody. Conclusion: immunization with liposomes containing DDA and/or TDB in combination with SLA induces a mixed Th1/Th2 immune response and is not an appropriate strategy for preferential induction of a Th1 response and protection against leishmaniasis.

  11. cAMP prevents TNF-induced apoptosis through inhibiting DISC complex formation in rat hepatocytes

    International Nuclear Information System (INIS)

    Bhattacharjee, Rajesh; Xiang, Wenpei; Wang, Yinna; Zhang, Xiaoying; Billiar, Timothy R.

    2012-01-01

    Highlights: ► cAMP blocks cell death induced by TNF and actinomycin D in cultured hepatocytes. ► cAMP blocks NF-κB activation induced by TNF and actinomycin D. ► cAMP blocks DISC formation following TNF and actinomycin D exposure. ► cAMP blocks TNF signaling at a proximal step. -- Abstract: Tumor necrosis factor α (TNF) is a pleiotropic proinflammatory cytokine that plays a role in immunity and the control of cell proliferation, cell differentiation, and apoptosis. The pleiotropic nature of TNF is due to the formation of different signaling complexes upon the binding of TNF to its receptor, TNF receptor type 1 (TNFR1). TNF induces apoptosis in various mammalian cells when the cells are co-treated with a transcription inhibitor like actinomycin D (ActD). When TNFR1 is activated, it recruits an adaptor protein, TNF receptor-associated protein with death domain (TRADD), through its cytoplasmic death effector domain (DED). TRADD, in turn, recruits other signaling proteins, including TNF receptor-associated protein 2 (TRAF2) and receptor-associated protein kinase (RIPK) 1, to form a complex. Subsequently, this complex combines with FADD and procaspase-8, converts into a death-inducing signaling complex (DISC) to induce apoptosis. Cyclic AMP (cAMP) is a second messenger that regulates various cellular processes such as cell proliferation, gene expression, and apoptosis. cAMP analogues are reported to act as anti-apoptotic agents in various cell types, including hepatocytes. We found that a cAMP analogue, dibutyryl cAMP (db-cAMP), inhibits TNF + ActD-induced apoptosis in rat hepatocytes. The protein kinase A (PKA) inhibitor KT-5720 reverses this inhibitory effect of cAMP on apoptosis. Cytoprotection by cAMP involves down-regulation of various apoptotic signal regulators like TRADD and FADD and inhibition of caspase-8 and caspase-3 cleavage. We also found that cAMP exerts its affect at the proximal level of TNF signaling by inhibiting the formation of the DISC

  12. cAMP prevents TNF-induced apoptosis through inhibiting DISC complex formation in rat hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Bhattacharjee, Rajesh [Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213 (United States); Xiang, Wenpei [Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213 (United States); Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People' s Republic of China (China); Wang, Yinna [Vascular Medicine Institute, University of Pittsburgh School of Medicine, 10051-5A BST 3, 3501 Fifth Avenue, Pittsburgh, PA 15261 (United States); Zhang, Xiaoying [Department of Medicine/Endocrinology Division, University of Pittsburgh Medical Center, 200 Lothrop St., Pittsburgh, PA 15213 (United States); Billiar, Timothy R., E-mail: billiartr@upmc.edu [Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213 (United States)

    2012-06-22

    Highlights: Black-Right-Pointing-Pointer cAMP blocks cell death induced by TNF and actinomycin D in cultured hepatocytes. Black-Right-Pointing-Pointer cAMP blocks NF-{kappa}B activation induced by TNF and actinomycin D. Black-Right-Pointing-Pointer cAMP blocks DISC formation following TNF and actinomycin D exposure. Black-Right-Pointing-Pointer cAMP blocks TNF signaling at a proximal step. -- Abstract: Tumor necrosis factor {alpha} (TNF) is a pleiotropic proinflammatory cytokine that plays a role in immunity and the control of cell proliferation, cell differentiation, and apoptosis. The pleiotropic nature of TNF is due to the formation of different signaling complexes upon the binding of TNF to its receptor, TNF receptor type 1 (TNFR1). TNF induces apoptosis in various mammalian cells when the cells are co-treated with a transcription inhibitor like actinomycin D (ActD). When TNFR1 is activated, it recruits an adaptor protein, TNF receptor-associated protein with death domain (TRADD), through its cytoplasmic death effector domain (DED). TRADD, in turn, recruits other signaling proteins, including TNF receptor-associated protein 2 (TRAF2) and receptor-associated protein kinase (RIPK) 1, to form a complex. Subsequently, this complex combines with FADD and procaspase-8, converts into a death-inducing signaling complex (DISC) to induce apoptosis. Cyclic AMP (cAMP) is a second messenger that regulates various cellular processes such as cell proliferation, gene expression, and apoptosis. cAMP analogues are reported to act as anti-apoptotic agents in various cell types, including hepatocytes. We found that a cAMP analogue, dibutyryl cAMP (db-cAMP), inhibits TNF + ActD-induced apoptosis in rat hepatocytes. The protein kinase A (PKA) inhibitor KT-5720 reverses this inhibitory effect of cAMP on apoptosis. Cytoprotection by cAMP involves down-regulation of various apoptotic signal regulators like TRADD and FADD and inhibition of caspase-8 and caspase-3 cleavage. We also found

  13. Retnla (relmalpha/fizz1 suppresses helminth-induced Th2-type immunity.

    Directory of Open Access Journals (Sweden)

    John T Pesce

    2009-04-01

    Full Text Available Retnla (Resistin-like molecule alpha/FIZZ1 is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla(-/- mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla(-/- mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla(-/- mice infected with the gastrointestinal (GI parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla(-/- mice developed stronger Th2 responses, which could be reversed by exogenous rRelmalpha treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-gamma, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses.

  14. Estradiol-induced vaginal mucus inhibits antigen penetration and CD8(+) T cell priming in response to intravaginal immunization.

    Science.gov (United States)

    Seavey, Matthew M; Mosmann, Tim R

    2009-04-14

    Although vaginal immunization has been explored as a strategy to induce mucosal immunity in the female reproductive tract, this site displays unique immunological features that probably evolved to inhibit anti-paternal T cell responses after insemination to allow successful pregnancy. We previously demonstrated that estradiol, which induces an estrus-like state, prevented CD8(+) T cell priming during intravaginal immunization of mice. We now show that estradiol prevented antigen loading of vaginal antigen presenting cells (APCs) after intravaginal immunization. Histological examination confirmed that estradiol prevented penetration of peptide antigen into the vaginal wall. Removal of the estradiol-induced mucus barrier by mucinase partially restored antigen loading of vaginal APC and CD8(+) T cell proliferation in vivo. The estradiol-induced mucus barrier may thus prevent exposure to antigens delivered intravaginally, supplementing additional estradiol-dependent mechanism(s) that inhibit CD8(+) T cell priming after insemination or vaginal vaccination.

  15. Estradiol-induced vaginal mucus inhibits antigen penetration and CD8+ T cell priming in response to intravaginal immunization

    Science.gov (United States)

    Seavey, Matthew M.; Mosmann, Tim R.

    2010-01-01

    Although vaginal immunization has been explored as a strategy to induce mucosal immunity in the female reproductive tract, this site displays unique immunological features that probably evolved to inhibit anti-paternal T cell responses after insemination to allow successful pregnancy. We previously demonstrated that estradiol, which induces an estrus-like state, prevented CD8+ T cell priming during intravaginal immunization of mice. We now show that estradiol prevented antigen loading of vaginal antigen presenting cells (APC) after intravaginal immunization. Histological examination confirmed that estradiol prevented penetration of peptide antigen into the vaginal wall. Removal of the estradiol-induced mucus barrier by mucinase partially restored antigen loading of vaginal APC and CD8+ T cell proliferation in vivo. The estradiol-induced mucus barrier may thus prevent exposure to antigens delivered intravaginally, supplementing additional estradiol-dependent mechanism(s) that inhibit CD8+ T cell priming after insemination or vaginal vaccination. PMID:19428849

  16. Interleukin-17-induced protein lipocalin 2 is dispensable for immunity to oral candidiasis.

    Science.gov (United States)

    Ferreira, Maria Carolina; Whibley, Natasha; Mamo, Anna J; Siebenlist, Ulrich; Chan, Yvonne R; Gaffen, Sarah L

    2014-03-01

    Oropharyngeal candidiasis (OPC; thrush) is an opportunistic fungal infection caused by the commensal microbe Candida albicans. Immunity to OPC is strongly dependent on CD4+ T cells, particularly those of the Th17 subset. Interleukin-17 (IL-17) deficiency in mice or humans leads to chronic mucocutaneous candidiasis, but the specific downstream mechanisms of IL-17-mediated host defense remain unclear. Lipocalin 2 (Lcn2; 24p3; neutrophil gelatinase-associated lipocalin [NGAL]) is an antimicrobial host defense factor produced in response to inflammatory cytokines, particularly IL-17. Lcn2 plays a key role in preventing iron acquisition by bacteria that use catecholate-type siderophores, and lipocalin 2(-/-) mice are highly susceptible to infection by Escherichia coli and Klebsiella pneumoniae. The role of Lcn2 in mediating immunity to fungi is poorly defined. Accordingly, in this study, we evaluated the role of Lcn2 in immunity to oral infection with C. albicans. Lcn2 is strongly upregulated following oral infection with C. albicans, and its expression is almost entirely abrogated in mice with defective IL-17 signaling (IL-17RA(-/-) or Act1(-/-) mice). However, Lcn2(-/-) mice were completely resistant to OPC, comparably to wild-type (WT) mice. Moreover, Lcn2 deficiency mediated protection from OPC induced by steroid immunosuppression. Therefore, despite its potent regulation during C. albicans infection, Lcn2 is not required for immunity to mucosal candidiasis.

  17. C3d enhanced DNA vaccination induced humoral immune response to glycoprotein C of pseudorabies virus

    International Nuclear Information System (INIS)

    Tong Tiezhu; Fan Huiying; Tan Yadi; Xiao Shaobo; Ling Jieyu; Chen Huanchun; Guo Aizhen

    2006-01-01

    Murine C3d were utilized to enhance immunogenicity of pseudorabies virus (PrV) gC DNA vaccination. Three copies of C3d and four copies of CR2-binding domain M28 4 were fused, respectively, to truncated gC gene encoding soluble glycoprotein C (sgC) in pcDNA3.1. BALB/c mice were, respectively, immunized with recombinant plasmids, blank vector, and inactivated vaccine. The antibody ELISA titer for sgC-C3d 3 DNA was 49-fold more than that for sgC DNA, and the neutralizing antibody obtained 8-fold rise. Protection of mice from death after lethal PrV (316 LD 5 ) challenge was augmented from 25% to 100%. Furthermore, C3d fusion increased Th2-biased immune response by inducing IL-4 production. The IL-4 level for sgC-C3d 3 DNA immunization approached that for the inactivated vaccine. Compared to C3d, M28 enhanced sgC DNA immunogenicity to a lesser extent. In conclusion, we demonstrated that murine C3d fusion significantly enhanced gC DNA immunity by directing Th1-biased to a balanced and more effective Th1/Th2 response

  18. Sunlight Effects on Immune System: Is There Something Else in addition to UV-Induced Immunosuppression?

    Directory of Open Access Journals (Sweden)

    D. H. González Maglio

    2016-01-01

    Full Text Available Sunlight, composed of different types of radiation, including ultraviolet wavelengths, is an essential source of light and warmth for life on earth but has strong negative effects on human health, such as promoting the malignant transformation of skin cells and suppressing the ability of the human immune system to efficiently detect and attack malignant cells. UV-induced immunosuppression has been extensively studied since it was first described by Dr. Kripke and Dr. Fisher in the late 1970s. However, skin exposure to sunlight has not only this and other unfavorable effects, for example, mutagenesis and carcinogenesis, but also a positive one: the induction of Vitamin D synthesis, which performs several roles within the immune system in addition to favoring bone homeostasis. The impact of low levels of UV exposure on the immune system has not been fully reported yet, but it bears interesting differences with the suppressive effect of high levels of UV radiation, as shown by some recent studies. The aim of this article is to put some ideas in perspective and pose some questions within the field of photoimmunology based on established and new information, which may lead to new experimental approaches and, eventually, to a better understanding of the effects of sunlight on the human immune system.

  19. Sunlight Effects on Immune System: Is There Something Else in addition to UV-Induced Immunosuppression?

    Science.gov (United States)

    Paz, M. L.; Leoni, J.

    2016-01-01

    Sunlight, composed of different types of radiation, including ultraviolet wavelengths, is an essential source of light and warmth for life on earth but has strong negative effects on human health, such as promoting the malignant transformation of skin cells and suppressing the ability of the human immune system to efficiently detect and attack malignant cells. UV-induced immunosuppression has been extensively studied since it was first described by Dr. Kripke and Dr. Fisher in the late 1970s. However, skin exposure to sunlight has not only this and other unfavorable effects, for example, mutagenesis and carcinogenesis, but also a positive one: the induction of Vitamin D synthesis, which performs several roles within the immune system in addition to favoring bone homeostasis. The impact of low levels of UV exposure on the immune system has not been fully reported yet, but it bears interesting differences with the suppressive effect of high levels of UV radiation, as shown by some recent studies. The aim of this article is to put some ideas in perspective and pose some questions within the field of photoimmunology based on established and new information, which may lead to new experimental approaches and, eventually, to a better understanding of the effects of sunlight on the human immune system. PMID:28070504

  20. Epitope-based vaccines with the Anaplasma marginale MSP1a functional motif induce a balanced humoral and cellular immune response in mice.

    Directory of Open Access Journals (Sweden)

    Paula S Santos

    Full Text Available Bovine anaplasmosis is a hemoparasitic disease that causes considerable economic loss to the dairy and beef industries. Cattle immunized with the Anaplasma marginale MSP1 outer membrane protein complex presents a protective humoral immune response; however, its efficacy is variable. Immunodominant epitopes seem to be a key-limiting factor for the adaptive immunity. We have successfully demonstrated that critical motifs of the MSP1a functional epitope are essential for antibody recognition of infected animal sera, but its protective immunity is yet to be tested. We have evaluated two synthetic vaccine formulations against A. marginale, using epitope-based approach in mice. Mice infection with bovine anaplasmosis was demonstrated by qPCR analysis of erythrocytes after 15-day exposure. A proof-of-concept was obtained in this murine model, in which peptides conjugated to bovine serum albumin were used for immunization in three 15-day intervals by intraperitoneal injections before challenging with live bacteria. Blood samples were analyzed for the presence of specific IgG2a and IgG1 antibodies, as well as for the rickettsemia analysis. A panel containing the cytokines' transcriptional profile for innate and adaptive immune responses was carried out through qPCR. Immunized BALB/c mice challenged with A. marginale presented stable body weight, reduced number of infected erythrocytes, and no mortality; and among control groups mortality rates ranged from 15% to 29%. Additionally, vaccines have significantly induced higher IgG2a than IgG1 response, followed by increased expression of pro-inflammatory cytokines. This is a successful demonstration of epitope-based vaccines, and protection against anaplasmosis may be associated with elicitation of effector functions of humoral and cellular immune responses in murine model.

  1. Assessment of serum copper, iron and immune complexes in potentially malignant disorders and oral cancer

    Directory of Open Access Journals (Sweden)

    Ritu TIWARI

    Full Text Available Abstract Potentially malignant disorders (PMDs of oral cavity and oral cancer remain a cause of serious concern despite intensive research and development. Diet and immunity have been identified to play a crucial role as modifying factors in these diseases. Our study intended to explore this relationship by estimating and comparing the serum levels of copper, iron and circulating immune complexes (CICs in patients diagnosed with PMDs and oral cancer and normal healthy individuals. In this study, 40 histopathologically diagnosed cases of PMDs and oral cancer were included along with 30 healthy controls and 5 ml of venous blood was drawn using venipuncture. Serum estimation of copper, iron and CIC then followed using the colorimetric and spectrophotometric methods. The data obtained was subjected to statistical analysis using one way ANOVA and Pearson’s Product-Moment Correlation Test. The mean serum copper level was measured as 138.98 ± 10.13µg/100ml in the PMD group and 141.99 ± 21.44 µg/100ml in the oral cancer as compared to 105.5 + 18.81µ/100ml in the controls. The mean serum CIC levels was highest in the oral cancer (9.65 ± 0.16OD470 followed by the PMD group (0.18 + 0.21 OD470 and least in the control group (0.048 ± 0.02OD470. Whereas, the serum levels of iron showed a significant decrease in the PMD group (110.9 ± 10.54 µg/100ml and the oral cancer group (114.29 ± 25.83 µg/100ml as compared with the control group (136.85 ± 14.48 µg/100ml. There was no positive correlation obtained between the three groups with respect to the chosen parameters indicating that the variables were independent of each other. It can be thus be ascertained that trace elements like copper and iron as well as humoral responses (CICs have a close relationship with PMDs and oral cancers.

  2. Transition in complex calcium bursting induced by IP3 degradation

    International Nuclear Information System (INIS)

    Zhang Feng; Lu Qishao; Su Jianzhong

    2009-01-01

    Complex intracellular Ca 2+ oscillations are systematically investigated in a mathematical model based on the mechanism of Ca 2+ -induced Ca 2+ release (CICR), taking account of the Ca 2+ -stimulated degradation of inositol 1,4,5-trisphosphate (IP 3 ) by a 3-kinase. Periodic, quasi-periodic and chaotic bursting oscillations exist in a wide range of parameter values and occur alternatively as the parameters change slightly. The transition among them can be observed by the evidence in their interspike interval and the Lyapunov exponent. These results reveal the role of agonist-stimulated of IP 3 degradation as a possible source for complex patterns in Ca 2+ signaling.

  3. Immunoglobulin GM and KM genes and measles vaccine-induced humoral immunity.

    Science.gov (United States)

    Ovsyannikova, Inna G; Larrabee, Beth R; Schaid, Daniel J; Poland, Gregory A

    2017-10-04

    Identifying genetic polymorphisms that explain variations in humoral immunity to live measles virus vaccine is of great interest. Immunoglobulin GM (heavy chain) and KM (light chain) allotypes are genetic markers known to be associated with susceptibility to several infectious diseases. We assessed associations between GM and KM genotypes and measles vaccine humoral immunity (neutralizing antibody titers) in a combined cohort (n=1796) of racially diverse healthy individuals (age 18-41years). We did not discover any significant associations between GM and/or KM genotypes and measles vaccine-induced neutralizing antibody titers. African-American subjects had higher neutralizing antibody titers than Caucasians (1260mIU/mL vs. 740mIU/mL, p=7.10×10 -13 ), and those titers remained statistically significant (p=1.68×10 -09 ) after adjusting for age at enrollment and time since last vaccination. There were no statistically significant sex-specific differences in measles-induced neutralizing antibody titers in our study (p=0.375). Our data indicate a surprising lack of evidence for an association between GM and KM genotypes and measles-specific neutralizing antibody titers, despite the importance of these immune response genes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Immune-relevant thrombocytes of common carp undergo parasite-induced nitric oxide-mediated apoptosis.

    Science.gov (United States)

    Fink, Inge R; Ribeiro, Carla M S; Forlenza, Maria; Taverne-Thiele, Anja; Rombout, Jan H W M; Savelkoul, Huub F J; Wiegertjes, Geert F

    2015-06-01

    Common carp thrombocytes account for 30-40% of peripheral blood leukocytes and are abundant in the healthy animals' spleen, the thrombopoietic organ. We show that, ex vivo, thrombocytes from healthy carp express a large number of immune-relevant genes, among which several cytokines and Toll-like receptors, clearly pointing at immune functions of carp thrombocytes. Few studies have described the role of fish thrombocytes during infection. Carp are natural host to two different but related protozoan parasites, Trypanoplasma borreli and Trypanosoma carassii, which reside in the blood and tissue fluids. We used the two parasites to undertake controlled studies on the role of fish thrombocytes during these infections. In vivo, but only during infection with T. borreli, thrombocytes were massively depleted from the blood and spleen leading to severe thrombocytopenia. Ex vivo, addition of nitric oxide induced a clear and rapid apoptosis of thrombocytes from healthy carp, supporting a role for nitric oxide-mediated control of immune-relevant thrombocytes during infection with T. borreli. The potential advantage for parasites to selectively deplete the host of thrombocytes via nitric oxide-induced apoptosis is discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Transit through the flea vector induces a pretransmission innate immunity resistance phenotype in Yersinia pestis.

    Directory of Open Access Journals (Sweden)

    Viveka Vadyvaloo

    2010-02-01

    Full Text Available Yersinia pestis, the agent of plague, is transmitted to mammals by infected fleas. Y. pestis exhibits a distinct life stage in the flea, where it grows in the form of a cohesive biofilm that promotes transmission. After transmission, the temperature shift to 37 degrees C induces many known virulence factors of Y. pestis that confer resistance to innate immunity. These factors are not produced in the low-temperature environment of the flea, however, suggesting that Y. pestis is vulnerable to the initial encounter with innate immune cells at the flea bite site. In this study, we used whole-genome microarrays to compare the Y. pestis in vivo transcriptome in infective fleas to in vitro transcriptomes in temperature-matched biofilm and planktonic cultures, and to the previously characterized in vivo gene expression profile in the rat bubo. In addition to genes involved in metabolic adaptation to the flea gut and biofilm formation, several genes with known or predicted roles in resistance to innate immunity and pathogenicity in the mammal were upregulated in the flea. Y. pestis from infected fleas were more resistant to phagocytosis by macrophages than in vitro-grown bacteria, in part attributable to a cluster of insecticidal-like toxin genes that were highly expressed only in the flea. Our results suggest that transit through the flea vector induces a phenotype that enhances survival and dissemination of Y. pestis after transmission to the mammalian host.

  6. Rotavirus nonstructural protein 1 antagonizes innate immune response by interacting with retinoic acid inducible gene I

    Directory of Open Access Journals (Sweden)

    Qin Lan

    2011-12-01

    Full Text Available Abstract Background The nonstructural protein 1 (NSP1 of rotavirus has been reported to block interferon (IFN signaling by mediating proteasome-dependent degradation of IFN-regulatory factors (IRFs and (or the β-transducin repeat containing protein (β-TrCP. However, in addition to these targets, NSP1 may subvert innate immune responses via other mechanisms. Results The NSP1 of rotavirus OSU strain as well as the IRF3 binding domain truncated NSP1 of rotavirus SA11 strain are unable to degrade IRFs, but can still inhibit host IFN response, indicating that NSP1 may target alternative host factor(s other than IRFs. Overexpression of NSP1 can block IFN-β promoter activation induced by the retinoic acid inducible gene I (RIG-I, but does not inhibit IFN-β activation induced by the mitochondrial antiviral-signaling protein (MAVS, indicating that NSP1 may target RIG-I. Immunoprecipitation experiments show that NSP1 interacts with RIG-I independent of IRF3 binding domain. In addition, NSP1 induces down-regulation of RIG-I in a proteasome-independent way. Conclusions Our findings demonstrate that inhibition of RIG-I mediated type I IFN responses by NSP1 may contribute to the immune evasion of rotavirus.

  7. Protein Kinase G Induces an Immune Response in Cows Exposed to Mycobacterium avium Subsp. paratuberculosis

    Directory of Open Access Journals (Sweden)

    Horacio Bach

    2018-01-01

    Full Text Available To establish infection, pathogens secrete virulence factors, such as protein kinases and phosphatases, to modulate the signal transduction pathways used by host cells to initiate immune response. The protein MAP3893c is annotated in the genome sequence of Mycobacterium avium subspecies paratuberculosis (MAP, the causative agent of Johne’s disease, as the serine/threonine protein kinase G (PknG. In this work, we report that PknG is a functional kinase that is secreted within macrophages at early stages of infection. The antigen is able to induce an immune response from cattle exposed to MAP in the form of interferon gamma production after stimulation of whole blood with PknG. These findings suggest that PknG may contribute to the pathogenesis of MAP by phosphorylating macrophage signalling and/or adaptor molecules as observed with other pathogenic mycobacterial species.

  8. HDAC inhibition induces HIV-1 protein and enables immune-based clearance following latency reversal

    DEFF Research Database (Denmark)

    Wu, Guoxin; Swanson, Michael; Talla, Aarthi

    2017-01-01

    Promising therapeutic approaches for eradicating HIV include transcriptional activation of provirus from latently infected cells using latency-reversing agents (LRAs) and immune-mediated clearance to purge reservoirs. Accurate detection of cells capable of producing viral antigens and virions......, and the measurement of clearance of infected cells, is essential to assessing therapeutic efficacy. Here, we apply enhanced methodology extending the sensitivity limits for the rapid detection of subfemtomolar HIV gag p24 capsid protein in CD4+ T cells from ART-suppressed HIV+ individuals, and we show viral protein...... induction following treatment with LRAs. Importantly, we demonstrate that clinical administration of histone deacetylase inhibitors (HDACis; vorinostat and panobinostat) induced HIV gag p24, and ex vivo stimulation produced sufficient viral antigen to elicit immune-mediated cell killing using anti-gp120/CD3...

  9. Complexity estimates based on integral transforms induced by computational units

    Czech Academy of Sciences Publication Activity Database

    Kůrková, Věra

    2012-01-01

    Roč. 33, September (2012), s. 160-167 ISSN 0893-6080 R&D Projects: GA ČR GAP202/11/1368 Institutional research plan: CEZ:AV0Z10300504 Institutional support: RVO:67985807 Keywords : neural networks * estimates of model complexity * approximation from a dictionary * integral transforms * norms induced by computational units Subject RIV: IN - Informatics, Computer Science Impact factor: 1.927, year: 2012

  10. Merck Ad5/HIV induces broad innate immune activation that predicts CD8⁺ T-cell responses but is attenuated by preexisting Ad5 immunity.

    Science.gov (United States)

    Zak, Daniel E; Andersen-Nissen, Erica; Peterson, Eric R; Sato, Alicia; Hamilton, M Kristina; Borgerding, Joleen; Krishnamurty, Akshay T; Chang, Joanne T; Adams, Devin J; Hensley, Tiffany R; Salter, Alexander I; Morgan, Cecilia A; Duerr, Ann C; De Rosa, Stephen C; Aderem, Alan; McElrath, M Juliana

    2012-12-11

    To better understand how innate immune responses to vaccination can lead to lasting protective immunity, we used a systems approach to define immune signatures in humans over 1 wk following MRKAd5/HIV vaccination that predicted subsequent HIV-specific T-cell responses. Within 24 h, striking increases in peripheral blood mononuclear cell gene expression associated with inflammation, IFN response, and myeloid cell trafficking occurred, and lymphocyte-specific transcripts decreased. These alterations were corroborated by marked serum inflammatory cytokine elevations and egress of circulating lymphocytes. Responses of vaccinees with preexisting adenovirus serotype 5 (Ad5) neutralizing antibodies were strongly attenuated, suggesting that enhanced HIV acquisition in Ad5-seropositive subgroups in the Step Study may relate to the lack of appropriate innate activation rather than to increased systemic immune activation. Importantly, patterns of chemoattractant cytokine responses at 24 h and alterations in 209 peripheral blood mononuclear cell transcripts at 72 h were predictive of subsequent induction and magnitude of HIV-specific CD8(+) T-cell responses. This systems approach provides a framework to compare innate responses induced by vectors, as shown here by contrasting the more rapid, robust response to MRKAd5/HIV with that to yellow fever vaccine. When applied iteratively, the findings may permit selection of HIV vaccine candidates eliciting innate immune response profiles more likely to drive HIV protective immunity.

  11. Colorectal irradiation induced immune response: 'toll like receptors' therapeutic manipulation

    International Nuclear Information System (INIS)

    Lacave-Lapalun, Jean-Victor

    2013-01-01

    Exposure of the abdomino-pelvic sphere to ionizing radiation is associated with a high incidence of complications. Radiation therapy may cause short and / or long-term harmful effects. In the most severe cases and in the absence of heavy treatments, the appearance of ulcers may induce the death of patients. Clinical trials are being conducted with Mesenchymal Stem Cells (MSC) to cure theses complications. Others studies indicate that the injection of bacterial motifs limits the radiotoxicity in the intestine. They stimulate receptors (Toll-Like- Receptors (TLR)) located on the surface of epithelial and intestinal immune cells. The first aim of this doctoral work is to characterize the effects of TLR stimulation on immunity and tissue repair using a model of localized colorectal irradiation at 20 Gy (acute effects of radiotherapy) on a rat. The thesis then aims to potentiate the effects of the MSC treatment when adding TLR ligands upon localized colorectal irradiation at 27 Gy (accidental complications). This work, using a 20 Gy exposure, show that TLR stimulation improves homeostasis (normalization of T cells, induction of regulatory T cells (Treg) and macrophages 'anti-inflammatory' M2). On the 27 Gy colorectal model, the injection of TLR ligand before CSM transplant improves the immune climate by reducing pro-inflammatory cytokines and inducting Treg and M2 cells. These modulations could contribute to improving the implantation and effectiveness of CSM. The observations have all shown that the stimulation of immunity is an approach to minimize radiation-induced lesions. (author) [fr

  12. Visible light induced changes in the immune response through an eye-brain mechanism (photoneuroimmunology).

    Science.gov (United States)

    Roberts, J E

    1995-07-01

    The immune system is susceptible to a variety of stresses. Recent work in neuroimmunology has begun to define how mood alteration, stress, the seasons, and daily rhythms can have a profound effect on immune response through hormonal modifications. Central to these factors may be light through an eye-brain hormonal modulation. In adult primates, only visible light (400-700 nm) is received by the retina. This photic energy is then transduced and delivered to the visual cortex and by an alternative pathway to the suprachiasmatic nucleus (SCN). The SCN is a part of the hypothalamic region in the brain believed to direct circadian rhythm. Visible light exposure also modulates the pituitary and pineal gland which leads to neuroendocrine changes. Melatonin, norepinephrine and acetylcholine decrease with light activation, while cortisol, serotonin, gaba and dopamine levels increase. The synthesis of vasoactive intestinal polypeptide (VIP), gastrin releasing peptide (GRP) and neuropeptide Y (NPY) in rat SCN has been shown to be modified by light. These induced neuroendocrine changes can lead to alterations in mood and circadian rhythm. All of these neuroendocrine changes can lead to immune modulation. An alternative pathway for immune modulation by light is through the skin. Visible light (400-700 nm) can penetrate epidermal and dermal layers of the skin and may directly interact with circulating lymphocytes to modulate immune function. However, even in the presence of phototoxic agents such as eosin and rose bengal, visible light did not produce suppression of contact hypersensitivity with suppresser cells. In contrast to visible light, in vivo exposure to UV-B (280-320 nm) and UV-A (320-400 nm) radiation can only alter normal human immune function by a skin mediated response. Each UV subgroup (B, A) induces an immunosuppressive response but by differing mechanisms involving the regulation of differing interleukins and growth factors. Some effects observed in humans are

  13. The Necrosome Promotes Pancreas Oncogenesis via CXCL1 and Mincle Induced Immune Suppression

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Barilla, Rocky; Daley, Donnele; Greco, Stephanie H.; Torres-Hernandez, Alejandro; Pergamo, Matthew; Ochi, Atsuo; Zambirinis, Constantinos P.; Pansari, Mridul; Rendon, Mauricio; Tippens, Daniel; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Engle, Dannielle; Miller, George

    2016-01-01

    Neoplastic pancreatic epithelial cells are widely believed to die via Caspase 8-dependant apoptotic cell death and chemotherapy is thought to further promote tumor apoptosis1. Conversely, disruption of apoptosis is a basic modality cancer cells exploit for survival2,3. However, the role of necroptosis, or programmed necrosis, in pancreatic ductal adenocarcinoma (PDA) is uncertain. There are a multitude of potential inducers of necroptosis in PDA including ligation of TNFR1, CD95, TRAIL receptors, Toll-like receptors, ROS, and Chemotherapeutics4,5. Here we report that the principal components of the necrosome, RIP1 and RIP3, are highly expressed in PDA and are further upregulated by chemotherapy. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo RIP3 deletion or RIP1 inhibition was protective against oncogenic progression and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumor microenvironment (TME) associated with intact RIP1/RIP3 signaling was in-part contingent on necroptosis-induced CXCL1 expression whereas CXCL1 blockade was protective against PDA. Moreover, we found that cytoplasmic SAP130 was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle – its cognate receptor – was upregulated in tumor-infiltrating myeloid cells. Mincle ligation by SAP130 promoted oncogenesis whereas Mincle deletion was protective and phenocopied the immunogenic reprogramming of the TME characteristic of RIP3 deletion. Cellular depletion experiments suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects in the context of RIP3 or Mincle deletion. As such, T cells which are dispensable to PDA progression in hosts with intact RIP3 or Mincle signaling become reprogrammed into indispensable mediators of anti-tumor immunity in absence of RIP3 or Mincle. Our work

  14. Transcutaneous immunization with a novel imiquimod nanoemulsion induces superior T cell responses and virus protection.

    Science.gov (United States)

    Lopez, Pamela Aranda; Denny, Mark; Hartmann, Ann-Kathrin; Alflen, Astrid; Probst, Hans Christian; von Stebut, Esther; Tenzer, Stefan; Schild, Hansjörg; Stassen, Michael; Langguth, Peter; Radsak, Markus P

    2017-09-01

    Transcutaneous immunization (TCI) is a novel vaccination strategy utilizing the skin associated lymphatic tissue to induce immune responses. TCI using a cytotoxic T lymphocyte (CTL) epitope and the Toll-like receptor 7 (TLR7) agonist imiquimod mounts strong CTL responses by activation and maturation of skin-derived dendritic cells (DCs) and their migration to lymph nodes. However, TCI based on the commercial formulation Aldara only induces transient CTL responses that needs further improvement for the induction of durable therapeutic immune responses. Therefore we aimed to develop a novel imiquimod solid nanoemulsion (IMI-Sol) for TCI with superior vaccination properties suited to induce high quality T cell responses for enhanced protection against infections. TCI was performed by applying a MHC class I or II restricted epitope along with IMI-Sol or Aldara (each containing 5% Imiquimod) on the shaved dorsum of C57BL/6, IL-1R, Myd88, Tlr7 or Ccr7 deficient mice. T cell responses as well as DC migration upon TCI were subsequently analyzed by flow cytometry. To determine in vivo efficacy of TCI induced immune responses, CTL responses and frequency of peptide specific T cells were evaluated on day 8 or 35 post vaccination and protection in a lymphocytic choriomeningitis virus (LCMV) infection model was assessed. TCI with the imiquimod formulation IMI-Sol displayed equal skin penetration of imiquimod compared to Aldara, but elicited superior CD8 + as well as CD4 + T cell responses. The induction of T-cell responses induced by IMI-Sol TCI was dependent on the TLR7/MyD88 pathway and independent of IL-1R. IMI-Sol TCI activated skin-derived DCs in skin-draining lymph nodes more efficiently compared to Aldara leading to enhanced protection in a LCMV infection model. Our data demonstrate that IMI-Sol TCI can overcome current limitations of previous imiquimod based TCI approaches opening new perspectives for transcutaneous vaccination strategies and allowing the use of this

  15. Inactivated Recombinant Rabies Viruses Displaying Canine Distemper Virus Glycoproteins Induce Protective Immunity against Both Pathogens.

    Science.gov (United States)

    da Fontoura Budaszewski, Renata; Hudacek, Andrew; Sawatsky, Bevan; Krämer, Beate; Yin, Xiangping; Schnell, Matthias J; von Messling, Veronika

    2017-04-15

    recombinant rabies viruses carrying only the CDV attachment protein according to the same immunization scheme died. Irrespective of the CDV antigens used, all animals developed protective titers against rabies virus, illustrating that a bivalent rabies virus-based vaccine against CDV induces protective immune responses against both pathogens. Copyright © 2017 American Society for Microbiology.

  16. Deposition of idiotype-anti-idiotype immune complexes in renal glomeruli after polyclonal B cell activation

    International Nuclear Information System (INIS)

    Goldman, M.; Rose, L.M.; Hochmann, A.; Lambert, P.H.

    1982-01-01

    We investigated the possible role of idiotypic interactions in the pathogenesis of the glomerular lesions observed in mice undergoing polyclonal B cell activation. BALB/c mice were studied for the presence of renal deposits of T15 idiotype-anti-T15 idiotype-immune complexes (IC) after injection of bacterial lipopolysaccharides (LPS). The T15 idiotype is the major idiotype of BALB/c mice anti-phosphorylcholine (PC) antibodies, which are cross-reactive with the idiotype of the TEPC-15 myeloma protein. This model was used because T15 idiotype-anti-T15 idiotype IC have been detected in the circulation of BALB/c mice after polyclonal B cell activation. First, an idiotype-specific immunofluorescence technique allowed us to detect T15 idiotype-bearing immunoglobulins in glomeruli from day 6 to day 28 after LPS injection. Second, fluorescein isothiocyanate-conjugated TEPC-15 myeloma protein was found to localize in the glomeruli after in vivo injection 18 d after LPS administration. This renal localization was shown to be idiotype-specific and could be quantified in a trace-labeling experiment. Third, kidney-deposited immunoglobulins of mice injected with LPS were eluted, radiolabeled, and analyzed by radioimmunoassay. Both T15 idiotype-bearing immunoglobulins and anti-T15 idiotype antibodies were detected in the eluates, providing further evidence for a renal deposition of T15 idiotype-anti-T15 idiotype IC. Polyclonal B cell activation is likely to result in a simultaneous triggering of many idiotypic clones and of corresponding anti-idiotypic clones represented in the B cell repertoire. This could lead to the formation of a variety of idiotype-anti-idiotype IC that could participate in the development of glomerular lesions

  17. Characterization of NF-κB Reporter U937 Cells and Their Application for the Detection of Inflammatory Immune-Complexes.

    Directory of Open Access Journals (Sweden)

    Csilla Kecse-Nagy

    Full Text Available Our study tested the hypothesis that immunoglobulins differ in their ability to activate the nuclear factor-κB pathway mediated cellular responses. These responses are modulated by several properties of the immune complex, including the ratio of antibody isotypes binding to antigen. Immunoassays allow the measurement of antigen specific antibodies belonging to distinct immunoglobulin classes and subclasses but not the net biological effect of the combination of these antibodies. We set out to develop a biosensor that is suitable for the detection and characterization of antigen specific serum antibodies. We genetically modified the monocytoid U937 cell line carrying Fc receptors with a plasmid encoding NF-κB promoter-driven GFP. This clone, U937-NF-κB, was characterized with respect to FcR expression and response to solid-phase immunoglobulins. Human IgG3, IgG4 and IgG1 induced GFP production in a time- and dose-dependent manner, in this order of efficacy, while IgG2 triggered no activation at the concentrations tested. IgA elicited no response alone but showed significant synergism with IgG3 and IgG4. We confirmed the importance of activation via FcγRI by direct stimulation with monoclonal antibody and by competition assays. We used citrullinated peptides and serum from rheumatoid arthritis patients to generate immune complexes and to study the activation of U937-NF-κB, observing again a synergistic effect between IgG and IgA. Our results show that immunoglobulins have distinct pro-inflammatory potential, and that U937-NF-κB is suitable for the estimation of biological effects of immune-complexes, offering insight into monocyte activation and pathogenesis of antibody mediated diseases.

  18. Immunization of baboons with attenuated schistosomula of Schistosoma haematobium: levels of protection induced by immunization with larvae irradiated with 20 and 60 krad

    International Nuclear Information System (INIS)

    Harrison, R.A.; Bickle, Q.D.; Sturrock, R.F.; Taylor, M.G.; Webbe, G.; Kiare, S.; James, E.R.; Andrews, B.J.

    1990-01-01

    The authors have demonstrated that baboons can be immunized with S. haemotobium schistosomula irradiated with 20 krad in a regimen that induces 90% protection. While this high level of protection has stimulated a discussion on the feasibility of a human volunteer trial (Von Lichtenberg, 1985), results of further studies particularly on (i) the pathogensis of immunization per se (Byram et al., 1989), (ii) the longevity of protection, and (iii) the protective efficacy of cryopreserved irradiated S. haemotobium schistosomula (R. Harrison et al., in preparation), prevent recommending this form of vaccination for human application. (author)

  19. Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation

    Science.gov (United States)

    Viswanathan, Kavitha; Dhabhar, Firdaus S.

    2005-04-01

    Effective immunoprotection requires rapid recruitment of leukocytes into sites of surgery, wounding, infection, or vaccination. In contrast to immunosuppressive chronic stressors, short-term acute stressors have immunoenhancing effects. Here, we quantify leukocyte infiltration within a surgical sponge to elucidate the kinetics, magnitude, subpopulation, and chemoattractant specificity of an acute stress-induced increase in leukocyte trafficking to a site of immune activation. Mice acutely stressed before sponge implantation showed 200-300% higher neutrophil, macrophage, natural killer cell, and T cell infiltration than did nonstressed animals. We also quantified the effects of acute stress on lymphotactin- (LTN; a predominantly lymphocyte-specific chemokine), and TNF-- (a proinflammatory cytokine) stimulated leukocyte infiltration. An additional stress-induced increase in infiltration was observed for neutrophils, in response to TNF-, macrophages, in response to TNF- and LTN, and natural killer cells and T cells in response to LTN. These results show that acute stress initially increases trafficking of all major leukocyte subpopulations to a site of immune activation. Tissue damage-, antigen-, or pathogen-driven chemoattractants subsequently determine which subpopulations are recruited more vigorously. Such stress-induced increases in leukocyte trafficking may enhance immunoprotection during surgery, vaccination, or infection, but may also exacerbate immunopathology during inflammatory (cardiovascular disease or gingivitis) or autoimmune (psoriasis, arthritis, or multiple sclerosis) diseases. chemokine | psychophysiological stress | surgical sponge | wound healing | lymphotactin

  20. Specific Genetic Immunotherapy Induced by Recombinant Vaccine Alpha-Fetoprotein-Heat Shock Protein 70 Complex

    Science.gov (United States)

    Wang, Xiaoping; Lin, Huanping; Wang, Qiaoxia

    Purposes: To construct a recombinant vaccine alpha-fetoprotein (AFP)-heat shock protein (HSP70) complex, and study its ability to induce specific CTL response and its protective effect against AFP-producing tumor. Material/Methods: A recombinant vaccine was constructed by conjugating mouse alpha-fetoprotein to heat shock protein 70. By way of intracutaneous injection, mice were primed and boosted with recombinant vaccine mAFP/HSP70, whereas single mAFP or HSP70 injection as controls. The ELISPOT and ELISA were used to measure the frequency of cells producing the cytokine IFN-γ in splenocytes and the level of anti-AFP antibody of serum from immunized mice respectively. In vivo tumor challenge were carried out to assess the immune effect of the recombinant vaccine. Results: By recombinant mAFP/HSP70 vaccine immunization, the results of ELISPOT and ELISA showed that the number of splenic cells producing IFN-γ and the level of anti-AFP antibody of serum were significantly higher in mAFP/HSP70 group than those in mAFP and HSP70 groups (108.50±11.70 IFN-γ spots/106 cells vs 41.60±10.40 IFN-γ spots/106 cells, 7.32±3.14 IFN-γ spots/106 cells, P<0.01; 156.32±10.42 μg/mL vs 66.52±7.35 μg/mL, 5.73±2.89 μg/mL, P<0.01). The tumor volume in mAFP/HSP70 group was significantly smaller than that in mAFP and HSP70 groups (42.44±7.14 mm3 vs 392.23±12.46 mm3, 838.63±13.84 mm3, P<0.01). Conclusions: The study further confirmed the function of heat shock protein 70's immune adjuvant. Sequential immunization with recombinant mAFP/HSP70 vaccine could generate effective antitumor immunity on AFP-producing tumor. The recombined mAFP/HSP70 vaccine may be suitable for serving as an immunotherapy for hepatocellular carcinoma.

  1. Mucosal immunization using proteoliposome and cochleate structures from Neisseria meningitidis serogroup B induce mucosal and systemic responses.

    Science.gov (United States)

    Campo, Judith Del; Zayas, Caridad; Romeu, Belkis; Acevedo, Reinaldo; González, Elizabeth; Bracho, Gustavo; Cuello, Maribel; Cabrera, Osmir; Balboa, Julio; Lastre, Miriam

    2009-12-01

    Most pathogens either invade the body or establish infection in mucosal tissues and represent an enormous challenge for vaccine development by the absence of good mucosal adjuvants. A proteoliposome-derived adjuvant from Neisseria meningitidis serogroup B (AFPL1, Adjuvant Finlay Proteoliposome 1) and its derived cochleate form (Co, AFCo1) contain multiple pathogen-associated molecular patterns as immunopotentiators, and can also serve as delivery systems to elicit a Th1-type immune response. The present studies demonstrate the ability of AFPL1and AFCo1 to induce mucosal and systemic immune responses by different mucosal immunizations routes and significant adjuvant activity for antibody responses of both structures: a microparticle and a nanoparticle with a heterologous antigen. Therefore, we used female mice immunized by intragastric, intravaginal, intranasal or intramuscular routes with both structures alone or incorporated with ovalbumin (OVA). High levels of specific IgG antibody were detected in all sera and in vaginal washes, but specific IgA antibody in external secretions was only detected in mucosally immunized mice. Furthermore, antigen specific IgG1 and IgG2a isotypes were all induced. AFPL1 and AFCo1 are capable of inducing IFN-gamma responses, and chemokine secretions, like MIP-1alpha and MIP-1beta. However, AFCo1 is a better alternative to induce immune responses at mucosal level. Even when we use a heterologous antigen, the AFCo1 response was better than with AFPL1 in inducing mucosal and systemic immune responses. These results support the use of AFCo1 as a potent Th1 inducing adjuvant particularly suitable for mucosal immunization.

  2. Persistence of Circulating Hepatitis C Virus Antigens-Specific Immune Complexes in Patients with Resolved HCV Infection.

    Science.gov (United States)

    Hu, Ke-Qin; Cui, Wei

    2018-05-01

    Our recent study indicated the possible presence of detectable hepatitis C virus antigens (HCV-Ags) after denaturation of sera with resolved HCV (R-HCV) infection. The present study determined and characterized persistent HCV-Ags-specific immune complexes (ICs) in these patients. Sixty-eight sera with R-HCV and 34 with viremic HCV (V-HCV) infection were tested for free and IC-bound HCV-Ags using HCV-Ags enzyme immunoassay (EIA), the presence of HCV-Ags-specific ICs by immunoprecipitation and Western blot (IP-WB), HCV ICs containing HCV virions using IP and HCV RNA RT-PCR, and correlation of HCV ICs with clinical presentation in these patients. Using HCV-Ags EIA, we found 57.4% of sera with R-HCV infection were tested positive for bound, but not free HCV-Ags. Using pooled or individual anti-HCV E1/E2, cAg, NS3, NS4b, and/or NS5a to precipitate HCV-specific-Ags, we confirmed persistent HCV-Ags ICs specific to various HCV structural and non-structural proteins not only in V-HCV infection, but also in R-HCV infection. Using IP and HCV RNA PCR, we then confirmed the presence of HCV virions within circulating ICs in V-HCV, but not in R-HCV sera. Multivariable analysis indicated significant and independent associations of persistent circulating HCV-Ags-specific ICs with both age and the presence of cirrhosis in patients with R-HCV infection. Various HCV-Ag-specific ICs, but not virions, persist in 57.4% of patients who had spontaneous or treatment-induced HCV clearance for 6 months to 20 years. These findings enriched our knowledge on HCV pathogenesis and support further study on its long-term clinical relevance, such as extrahepatic manifestation, transfusion medicine, and hepatocarcinogenesis.

  3. Immune Aspects of Female Infertility

    Directory of Open Access Journals (Sweden)

    Andrea Brazdova

    2016-05-01

    Full Text Available Immune infertility, in terms of reproductive failure, has become a serious health issue involving approximately 1 out of 5 couples at reproductive age. Semen that is defined as a complex fluid containing sperm, cellular vesicles and other cells and components, could sensitize the female genital tract. The immune rejection of male semen in the female reproductive tract is explained as the failure of natural tolerance leading to local and/or systemic immune response. Present active immune mechanism may induce high levels of anti-seminal/sperm antibodies. It has already been proven that iso-immunization is associated with infertility. Comprehensive studies with regards to the identification of antibody-targets and the determination of specific antibody class contribute to the development of effective immuno-therapy and, on the other hand, potential immuno-contraception, and then of course to complex patient diagnosis. This review summarizes the aspects of female immune infertility.

  4. TU-CD-303-03: Localized Radiation Can Induce Systemic Anti-Cancer Immune and Non-Immune Responses and How We Might Utilize It

    Energy Technology Data Exchange (ETDEWEB)

    Ahmed, M. [National Institutes of Health (United States)

    2015-06-15

    Recent advances in cancer research have shed new light on the complex processes of how therapeutic radiation initiates changes at cellular, tissue, and system levels that may lead to clinical effects. These new advances may transform the way we use radiation to combat certain types of cancers. For the past two decades many technological advancements in radiation therapy have been largely based on the hypothesis that direct radiation-induced DNA double strand breaks cause cell death and thus tumor control and normal tissue damage. However, new insights have elucidated that in addition to causing cellular DNA damage, localized therapeutic radiation also initiates cascades of complex downstream biological responses in tissue that extend far beyond where therapeutic radiation dose is directly deposited. For instance, studies show that irradiated dying tumor cells release tumor antigens that can lead the immune system to a systemic anti-cancer attack throughout the body of cancer patient; targeted irradiation to solid tumor also increases the migration of tumor cells already in bloodstream, the seeds of potential metastasis. Some of the new insights may explain the long ago discovered but still unexplained non-localized radiation effects (bystander effect and abscopal effect) and the efficacy of spatially fractionated radiation therapy (microbeam radiation therapy and GRID therapy) where many “hot” and “cold” spots are intentionally created throughout the treatment volume. Better understanding of the mechanisms behind the non-localized radiation effects creates tremendous opportunities to develop new and integrated cancer treatment strategies that are based on radiotherapy, immunology, and chemotherapy. However, in the multidisciplinary effort to advance new radiobiology, there are also tremendous challenges including a lack of multidisciplinary researchers and imaging technologies for the microscopic radiation-induced responses. A better grasp of the essence of

  5. TU-CD-303-03: Localized Radiation Can Induce Systemic Anti-Cancer Immune and Non-Immune Responses and How We Might Utilize It

    International Nuclear Information System (INIS)

    Ahmed, M.

    2015-01-01

    Recent advances in cancer research have shed new light on the complex processes of how therapeutic radiation initiates changes at cellular, tissue, and system levels that may lead to clinical effects. These new advances may transform the way we use radiation to combat certain types of cancers. For the past two decades many technological advancements in radiation therapy have been largely based on the hypothesis that direct radiation-induced DNA double strand breaks cause cell death and thus tumor control and normal tissue damage. However, new insights have elucidated that in addition to causing cellular DNA damage, localized therapeutic radiation also initiates cascades of complex downstream biological responses in tissue that extend far beyond where therapeutic radiation dose is directly deposited. For instance, studies show that irradiated dying tumor cells release tumor antigens that can lead the immune system to a systemic anti-cancer attack throughout the body of cancer patient; targeted irradiation to solid tumor also increases the migration of tumor cells already in bloodstream, the seeds of potential metastasis. Some of the new insights may explain the long ago discovered but still unexplained non-localized radiation effects (bystander effect and abscopal effect) and the efficacy of spatially fractionated radiation therapy (microbeam radiation therapy and GRID therapy) where many “hot” and “cold” spots are intentionally created throughout the treatment volume. Better understanding of the mechanisms behind the non-localized radiation effects creates tremendous opportunities to develop new and integrated cancer treatment strategies that are based on radiotherapy, immunology, and chemotherapy. However, in the multidisciplinary effort to advance new radiobiology, there are also tremendous challenges including a lack of multidisciplinary researchers and imaging technologies for the microscopic radiation-induced responses. A better grasp of the essence of

  6. Effect of isologous and autologous insulin antibodies on in vivo bioavailability and metabolic fate of immune-complexed insulin in Lou/M rats

    International Nuclear Information System (INIS)

    Arquilla, E.R.; McDougall, B.R.; Stenger, D.P.

    1989-01-01

    The in vivo bioavailability, distribution, and metabolic fate of 125I-labeled insulin complexed to isologous and autologous antibodies were studied in inbred Lou/M rats. There was an impaired bioavailability of the 125I-insulin bound to the isologous and autologous antibodies. Very little of the 125I-insulin in these immune complexes could bind to insulin receptors on hepatocytes or renal tubular cells and be degraded, because the amounts of 125I from degraded 125I-insulin in the blood or secreted into the stomach were markedly attenuated in both cases for at least 30 min after injection. There was a simultaneous accumulation of 125I-insulin immune complexes in the liver and the kidneys of Lou/M rats injected with 125I-insulin complexed with isologous antibodies or when insulin-immunized Lou/M rats were injected with 125I-insulin during the same interval. The impaired bioavailability of immune-complexed insulin and altered distribution of radioactivity due to the accumulation of immune complexes in the liver and kidney were also observed in previous experiments in which Lewis rats were injected with xenogenic guinea pig and homologous insulin antibodies. These observations are therefore submitted as evidence that the Lou/M rat is a valid model in which to study the bioavailability of insulin immune complexed to isologous, homologous, and xenogenic antibodies and the metabolic fate of the respective insulin-antibody immune complexes

  7. Vaccination with lipid core peptides fails to induce epitope-specific T cell responses but confers non-specific protective immunity in a malaria model.

    Directory of Open Access Journals (Sweden)

    Simon H Apte

    Full Text Available Vaccines against many pathogens for which conventional approaches have failed remain an unmet public health priority. Synthetic peptide-based vaccines offer an attractive alternative to whole protein and whole organism vaccines, particularly for complex pathogens that cause chronic infection. Previously, we have reported a promising lipid core peptide (LCP vaccine delivery system that incorporates the antigen, carrier, and adjuvant in a single molecular entity. LCP vaccines have been used to deliver several peptide subunit-based vaccine candidates and induced high titre functional antibodies and protected against Group A streptococcus in mice. Herein, we have evaluated whether LCP constructs incorporating defined CD4(+ and/or CD8(+ T cell epitopes could induce epitope-specific T cell responses and protect against pathogen challenge in a rodent malaria model. We show that LCP vaccines failed to induce an expansion of antigen-specific CD8(+ T cells following primary immunization or by boosting. We further demonstrated that the LCP vaccines induced a non-specific type 2 polarized cytokine response, rather than an epitope-specific canonical CD8(+ T cell type 1 response. Cytotoxic responses of unknown specificity were also induced. These non-specific responses were able to protect against parasite challenge. These data demonstrate that vaccination with lipid core peptides fails to induce canonical epitope-specific T cell responses, at least in our rodent model, but can nonetheless confer non-specific protective immunity against Plasmodium parasite challenge.

  8. SUMO-, MAPK- and resistance protein-signaling converge at transcription complexes that regulate plant innate immunity

    NARCIS (Netherlands)

    Burg, van den H.A.; Takken, F.L.W.

    2010-01-01

    Upon pathogen perception plant innate immune receptors activate various signaling pathways that trigger host defenses. PAMP-triggered defense signaling requires mitogen-activated protein kinase (MAPK) pathways, which modulate the activity of transcription factors through phosphorylation. Here, we

  9. SUMO-, MAPK-, and resistance protein-signaling converge at transcription complexes that regulate plant innate immunity

    NARCIS (Netherlands)

    van den Burg, H.A.; Takken, F.L.W.

    2010-01-01

    Upon pathogen perception plant innate immune receptors activate various signaling pathways that trigger host defenses. PAMP-triggered defense signaling requires mitogen-activated protein kinase (MAPK) pathways, which modulate the activity of transcription factors through phosphorylation. Here, we

  10. Evidence against the existence of specific Schistosoma mansoni subpopulations which are resistant to irradiated vaccine-induced immunity

    International Nuclear Information System (INIS)

    Lewis, F.A.; Hieny, S.; Sher, A.

    1985-01-01

    When mice are immunized with irradiated Schistosoma mansoni cercariae a proportion of the subsequent cercarial challenge always escapes killing and matures to egg-laying adults. This report investigates the possibility that incomplete immunity in this system is governed by a genetically-determined insusceptibility of a particular schistosome subpopulation. To do this the authors tested whether more immunoresistant schistosomes would develop following successive passages of progeny of the resistant worms through immunized mice. Mice were immunized with 500 50 Krad-irradiated cercariae, and challenged with normal cercariae when immunity was at its peak. After five successive passages through snails and immune mice, progeny of those parasites which escaped immune killing were no more refractory to vaccine-induced resistance than the original stock maintained in nonimmune mice. Additionally, the passaged isolates did not differ from the original stock in their ability to induce protection following irradiation. The results indicate that with this model of acquired resistance incomplete immunity is unlikely to be due to a subpopulation of the parasites possessing a genetically-determined insusceptibility to killing

  11. Procedure for Selection of Suitable Resources in Interactions in Complex Dynamic Systems Using Artificial Immunity

    Directory of Open Access Journals (Sweden)

    Naors Y. anadalsaleem

    2017-03-01

    Full Text Available The dynamic optimization procedure for -dimensional vector function of a system, the state of which is interpreted as adaptable immune cell, is considered Using the results of the theory of artificial immune systems. The procedures for estimate of monitoring results are discussed. The procedure for assessing the entropy is recommended as a general recursive estimation algorithm. The results are focused on solving the optimization problems of cognitive selection of suitable physical resources, what expands the scope of Electromagnetic compatibility.

  12. The tumor necrosis factor-alpha-induced protein 8 family in immune homeostasis and inflammatory cancer diseases.

    Science.gov (United States)

    Luan, Y Y; Yao, Y M; Sheng, Z Y

    2013-01-01

    Within the immune system homeostasis is maintained by a myriad of mechanisms that include the regulation of immune cell activation and programmed cell death. The breakdown of immune homeostasis may lead to fatal inflammatory diseases. We set out to identify genes of tumor necrosis factor-alpha-induced protein 8 (TNFAIP8) family that has a functional role in the process of immune homeostasis. Tumor necrosis factor-alpha-induced protein 8 (TNFAIP8), which functions as an oncogenic molecule, is also associated with enhanced cell survival and inhibition of apoptosis. Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) governs immune homeostasis in both the innate and adaptive immune system and prevents hyper-responsiveness by negatively regulating signaling via T cell receptors and Toll-like receptors (TLRs). There also exist two highly homologous but uncharacterized proteins, TIPE1 and TIPE3. This review is an attempt to provide a summary of TNFAIP8 family associated with immune homeostasis and inflammatory cancer diseases.

  13. Immunization with Paracoccidioides brasiliensis radioattenuated yeast cells induces Th1 immune response in Balb/C mice

    International Nuclear Information System (INIS)

    Martins, Estefania M.N.; Andrade, Antero S.R.; Resende, Maria Aparecida de; Reis, Bernardo S.; Goes, Alfredo M.

    2009-01-01

    Paracoccidioides brasiliensis is the agent of paracoccidioidomycosis, the most prevalent mycosis in Latin America. To date, there is no effective vaccine. In our laboratory yeast cells of P. brasiliensis were attenuated by gamma irradiation. We defined an absorbed dose in which the pathogen loses the reproductive ability, while retaining the morphology, the synthesis and secretion of proteins and the oxidative metabolism. The immunization with these cells was able to confer protection in BALB/c mice. The aim of the present work was evaluate the immune response pathway activated in mice immunized with P. brasiliensis radioattenuated yeast cells. The protector effect was evaluated in BALB/c mice groups immunized once or twice, respectively. Each group was divided in three sub groups that were challenge 30, 45 or 60 days after the immunization. These groups were called G1A, G1B and G1C in the group immunized once and G2A, G2B and G2C in the group immunized twice. Recovery of CFUs and cytokines determination (IFN - γ, IL - 10 and IL IV 4) were performed three months post challenge. Quantitative RT-PCR was the method of choice used to quantify the expression of cytokines. The sera were collected weekly to evaluate the IgG antibody titers and the IgG1 and IgG2a pattern in the course of infection. A significant reduction in CFUs recovery was verified 90 days post challenge in mice submitted to one immunization: 73.0%, 96.0% and 76.3% for sub-groups G1A, G1B and G1C, respectively. In the group submitted to two immunizations, a remarkable increase in the protection was obtained. No CFUs was recovered from sub-groups G2B and G2C and very few CFUs (reduction of 98.6%) were recovered from the lungs of sub group G2A. In mice submitted to one immunization, Th1 and Th2 cytokines were simultaneously produced. In the group submitted to two immunizations, levels of IL-10 and IL-4 were very low, while IFN-γ production was maintained indicating that a Th1 pattern was dominant. For

  14. Immunization with Paracoccidioides brasiliensis radioattenuated yeast cells induces Th1 immune response in Balb/C mice

    Energy Technology Data Exchange (ETDEWEB)

    Martins, Estefania M.N.; Andrade, Antero S.R. [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN-CNEN/MG), Belo Horizonte, MG (Brazil)], e-mail: estefaniabio@yahoo.com.br, e-mail: antero@cdtn.br; Resende, Maria Aparecida de [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Dept. de Microbiologia], e-mail: maresend@mono.icb.ufmg.br; Reis, Bernardo S.; Goes, Alfredo M. [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Dept. de Bioquimica e Imunologia], e-mail: goes@mono.icb.ufmg.br, e-mail: brsgarbi@mono.icb.ufmg.br

    2009-07-01

    Paracoccidioides brasiliensis is the agent of paracoccidioidomycosis, the most prevalent mycosis in Latin America. To date, there is no effective vaccine. In our laboratory yeast cells of P. brasiliensis were attenuated by gamma irradiation. We defined an absorbed dose in which the pathogen loses the reproductive ability, while retaining the morphology, the synthesis and secretion of proteins and the oxidative metabolism. The immunization with these cells was able to confer protection in BALB/c mice. The aim of the present work was evaluate the immune response pathway activated in mice immunized with P. brasiliensis radioattenuated yeast cells. The protector effect was evaluated in BALB/c mice groups immunized once or twice, respectively. Each group was divided in three sub groups that were challenge 30, 45 or 60 days after the immunization. These groups were called G1A, G1B and G1C in the group immunized once and G2A, G2B and G2C in the group immunized twice. Recovery of CFUs and cytokines determination (IFN - {gamma}, IL - 10 and IL IV 4) were performed three months post challenge. Quantitative RT-PCR was the method of choice used to quantify the expression of cytokines. The sera were collected weekly to evaluate the IgG antibody titers and the IgG1 and IgG2a pattern in the course of infection. A significant reduction in CFUs recovery was verified 90 days post challenge in mice submitted to one immunization: 73.0%, 96.0% and 76.3% for sub-groups G1A, G1B and G1C, respectively. In the group submitted to two immunizations, a remarkable increase in the protection was obtained. No CFUs was recovered from sub-groups G2B and G2C and very few CFUs (reduction of 98.6%) were recovered from the lungs of sub group G2A. In mice submitted to one immunization, Th1 and Th2 cytokines were simultaneously produced. In the group submitted to two immunizations, levels of IL-10 and IL-4 were very low, while IFN-{gamma} production was maintained indicating that a Th1 pattern was

  15. Yulangsan polysaccharide improves redox homeostasis and immune impairment in D-galactose-induced mimetic aging.

    Science.gov (United States)

    Doan, Van Minh; Chen, Chunxia; Lin, Xing; Nguyen, Van Phuc; Nong, Zhihuan; Li, Weisi; Chen, Qingquan; Ming, Jianjun; Xie, Qiuqiao; Huang, Renbin

    2015-05-01

    Yulangsan polysaccharide (YLSP) is a traditional Chinese medicine used in long-term treatment as a modulator of brain dysfunction and immunity. In this study, we evaluated the protective effect of YLSP against D-galactose-induced impairment of oxidative stress and the immune system and evaluated its possible mechanism of action. D-galactose was subcutaneously injected into the dorsal neck of mice daily for 8 weeks to establish the aging model. YLSP was simultaneously administered once daily. The results indicate that YLSP significantly improves the general appearance of the aging mice. YLSP significantly increased the levels of antioxidant enzymes, such as super oxide dismutase, glutathione peroxidase, catalase and total anti-oxidation capability, while decreasing the content of malondialdehyde in different tissues, including the liver, brain, and serum. YLSP also increased the interleukin-2 level while decreasing the interleukin-6 level. Moreover, YLSP significantly inhibited advanced glycation end product formation. Furthermore, YLSP decreased p21 and p53 gene expressions in the liver and brain of D-galactose-treated mice. These results suggest that YLSP may have a protective effect suppressing the aging process by enhancing antioxidant activity and immunity, as well as modulating aging-related gene expression.

  16. Immunization of mice with LRP4 induces myasthenia similar to MuSK-associated myasthenia gravis.

    Science.gov (United States)

    Mori, Shuuichi; Motohashi, Norio; Takashima, Rumi; Kishi, Masahiko; Nishimune, Hiroshi; Shigemoto, Kazuhiro

    2017-11-01

    Since the first report of experimental animal models of myasthenia gravis (MG) with autoantibodies against low-density lipoprotein receptor-related protein 4 (LRP4), there have not been any major reports replicating the pathogenicity of anti-LRP4 antibodies (Abs). Recent clinical studies have cast doubt on the specificity and pathogenicity of anti-LRP4 antibodies for MG, highlighting the need for further research. In this study, we purified antigens corresponding to the extracellular region of human LRP4 stably expressed with chaperones in 293 cells and used these antigens to immunize female A/J mice. Immunization with LRP4 protein caused mice to develop myasthenia having similar electrophysiological and histological features as are observed in MG patients with circulating Abs against muscle-specific kinase (MuSK). Our results clearly demonstrate that active immunization of mice with LRP4 proteins causes myasthenia similar to the MG induced by anti-MuSK Abs. Further experimental and clinical studies are required to prove the pathogenicity of anti-LRP4 Abs in MG patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  17. PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia.

    Science.gov (United States)

    Padua, Rose Ann; Larghero, Jerome; Robin, Marie; le Pogam, Carol; Schlageter, Marie-Helene; Muszlak, Sacha; Fric, Jan; West, Robert; Rousselot, Philippe; Phan, Thi Hai; Mudde, Liesbeth; Teisserenc, Helene; Carpentier, Antoine F; Kogan, Scott; Degos, Laurent; Pla, Marika; Bishop, J Michael; Stevenson, Freda; Charron, Dominique; Chomienne, Christine

    2003-11-01

    Despite improved molecular characterization of malignancies and development of targeted therapies, acute leukemia is not curable and few patients survive more than 10 years after diagnosis. Recently, combinations of different therapeutic strategies (based on mechanisms of apoptosis, differentiation and cytotoxicity) have significantly increased survival. To further improve outcome, we studied the potential efficacy of boosting the patient's immune response using specific immunotherapy. In an animal model of acute promyelocytic leukemia, we developed a DNA-based vaccine by fusing the human promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) oncogene to tetanus fragment C (FrC) sequences. We show for the first time that a DNA vaccine specifically targeted to an oncoprotein can have a pronounced effect on survival, both alone and when combined with all-trans retinoic acid (ATRA). The survival advantage is concomitant with time-dependent antibody production and an increase in interferon-gamma (IFN-gamma). We also show that ATRA therapy on its own triggers an immune response in this model. When DNA vaccination and conventional ATRA therapy are combined, they induce protective immune responses against leukemia progression in mice and may provide a new approach to improve clinical outcome in human leukemia.

  18. Plasmodium berghei: immunosuppression of the cell-mediated immune response induced by nonviable antigenic preparations

    International Nuclear Information System (INIS)

    Gross, A.; Frankenburg, S.

    1989-01-01

    In this work, plasmodial antigens were examined for their ability to suppress the cellular immune response during lethal Plasmodium berghei infection. Splenic enlargement and the number and function of white spleen cells were assessed after injection of normal mice with irradiated parasitized erythrocytes (IPE) or with parasitized erythrocytes (PE) membranes. Both IPE and PE membranes caused splenomegaly and an increase in the number of splenic white cells with concurrent alteration of the relative proportions of T cells and macrophages. The percentage of T lymphocytes was fractionally diminished, but there was a marked increase in Lyt 2.2 positive (suppressor and cytotoxic) T subsets and in the number of splenic macrophage precursors. The pathological enlargement of the spleen was induced by various plasma membrane-derived antigens containing both proteins and carbohydrates. Splenocytes of mice injected with liposomes containing deoxycholate-treated PE or PE fractions showed both diminished interleukin 2 production and a decreased response to mitogen. It appears that some of the changes in the cellular immune response during P. berghei infection are a consequence of the massive provision of a wide spectrum of antigens, capable of suppressing the immune response. Thus, it may be appropriate to evaluate the possible negative effect of parasite epitopes that are candidates for vaccine

  19. Neutralized adenovirus-immune complexes can mediate effective gene transfer via an Fc receptor-dependent infection pathway.

    Science.gov (United States)

    Leopold, Philip L; Wendland, Rebecca L; Vincent, Theresa; Crystal, Ronald G

    2006-10-01

    Neutralization of adenovirus (Ad) by anti-Ad neutralizing antibodies in serum involves formation of Ad-immune complexes that prevent the virus from interacting with target cells. We hypothesized that Ad-immune complexes likely contain viable Ad vectors which, although no longer capable of gaining access to receptors on target cells, may be able to express transgenes in cells bearing Fc receptors for immunoglobulins, i.e., that antibody-based "neutralization" of Ad vectors may be circumvented by the Fc receptor pathway. To test this hypothesis, we expressed the Fcgamma receptor IIA (FcgammaR) in A549 lung epithelial cells or human dermal fibroblasts and evaluated gene transfer in the presence of human neutralizing anti-Ad serum. FcgammaR-expressing cells bound and internalized copious amounts of Ad, with a distinct population of internalized Ad trafficking to the nucleus. The dose-response curves for inhibition of gene transfer revealed that FcgammaR-expressing cells required a more-than-10-fold higher concentration of anti-Ad serum to achieve 50% inhibition of Ad-encoded beta-galactosidase expression compared with non-FcgammaR-expressing cells. The discrepancy between neutralization of Ad during infection of FcgammaR-expressing cells and neutralization of Ad during infection of non-FcgammaR-expressing cells occurred with either heat-inactivated or non-heat-inactivated sera, was blocked by addition of purified Fc domain protein, and did not require the cytoplasmic domain of FcgammaR, suggesting that immune complex internalization proceeded via endocytosis rather than phagocytosis. FcgammaR-mediated infection by Ad-immune complexes did not require expression of the coxsackie virus-Ad receptor (CAR) since similar data were obtained when CAR-deficient human dermal fibroblasts were engineered to express FcgammaR. However, interaction of the Ad penton base with cell surface integrins contributed to the difference in neutralization between FcgammaR-expressing and non

  20. Membrane microdomains and the cytoskeleton constrain AtHIR1 dynamics and facilitate the formation of an AtHIR1-associated immune complex.

    Science.gov (United States)

    Lv, Xueqin; Jing, Yanping; Xiao, Jianwei; Zhang, Yongdeng; Zhu, Yingfang; Julian, Russell; Lin, Jinxing

    2017-04-01

    Arabidopsis hypersensitive-induced reaction (AtHIR) proteins function in plant innate immunity. However, the underlying mechanisms by which AtHIRs participate in plant immunity remain elusive. Here, using VA-TIRFM and FLIM-FRET, we revealed that AtHIR1 is present in membrane microdomains and co-localizes with the membrane microdomain marker REM1.3. Single-particle tracking analysis revealed that membrane microdomains and the cytoskeleton, especially microtubules, restrict the lateral mobility of AtHIR1 at the plasma membrane and facilitate its oligomerization. Furthermore, protein proximity index measurements, fluorescence cross-correlation spectroscopy, and biochemical experiments demonstrated that the formation of the AtHIR1 complex upon pathogen perception requires intact microdomains and cytoskeleton. Taken together, these findings suggest that microdomains and the cytoskeleton constrain AtHIR1 dynamics, promote AtHIR1 oligomerization, and increase the efficiency of the interactions of AtHIR1 with components of the AtHIR1 complex in response to pathogens, thus providing valuable insight into the mechanisms of defense-related responses in plants. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  1. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists' perspective.

    Science.gov (United States)

    Karamchandani, Dipti M; Chetty, Runjan

    2018-04-27

    Immune checkpoint inhibitors (CPIs) are a relatively new class of 'miracle' dugs that have revolutionised the treatment and prognosis of some advanced-stage malignancies, and have increased the survival rates significantly. This class of drugs includes cytotoxic T lymphocyte antigen-4 inhibitors such as ipilimumab; programmed cell death protein-1 inhibitors such as nivolumab, pembrolizumab and avelumab; and programmed cell death protein ligand-1 inhibitors such as atezolizumab. These drugs stimulate the immune system by blocking the coinhibitory receptors on the T cells and lead to antitumoural response. However, a flip side of these novel drugs is immune-related adverse events (irAEs), secondary to immune-mediated process due to disrupted self-tolerance. The irAEs in the gastrointestinal (GI) tract/liver may result in diarrhoea, colitis or hepatitis. An accurate diagnosis of CPI-induced colitis and/or hepatitis is essential for optimal patient management. As we anticipate greater use of these drugs in the future given the significant clinical response, pathologists need to be aware of the spectrum of histological findings that may be encountered in GI and/or liver biopsies received from these patients, as well as differentiate them from its histopathological mimics. This present review discusses the clinical features, detailed histopathological features, management and the differential diagnosis of the luminal GI and hepatic irAEs that may be encountered secondary to CPI therapy. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  2. Mechanism study of tumor-specific immune responses induced by laser immunotherapy

    Science.gov (United States)

    Li, Xiaosong; Zhou, Feifan; Le, Henry; Wolf, Roman F.; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

    2011-03-01

    Laser immunotherapy (LIT) has shown its efficacy against late-stage, metastatic cancers, both in pre-clinical studies and clinical pilot trials. However, the possible mechanism of LIT is still not fully understood. In our previous studies, we have shown that LIT induces tumor-specific antibodies that strongly bind to the target tumors. Tumor resistance in cured animals demonstrated long-term immunological effect of LIT. Successful transfer of adoptive immunity using spleen cells from LIT-cured animals indicated a long-term immunological memory of the host system. In clinical trials for the treatment of late-stage melanoma patients and breast cancer patients, the similar long-term, systemic effects have also been observed. To further study the immunological mechanism of LIT, immuno-histochemical analysis of patient tumor samples has performed before and after LIT treatment. Our results showed strong evidence that LIT significantly increases the infiltration of immune cells in the target tumors. Specifically, LIT appeared to drive the infiltrating immune cell populations in the direction of CD4, CD8 and CD68 T-cells. It is possible that activation and enhancement of both humeral and cellular arms of the host immune system are achievable by the treatment of LIT. These special features of LIT have contributed to the success of patient treatment. The underlying mechanism of LIT appears to be an in-situ autologous whole-cell cancer vaccination, using all components of tumors as sources of tumor antigens. Our preliminary mechanistic studies and future in-depth studies will contribute to the understanding and development of LIT as an effective modality for the treatment of late stage cancer patients who are facing severely limited options.

  3. Loss of Roquin induces early death and immune deregulation but not autoimmunity

    Science.gov (United States)

    Bertossi, Arianna; Aichinger, Martin; Sansonetti, Paola; Lech, Maciej; Neff, Frauke; Pal, Martin; Wunderlich, F. Thomas; Anders, Hans-Joachim; Klein, Ludger

    2011-01-01

    The substitution of one amino acid in the Roquin protein by the sanroque mutation induces a dramatic autoimmune syndrome in mice. This is believed to occur through ectopic expression of inducible T cell co-stimulator (ICOS) and unrestrained differentiation of follicular T helper cells, which induce spontaneous germinal center reactions to self-antigens. In this study, we demonstrate that tissue-specific ablation of Roquin in T or B cells, in the entire hematopoietic system, or in epithelial cells of transplanted thymi did not cause autoimmunity. Loss of Roquin induced elevated expression of ICOS through T cell–intrinsic and –extrinsic mechanisms, which itself was not sufficient to break self-tolerance. Instead, ablation of Roquin in the hematopoietic system caused defined changes in immune homeostasis, including the expansion of macrophages, eosinophils, and T cell subsets, most dramatically CD8 effector–like T cells, through cell-autonomous and nonautonomous mechanisms. Germline Roquin deficiency led to perinatal lethality, which was partially rescued on the genetic background of an outbred strain. However, not even complete absence of Roquin resulted in overt self-reactivity, suggesting that the sanroque mutation induces autoimmunity through an as yet unknown mechanism. PMID:21844204

  4. Ficolins do not alter host immune responses to lipopolysaccharide-induced inflammation in vivo

    DEFF Research Database (Denmark)

    Genster, Ninette; Østrup, Olga; Schjalm, Camilla

    2017-01-01

    . Yet, the contribution of ficolins to inflammatory disease processes remains elusive. To address this, we investigated ficolin deficient mice during a lipopolysaccharide (LPS)-induced model of systemic inflammation. Although murine serum ficolin was shown to bind LPS in vitro, there was no difference...... an unaltered spleen transcriptome profile in ficolin deficient mice compared to wildtype mice. Collectively, results from this study demonstrate that ficolins are not involved in host response to LPS-induced systemic inflammation.......Ficolins are a family of pattern recognition molecules that are capable of activating the lectin pathway of complement. A limited number of reports have demonstrated a protective role of ficolins in animal models of infection. In addition, an immune modulatory role of ficolins has been suggested...

  5. Duox2-induced innate immune responses in the respiratory epithelium and intranasal delivery of Duox2 DNA using polymer that mediates immunization.

    Science.gov (United States)

    Jeon, Yung Jin; Kim, Hyun Jik

    2018-05-01

    Respiratory mucosa especially nasal epithelium is well known as the first-line barrier of air-borne pathogens. High levels of reactive oxygen species (ROS) are detected in in vitro cultured human epithelial cells and in vivo lung. With identification of NADPH oxidase (Nox) system of respiratory epithelium, the antimicrobial role of ROS has been studied. Duox2 is the most abundant Nox isoform and produces the regulated amount of ROS in respiratory epithelium. Duox2-derived ROS are involved in antiviral innate immune responses but more studies are needed to verify the mechanism. In respiratory epithelium, Duox2-derived ROS is critical for recognition of virus through families retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) at the early stage of antiviral innate immune responses. Various secreted interferons (IFNs) play essential roles for antiviral host defense by downstream cell signaling, and transcription of IFN-stimulated genes is started to suppress viral replication. Type I and type III IFNs are verified more responsible for influenza A virus (IAV) infection in respiratory epithelium and Duox2 is required to regulate IFN-related immune responses. Transient overexpression of Duox2 using cationic polymer polyethylenimine (PEI) induces secretion of type I and type III IFNs and significantly attenuated IAV replication in respiratory epithelium. Here, we discuss Duox2-mediated antiviral innate immune responses and the role of Duox2 as a mucosal vaccine to resist respiratory viral infection.

  6. ERAP1 overexpression in HPV-induced malignancies: A possible novel immune evasion mechanism.

    Science.gov (United States)

    Steinbach, Alina; Winter, Jan; Reuschenbach, Miriam; Blatnik, Renata; Klevenz, Alexandra; Bertrand, Miriam; Hoppe, Stephanie; von Knebel Doeberitz, Magnus; Grabowska, Agnieszka K; Riemer, Angelika B

    2017-01-01

    Immune evasion of tumors poses a major challenge for immunotherapy. For human papillomavirus (HPV)-induced malignancies, multiple immune evasion mechanisms have been described, including altered expression of antigen processing machinery (APM) components. These changes can directly influence epitope presentation and thus T-cell responses against tumor cells. To date, the APM had not been studied systematically in a large array of HPV + tumor samples. Therefore in this study, systematic expression analysis of the APM was performed on the mRNA and protein level in a comprehensive collection of HPV16 + cell lines. Subsequently, HPV + cervical tissue samples were examined by immunohistochemistry. ERAP1 (endoplasmic reticulum aminopeptidase 1) was the only APM component consistently altered - namely overexpressed - in HPV16 + tumor cell lines. ERAP1 was also found to be overexpressed in cervical intraepithelial neoplasia and cervical cancer samples; expression levels were increasing with disease stage. On the functional level, the influence of ERAP1 expression levels on HPV16 E7-derived epitope presentation was investigated by mass spectrometry and in cytotoxicity assays with HPV16-specific T-cell lines. ERAP1 overexpression did not cause a complete destruction of any of the HPV epitopes analyzed, however, an influence of ERAP1 overexpression on the presentation levels of certain HPV epitopes could be demonstrated by HPV16-specific CD8 + T-cells. These showed enhanced killing toward HPV16 + CaSki cells whose ERAP1 expression had been attenuated to normal levels. ERAP1 overexpression may thus represent a novel immune evasion mechanism in HPV-induced malignancies, in cases when presentation of clinically relevant epitopes is reduced by overactivity of this peptidase.

  7. DEMONSTRATION OF ELECTROCHEMICAL REMEDIATION TECHNOLOGIES-INDUCED COMPLEXATION

    Energy Technology Data Exchange (ETDEWEB)

    Barry L. Burks

    2002-12-01

    The Project Team is submitting this Topical Report on the results of its bench-scale demonstration of ElectroChemical Remediation Technologies (ECRTs) and in particular the Induced Complexation (ECRTs-IC) process for remediation of mercury contaminated soils at DOE Complex sites. ECRTs is an innovative, in-situ, geophysically based soil remediation technology with over 50 successful commercial site applications involving remediation of over two million metric tons of contaminated soils. ECRTs-IC has been successfully used to remediate 220 cu m of mercury-contaminated sediments in the Union Canal, Scotland. In that operation, ECRTs-IC reduced sediment total mercury levels from an average of 243 mg/kg to 6 mg/kg in 26 days of operation. The clean up objective was to achieve an average total mercury level in the sediment of 20 mg/kg.

  8. Laser-induced immune modulation inhibits tumor growth in vivo (Conference Presentation)

    Science.gov (United States)

    Ottaviani, Giulia; Martinelli, Valentina; Rupel, Katia; Caronni, Nicoletta; Naseem, Asma; Zandonà, Lorenzo; Perinetti, Giuseppe; Gobbo, Margherita; Di Lenarda, Roberto; Bussani, Rossana; Benvenuti, Federica; Giacca, Mauro; Biasotto, Matteo; Zacchigna, Serena

    2017-02-01

    Photobiomodulation stands as a recommended therapy for oral mucositis induced by oncological therapies. However, its mechanisms of action and, more importantly, its safety in cancer patients, are still unclear. We assessed cancer cell metabolism and proliferation in vitro and in vivo after exposure to different laser protocols. We exploited both ectopic melanoma and a more physiological oral carcinogenesis mouse model, followed by molecular, histological and immunohistochemical characterization. Laser irradiation resulted in a slightly increase in cell metabolism and proliferation in vitro, albeit each protocol exerted a difference response. Of notice, in vivo laser light reduced tumour growth and invasiveness, indicating e beneficial effect on tumor microenvironment. Laser-treated tumors were surrounded and infiltrated by immune cells, mainly lymphocytes and dendritic cells, paralleled by an enhanced secretion of type I interferons. In contrast, the number of pro-angiogenic macrophages was reduced in response to laser irradiation, with consequent normalization of the tumor vasculature. Based on these finding we have also started exploring the effect of photobiomodulation on lymphocyte response in an experimental model of vaccination. Preliminary data indicate that laser light induced antigen-specific CD8+ and CD4+ T cell responses. In conclusion, our data point toward photobiomodulation as an effective strategy to boost the immune response in vivo, with relevant, therapeutic activities in both cancer and vaccination experimental models. These results support the safe use of laser light on cancer patients and open the way to innovative therapeutic opportunities.

  9. Vaccination with dengue virus-like particles induces humoral and cellular immune responses in mice

    Directory of Open Access Journals (Sweden)

    Zhang Quanfu

    2011-06-01

    Full Text Available Abstract Background The incidence of dengue, an infectious disease caused by dengue virus (DENV, has dramatically increased around the world in recent decades and is becoming a severe public health threat. However, there is currently no specific treatment for dengue fever, and licensed vaccine against dengue is not available. Vaccination with virus-like particles (VLPs has shown considerable promise for many viral diseases, but the effect of DENV VLPs to induce specific immune responses has not been adequately investigated. Results By optimizing the expression plasmids, recombinant VLPs of four antigenically different DENV serotypes DENV1-4 were successfully produced in 293T cells. The vaccination effect of dengue VLPs in mice showed that monovalent VLPs of each serotype stimulated specific IgG responses and potent neutralizing antibodies against homotypic virus. Tetravalent VLPs efficiently enhanced specific IgG and neutralizing antibodies against all four serotypes of DENV. Moreover, vaccination with monovalent or tetravalent VLPs resulted in the induction of specific cytotoxic T cell responses. Conclusions Mammalian cell expressed dengue VLPs are capable to induce VLP-specific humoral and cellular immune responses in mice, and being a promising subunit vaccine candidate for prevention of dengue virus infection.

  10. Immunity induced shortly after DNA vaccination of rainbow trout against rhabdoviruses protects against heterologous virus but not against bacterial pathogens

    DEFF Research Database (Denmark)

    Lorenzen, Niels; Lorenzen, Ellen; Einer-Jensen, Katja

    2002-01-01

    whereas no increased survival was found upon challenge with bacterial pathogens. Within two months after vaccination, the cross-protection disappeared while the specific immunity to homologous virus remained high. The early immunity induced by the DNA vaccines thus appeared to involve short-lived non......It was recently reported that DNA vaccination of rainbow trout fingerlings against viral hemorrhagic septicaemia virus (VHSV) induced protection within 8 days after intramuscular injection of plasmid DNA. In order to analyse the specificity of this early immunity, fish were vaccinated with plasmid...... DNA encoding the VHSV or the infectious haematopoietic necrosis virus (IHNV) glycoprotein genes and later challenged with homologous or heterologous pathogens. Challenge experiments revealed that immunity established shortly after vaccination was cross-protective between the two viral pathogens...

  11. Complex DNA Damage: A Route to Radiation-Induced Genomic Instability and Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Ifigeneia V. Mavragani

    2017-07-01

    Full Text Available Cellular effects of ionizing radiation (IR are of great variety and level, but they are mainly damaging since radiation can perturb all important components of the cell, from the membrane to the nucleus, due to alteration of different biological molecules ranging from lipids to proteins or DNA. Regarding DNA damage, which is the main focus of this review, as well as its repair, all current knowledge indicates that IR-induced DNA damage is always more complex than the corresponding endogenous damage resulting from endogenous oxidative stress. Specifically, it is expected that IR will create clusters of damage comprised of a diversity of DNA lesions like double strand breaks (DSBs, single strand breaks (SSBs and base lesions within a short DNA region of up to 15–20 bp. Recent data from our groups and others support two main notions, that these damaged clusters are: (1 repair resistant, increasing genomic instability (GI and malignant transformation and (2 can be considered as persistent “danger” signals promoting chronic inflammation and immune response, causing detrimental effects to the organism (like radiation toxicity. Last but not least, the paradigm shift for the role of radiation-induced systemic effects is also incorporated in this picture of IR-effects and consequences of complex DNA damage induction and its erroneous repair.

  12. Priming of innate antimycobacterial immunity by heat-killed Listeria monocytogenes induces sterilizing response in the adult zebrafish tuberculosis model

    Directory of Open Access Journals (Sweden)

    Hanna Luukinen

    2018-01-01

    Full Text Available Mycobacterium tuberculosis remains one of the most problematic infectious agents, owing to its highly developed mechanisms to evade host immune responses combined with the increasing emergence of antibiotic resistance. Host-directed therapies aiming to optimize immune responses to improve bacterial eradication or to limit excessive inflammation are a new strategy for the treatment of tuberculosis. In this study, we have established a zebrafish-Mycobacterium marinum natural host-pathogen model system to study induced protective immune responses in mycobacterial infection. We show that priming adult zebrafish with heat-killed Listeria monocytogenes (HKLm at 1 day prior to M. marinum infection leads to significantly decreased mycobacterial loads in the infected zebrafish. Using rag1−/− fish, we show that the protective immunity conferred by HKLm priming can be induced through innate immunity alone. At 24 h post-infection, HKLm priming leads to a significant increase in the expression levels of macrophage-expressed gene 1 (mpeg1, tumor necrosis factor α (tnfa and nitric oxide synthase 2b (nos2b, whereas superoxide dismutase 2 (sod2 expression is downregulated, implying that HKLm priming increases the number of macrophages and boosts intracellular killing mechanisms. The protective effects of HKLm are abolished when the injected material is pretreated with nucleases or proteinase K. Importantly, HKLm priming significantly increases the frequency of clearance of M. marinum infection by evoking sterilizing immunity (25 vs 3.7%, P=0.0021. In this study, immune priming is successfully used to induce sterilizing immunity against mycobacterial infection. This model provides a promising new platform for elucidating the mechanisms underlying sterilizing immunity and to develop host-directed treatment or prevention strategies against tuberculosis. This article has an associated First Person interview with the first author of the paper.

  13. Hyperthermic treatment at 56 °C induces tumour-specific immune protection in a mouse model of prostate cancer in both prophylactic and therapeutic immunization regimens.

    Science.gov (United States)

    De Sanctis, Francesco; Sandri, Sara; Martini, Matteo; Mazzocco, Marta; Fiore, Alessandra; Trovato, Rosalinda; Garetto, Stefano; Brusa, Davide; Ugel, Stefano; Sartoris, Silvia

    2018-06-14

    Most active cancer immunotherapies able to induce a long-lasting protection against tumours are based on the activation of tumour-specific cytotoxic T lymphocytes (CTLs). Cell death by hyperthermia induces apoptosis followed by secondary necrosis, with the production of factors named "danger associated molecular pattern" (DAMP) molecules (DAMPs), that activate dendritic cells (DCs) to perform antigen uptake, processing and presentation, followed by CTLs cross priming. In many published studies, hyperthermia treatment of tumour cells is performed at 42-45 °C; these temperatures mainly promote cell surface expression of DAMPs. Treatment at 56 °C of tumour cells was shown to induce DAMPs secretion rather than their cell surface expression, improving DC activation and CTL cross priming in vitro. Thus we tested the relevance of this finding in vivo on the generation of a tumour-specific memory immune response, in the TRAMP-C2 mouse prostate carcinoma transplantable model. TRAMP-C2 tumour cells treated at 56 °C were able not only to activate DCs in vitro but also to trigger a tumour-specific CTL-dependent immune response in vivo. Prophylactic vaccination with 56 °C-treated TRAMP-C2 tumour cells alone provided protection against TRAMP-C2 tumour growth in vivo, whilst in the therapeutic regimen, control of tumour growth was achieved combining immunization with adjuvant chemotherapy. Copyright © 2018 Elsevier Ltd. All rights reserved.

  14. Identification of anti-CD98 antibody mimotopes for inducing antibodies with antitumor activity by mimotope immunization.

    Science.gov (United States)

    Saito, Misa; Kondo, Masahiro; Ohshima, Motohiro; Deguchi, Kazuki; Hayashi, Hideki; Inoue, Kazuyuki; Tsuji, Daiki; Masuko, Takashi; Itoh, Kunihiko

    2014-04-01

    A mimotope is an antibody-epitope-mimicking peptide retrieved from a phage display random peptide library. Immunization with antitumor antibody-derived mimotopes is promising for inducing antitumor immunity in hosts. In this study, we isolated linear and constrained mimotopes from HBJ127, a tumor-suppressing anti-CD98 heavy chain mAb, and determined their abilities for induction of antitumor activity equal to that of the parent antibody. We detected elevated levels of antipeptide responses, but failed to detect reactivity against native CD98-expressing HeLa cells in sera of immunized mice. Phage display panning and selection of mimotope-immunized mouse spleen-derived antibody Fab library showed that HeLa cell-reactive Fabs were successfully retrieved from the library. This finding indicates that native antigen-reactive Fab clones represented an undetectable minor population in mimotope-induced antibody repertoire. Functional and structural analysis of retrieved Fab clones revealed that they were almost identical to the parent antibody. From these results, we confirmed that mimotope immunization was promising for retrieving antitumor antibodies equivalent to the parent antibody, although the co-administration of adjuvant compounds such as T-cell epitope peptides and Toll-like receptor 4 agonist peptides is likely to be necessary for inducing stronger antitumor immunity than mimotope injection alone. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  15. The impact of shift work induced chronic circadian disruption on IL-6 and TNF-α immune responses

    Directory of Open Access Journals (Sweden)

    Spallek Michael

    2010-07-01

    Full Text Available Abstract AIM Sleep disturbances induce proinflammatory immune responses, which might increase cardiovascular disease risk. So far the effects of acute sleep deprivation and chronic sleep illnesses on the immune system have been investigated. The particular impact of shift work induced chronic circadian disruption on specific immune responses has not been addressed so far. Methods Pittsburgh-Sleep-Quality-Index (PSQI questionnaire and blood sampling was performed by 225 shift workers and 137 daytime workers. As possible markers the proinflammatory cytokines IL-6 and TNF-α and lymphocyte cell count were investigated. A medical examination was performed and biometrical data including age, gender, height, weight, waist and hip circumference and smoking habits were collected by a structured interview. Results Shift workers had a significantly higher mean PSQI score than day workers (6.73 vs. 4.66; p Conclusion Shift work induces chronic sleep debt. Our data reveals that chronic sleep debt might not always lead to an activation of the immune system, as we did not observe differences in lymphocyte count or level of IL-6 or TNF-α serum concentration between shift workers and day workers. Therefore chronic sleep restriction might be eased by a long-term compensating immune regulation which (in healthy protects against an overstimulation of proinflammatory immune mechanisms and moderates metabolic changes, as they are known from short-term sleep deprivation or sleep related breathing disorders.

  16. Investigation of HIFU-induced anti-tumor immunity in a murine tumor model

    Directory of Open Access Journals (Sweden)

    Lyerly H Kim

    2007-07-01

    Full Text Available Abstract Background High intensity focused ultrasound (HIFU is an emerging non-invasive treatment modality for localized treatment of cancers. While current clinical strategies employ HIFU exclusively for thermal ablation of the target sites, biological responses associated with both thermal and mechanical damage from focused ultrasound have not been thoroughly investigated. In particular, endogenous danger signals from HIFU-damaged tumor cells may trigger the activation of dendritic cells. This response may play a critical role in a HIFU-elicited anti-tumor immune response which can be harnessed for more effective treatment. Methods Mice bearing MC-38 colon adenocarcinoma tumors were treated with thermal and mechanical HIFU exposure settings in order to independently observe HIFU-induced effects on the host's immunological response. In vivo dendritic cell activity was assessed along with the host's response to challenge tumor growth. Results Thermal and mechanical HIFU were found to increase CD11c+ cells 3.1-fold and 4-fold, respectively, as compared to 1.5-fold observed for DC injection alone. In addition, thermal and mechanical HIFU increased CFSE+ DC accumulation in draining lymph nodes 5-fold and 10-fold, respectively. Moreover, focused ultrasound treatments not only caused a reduction in the growth of primary tumors, with tumor volume decreasing by 85% for thermal HIFU and 43% for mechanical HIFU, but they also provided protection against subcutaneous tumor re-challenge. Further immunological assays confirmed an enhanced CTL activity and increased tumor-specific IFN-γ-secreting cells in the mice treated by focused ultrasound, with cytotoxicity induced by mechanical HIFU reaching as high as 27% at a 10:1 effector:target ratio. Conclusion These studies present initial encouraging results confirming that focused ultrasound treatment can elicit a systemic anti-tumor immune response, and they suggest that this immunity is closely related to

  17. EFFECT OF PHLEBODIUM DECUMANUM ON THE IMMUNE RESPONSE INDUCED BY TRAINING IN SEDENTARY UNIVERSITY STUDENTS

    Directory of Open Access Journals (Sweden)

    Jose A. Gonzalez-Jurado

    2011-06-01

    Full Text Available Exercise training is considered a good model to provoke different degrees of immune dysfunction affecting physical performance and some physiological responses related to oxidative stress and low grade inflammation. Phlebodium decumanum is a polypodiaceae may induce shown immunomodulating effects, specifically directed to the release of proinflammatory cytokines by macrophages in response to various stimuli, as reported different in vitro studies. The aim of this study was to evaluate the modulating effect of phlebodium decumanum, on the immune response induced by physical exercise. Thirty-one subjects (males only were randomly divided into two groups: Group PD (n = 18; age: 22.1 ± 1.81, weight 74.21 ± 8.74 kg that was treated with phlebodium decumanum; Group P (n = 13; age: 22.5 ± 1.63, weight 78 ± 12.5 kg that was treated with a placebo. Before and after one month training program performed by both groups (three times a week, the following performance parameters and immune response variables were measured: Dynamic Maximum Force; Interval-Training; Tennis test; pro-inflammatory (TNF , IL6 and anti-inflammatory (TNFα-IIrs, IL1-ra cytokines levels. Data were statistically analyzed with Mann- Whitney U test and Wilcoxon paired test (p < 0.05. Statistically significant differences were recorded within groups before and after the training program. PD group showed a significant improvement in the performance parameters (Strength Muscle Test: dorsal: p < 0.002; deltoids: p < 0.03; and pectorals: p < 0.07; Interval Training: p < 0.06; Tennis Test: p < 0.02. Cytokine levels resulted in a more positive profile in the PD group rather than in the P group, in which higher levels of IL-6 (p < 0.02 and a reduction of TNF-IIrs (p < 0.003 and IL1-ra (p < 0.03 were recorded. In this study the use of phlebodium decumanum demonstrated beneficial effects in the modulation of the immune response during physical performance

  18. Ozone-Induced Nasal Type 2 Immunity in Mice Is Dependent on Innate Lymphoid Cells.

    Science.gov (United States)

    Kumagai, Kazuyoshi; Lewandowski, Ryan; Jackson-Humbles, Daven N; Li, Ning; Van Dyken, Steven J; Wagner, James G; Harkema, Jack R

    2016-06-01

    Epidemiological studies suggest that elevated ambient concentrations of ozone are associated with activation of eosinophils in the nasal airways of atopic and nonatopic children. Mice repeatedly exposed to ozone develop eosinophilic rhinitis and type 2 immune responses. In this study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced eosinophilic rhinitis by using lymphoid-sufficient C57BL/6 mice, Rag2(-/-) mice that are devoid of T cells and B cells, and Rag2(-/-)Il2rg(-/-) mice that are depleted of all lymphoid cells including ILCs. The animals were exposed to 0 or 0.8 ppm ozone for 9 consecutive weekdays (4 h/d). Mice were killed 24 hours after exposure, and nasal tissues were selected for histopathology and gene expression analysis. ILC-sufficient C57BL/6 and Rag2(-/-) mice exposed to ozone developed marked eosinophilic rhinitis and epithelial remodeling (e.g., epithelial hyperplasia and mucous cell metaplasia). Chitinase-like proteins and alarmins (IL-33, IL-25, and thymic stromal lymphopoietin) were also increased morphometrically in the nasal epithelium of ozone-exposed C57BL/6 and Rag2(-/-) mice. Ozone exposure elicited increased expression of Il4, Il5, Il13, St2, eotaxin, MCP-2, Gob5, Arg1, Fizz1, and Ym2 mRNA in C57BL/6 and Rag2(-/-) mice. In contrast, ozone-exposed ILC-deficient Rag2(-/-)Il2rg(-/-) mice had no nasal lesions or overexpression of Th2- or ILC2-related transcripts. These results indicate that ozone-induced eosinophilic rhinitis, nasal epithelial remodeling, and type 2 immune activation are dependent on ILCs. To the best of our knowledge, this is the first study to demonstrate that ILCs play an important role in the nasal pathology induced by repeated ozone exposure.

  19. Complex multicellular functions at a unicellular eukaryote level: Learning, memory, and immunity.

    Science.gov (United States)

    Csaba, György

    2017-06-01

    According to experimental data, eukaryote unicellulars are able to learn, have immunity and memory. Learning is carried out in a very primitive form, and the memory is not neural but an epigenetic one. However, this epigenetic memory, which is well justified by the presence and manifestation of hormonal imprinting, is strong and permanent in the life of cell and also in its progenies. This memory is epigenetically executed by the alteration and fixation of methylation pattern of genes without changes in base sequences. The immunity of unicellulars is based on self/non-self discrimination, which leads to the destruction of non-self invaders and utilization of them as nourishment (by phagocytosis). The tools of learning, memory, and immunity of unicellulars are uniformly found in plasma membrane receptors, which formed under the effect of dynamic receptor pattern generation, suggested by Koch et al., and this is the basis of hormonal imprinting, by which the encounter between a chemical substance and the cell is specifically memorized. The receptors and imprinting are also used in the later steps of evolution up to mammals (including man) in each mentioned functions. This means that learning, memory, and immunity can be deduced to a unicellular eukaryote level.

  20. Prime immunization with rotavirus VLP 2/6 followed by boosting with an adenovirus expressing VP6 induces protective immunization against rotavirus in mice

    Directory of Open Access Journals (Sweden)

    Qu Jianguo

    2011-01-01

    Full Text Available Abstract Background Rotavirus (RV is the main cause of severe gastroenteritis in children. An effective vaccination regime against RV can substantially reduce morbidity and mortality. Previous studies have demonstrated the efficacy of virus-like particles formed by RV VP2 and VP6 (VLP2/6, as well as that of recombinant adenovirus expressing RV VP6 (rAd, in eliciting protective immunities against RV. However, the efficacy of such prime-boost strategy, which incorporates VLP and rAd in inducing protective immunities against RV, has not been addressed. We assessed the immune effects of different regimens in mice, including rAd prime-VLP2/6 boost (rAd+VLP, VLP2/6 prime-rAd boost (VLP+rAd, rAd alone, and VLP alone. Results Mice immunized with the VLP+rAd regimen elicit stronger humoral, mucosal, and cellular immune responses than those immunized with other regimens. RV challenging experiments showed that the highest reduction (92.9% in viral shedding was achieved in the VLP+rAd group when compared with rAd+VLP (25%, VLP alone (75%, or rAd alone (40% treatment groups. The reduction in RV shedding in mice correlated with fecal IgG (r = 0.95773, P = 0.04227 and IgA (r = 0.96137, P = 0.038663. Conclusions A VLP2/6 prime-rAd boost regimen is effective in conferring immunoprotection against RV challenge in mice. This finding may lay the groundwork for an alternative strategy in novel RV vaccine development.

  1. Diminished ability of erythrocytes from patients with systemic lupus erythematosus to limit opsonized immune complex deposition on leukocytes and activation of granulocytes

    DEFF Research Database (Denmark)

    Nielsen, C H; Rasmussen, J M; Voss, A

    1998-01-01

    OBJECTIVE: To compare the ability of normal erythrocytes and erythrocytes from systemic lupus erythematosus (SLE) patients to bind immune complexes (IC), thereby inhibiting IC deposition on polymorphonuclear leukocytes (PMN) and the consequent induction of a PMN respiratory burst (RB). METHODS...

  2. Studies on immunity to Schistosoma mansoni in vivo: whole-body irradiation has no effect on vaccine-induced resistance in mice

    International Nuclear Information System (INIS)

    Vignali, D.A.A.; Bickle, Q.D.; Taylor, M.G.

    1988-01-01

    Actively immunized mice, whole-body irradiated with 650 or 525 rad., manifested comparable levels of resistance to Schistosoma mansoni compared with unirradiated, immunized mice in spite of a marked reduction in circulating leucocytes and platelets, and despite an abrogation of delayed-type hypersensitivity (DTH) (Type IV) reponse to schistosomular antigens. However, limited histopathological comparison of lung sections from irradiated and unirradiated mice 7 days post-challenge showed that cellular reactions ('foci') around parasites were similar in size and cellular composition except that in irradiated mice, eosinophils were poorly represented both in the foci and in lung tissue in general. Neither presumed immune complex-mediated (Type III, Arthus reaction) hypersensitivity nor serum anti-schistosomulum extract antibody levels were affected. The pattern of 125 I-labelled schistosomular surface antigens immunoprecipitated with serum from irradiated and unirradiated mice was essentially similar. These results are consistent with antibody playing an important role in vaccine-induced immunity in mice but suggest that radiosensitive T cell function and radiosensitive cells, such as platelets and polymorphonuclear cells, including eosinophils, may not be essential. (author)

  3. Immune-regulating effects of exercise on cigarette smoke-induced inflammation

    Science.gov (United States)

    Madani, Ashkan; Alack, Katharina; Richter, Manuel Jonas; Krüger, Karsten

    2018-01-01

    Long-term cigarette smoking (LTCS) represents an important risk factor for cardiac infarction and stroke and the central risk factor for the development of a bronchial carcinoma, smoking-associated interstitial lung fibrosis, and chronic obstructive pulmonary disease. The pathophysiologic development of these diseases is suggested to be promoted by chronic and progressive inflammation. Cigarette smoking induces repetitive inflammatory insults followed by a chronic and progressive activation of the immune system. In the pulmonary system of cigarette smokers, oxidative stress, cellular damage, and a chronic activation of pattern recognition receptors are described which are followed by the translocation of the NF-kB, the release of pro-inflammatory cytokines, chemokines, matrix metalloproteases, and damage-associated molecular patterns. In parallel, smoke pollutants cross directly through the alveolus–capillary interface and spread through the systemic bloodstream targeting different organs. Consequently, LTCS induces a systemic low-grade inflammation and increased oxidative stress in the vascular system. In blood, these processes promote an increased coagulation and endothelial dysfunction. In muscle tissue, inflammatory processes activate catabolic signaling pathways followed by muscle wasting and sarcopenia. In brain, several characteristics of neuroinflammation were described. Regular exercise training has been shown to be an effective nonpharmacological treatment strategy in smoke-induced pulmonary diseases. It is well established that exercise training exerts immune-regulating effects by activating anti-inflammatory signaling pathways. In this regard, the release of myokines from contracting skeletal muscle, the elevations of cortisol and adrenalin, the reduced expression of Toll-like receptors, and the increased mobilization of immune-regulating leukocyte subtypes might be of vital importance. Exercise training also increases the local and systemic

  4. Immune-regulating effects of exercise on cigarette smoke-induced inflammation

    Directory of Open Access Journals (Sweden)

    Madani A

    2018-04-01

    Full Text Available Ashkan Madani,1 Katharina Alack,2 Manuel Jonas Richter,3,4 Karsten Krüger1 1Department of Exercise and Health, Institute of Sports Science, Leibniz University Hannover, Germany; 2Department of Sports Medicine, University of Giessen, Germany; 3Department of Internal Medicine, Justus Liebig University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC, Germany; 4German Center for Lung Research (DZL, Giessen, Germany Abstract: Long-term cigarette smoking (LTCS represents an important risk factor for cardiac infarction and stroke and the central risk factor for the development of a bronchial carcinoma, smoking-associated interstitial lung fibrosis, and chronic obstructive pulmonary disease. The pathophysiologic development of these diseases is suggested to be promoted by chronic and progressive inflammation. Cigarette smoking induces repetitive inflammatory insults followed by a chronic and progressive activation of the immune system. In the pulmonary system of cigarette smokers, oxidative stress, cellular damage, and a chronic activation of pattern recognition receptors are described which are followed by the translocation of the NF-kB, the release of pro-inflammatory cytokines, chemokines, matrix metalloproteases, and damage-associated molecular patterns. In parallel, smoke pollutants cross directly through the alveolus–capillary interface and spread through the systemic bloodstream targeting different organs. Consequently, LTCS induces a systemic low-grade inflammation and increased oxidative stress in the vascular system. In blood, these processes promote an increased coagulation and endothelial dysfunction. In muscle tissue, inflammatory processes activate catabolic signaling pathways followed by muscle wasting and sarcopenia. In brain, several characteristics of neuroinflammation were described. Regular exercise training has been shown to be an effective nonpharmacological treatment strategy in smoke-induced pulmonary diseases

  5. Immunization with Recombinantly Expressed LRP4 Induces Experimental Autoimmune Myasthenia Gravis in C57BL/6 Mice.

    Science.gov (United States)

    Ulusoy, Canan; Çavuş, Filiz; Yılmaz, Vuslat; Tüzün, Erdem

    2017-07-01

    Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ), characterized with muscle weakness. While MG develops due to acetylcholine receptor (AChR) antibodies in most patients, antibodies to muscle-specific receptor tyrosine kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4) may also be identified. Experimental autoimmune myasthenia gravis (EAMG) has been previously induced by both LRP4 immunization and passive transfer of LRP4 antibodies. Our aim was to confirm previous results and to test the pathogenic effects of LRP4 immunization in a commonly used mouse strain C57BL/6 (B6) using a recombinantly expressed human LRP4 protein. B6 mice were immunized with human LRP4 in CFA, Torpedo Californica AChR in CFA or only CFA. Clinical and pathogenic aspects of EAMG were compared among groups. LRP4- and AChR-immunized mice showed comparable EAMG clinical severity. LRP4-immunized mice displayed serum antibodies to LRP4 and NMJ IgG and complement factor C3 deposits. IgG2 was the dominant anti-LRP4 isotype. Cultured lymph node cells of LRP4- and AChR-immunized mice gave identical pro-inflammatory cytokine (IL-6, IFN-γ and IL-17) responses to LRP4 and AChR stimulation, respectively. Our results confirm the EAMG-inducing action of LRP4 immunization and identify B6 as a LRP4-EAMG-susceptible mouse strain. Demonstration of complement fixing anti-LRP4 antibodies in sera and complement/IgG deposits at the NMJ of LRP4-immunized mice indicates complement activation as a putative pathogenic mechanism. We have thus developed a practical LRP4-induced EAMG model using a non-conformational protein and a widely available mouse strain for future investigation of LRP4-related MG.

  6. Nanoparticles modify dendritic cell homeostasis and induce non-specific effects on immunity to malaria.

    Science.gov (United States)

    Xiang, Sue D; Kong, Ying Y; Hanley, Jennifer; Fuchsberger, Martina; Crimeen-Irwin, Blessing; Plebanski, Magdalena

    2015-01-01

    Many current vaccines to a specific pathogen influence responses to other pathogens in a process called heterologous immunity. We propose that their particulate nature contributes to non-specific effects. Herein, we demonstrate polystyrene nanoparticles modulate dendritic cell (DC) homeostasis, thereby promoting a persistent enhanced state of immune readiness to a subsequent infectious challenge. Particles (approximately 40 nm and 500 nm carboxylated polystyrene nanoparticles; PSNPs) alone or conjugated to a model antigen were injected in mice, and DCs in draining lymph nodes (dLNs) and bone-marrow (BM) quantified by flow cytometry. BM cells were tested for capacity to generate DCs upon culture with granulocyte and macrophage colony stimulating factor. Mice were challenged with Plasmodium yoelli. Blood parasitaemias were monitored by GIEMSA. Sera was analyzed for antibodies by ELISA. Intradermal administration of 40 nm PSNPs induced anti-inflammatory cytokines, chemokines and growth factors, increased numbers and proportions of DCs in the dLN, and increased the capacity of BM to generate DCs. Consistent with these unexpected changes, 40 nm PSNPs pre-injected mice had enhanced ability to generate immunity to a subsequent malarial infection. Intradermal administration of 40 nm PSNPs modifies DC homeostasis, which may at least in part explain the observed beneficial heterologous effects of current particulate vaccines. Further nanotechnological developments may exploit such strategies to promote beneficial non-specific effects. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. CCR2 mediates Helicobacter pylori-induced immune tolerance and contributes to mucosal homeostasis.

    Science.gov (United States)

    Sun, Xia; Zhang, Min; El-Zaatari, Mohamad; Huffnagle, Gray B; Kao, John Y

    2017-04-01

    We previously demonstrated that H. pylori infection leads to increased induction of regulatory T cells in local and systemic immune compartments. Here, we investigate the role of CCR2 in the tolerogenic programing of dendritic cells in a mouse model of H. pylori infection. CCR2 deficient (CCR2KO) mice and wild-type (Wt) mice infected with H. pylori SS1 strain were analyzed by qPCR and FACS analysis. In vitro, bone marrow-derived DC on day 6 from CCR2KO and Wt mice cocultured with or without H. pylori were examined to determine the impact of CCR2 signaling on dendritic cells function by qPCR, ELISA, and FACS analyses. Acute H. pylori infection was associated with a threefold increase in CCR2 mRNA expression in the gastric mucosa. H. pylori-infected CCR2KO mice exhibited a higher degree of mucosal inflammation, that is, increased gastritis scores and pro-inflammatory cytokine mRNA levels, but lower degree of H. pylori gastric colonization compared to infected Wt mice. Peripheral H. pylori-specific immune response measured in the CCR2KO spleen was characterized by a higher Th17 response and a lower Treg response. In vitro, CCR2KO bone marrow-derived DC was less mature and shown a lower Treg/Th17 ratio. Moreover, blockade of CCR2 signaling by MCP-1 neutralizing antibody inhibited H. pylori-stimulated bone marrow-derived DC maturation. Our results indicate that CCR2 plays an essential role in H. pylori-induced immune tolerance and shed light on a novel mechanism of CCR2-dependent DC Treg induction, which appears to be important in maintaining mucosal homeostasis during H. pylori infection. © 2016 John Wiley & Sons Ltd.

  8. Immune response of cattle against fasciolopsis induced by inoculation of irradiated metacercariae of fasciola gigantic

    International Nuclear Information System (INIS)

    M-Arifin

    2006-01-01

    An experiment was carried out to study the immune response of cattle against fasciolopsis induced by inoculation of irradiated metacercariae of F. gigantic. Four groups of experimental cattle were used e.g: the first group (Vp) were inoculated by the unirradiated metacercariae as a positive control, the second group (Vi) were once inoculated with irradiated metacercariae and then challenged with the infected metacercariae three weeks later, the third group (Vii) were twice inoculated with irradiated metacercariae and then challenged with the infected metacercariae three weeks later, while the forth group (Vn), the negative control without any inoculation of metacercariae. Irradiation dose of 45 Gy was used, and each experimental animal received 700 live’s metacercariae of F. gigantic. The immune response towards fasciolopsis in cattle has been observed in the development of body weight, the number of red blood cells (RBC), the number of white blood cells (WBC), level of haemoglobin (Hb), percentages of Packed cell volume (PCV), the number of eosinophil cells, serological test by ELISA, pathology anatomic inspection and evaluation of the development of worm.The average every measurement of body weight development are Vp = 6 kg, Vi = 9 kg, Vii = 9 kg and Vn = 10 kg. The group of Vi, Vii and Vn were normal of their heart, but the group of Vp was disorder. The group of Vi, Vii and Vn were negative of adult worm’s, while the group of Vp was positive of adult worm’s. These results showed that inoculation of irradiated metacercariae F. gigantic could stimulate good immune response which was able to protect against the infectivity of the challenge in cattle. (author)

  9. Hemocyanins Stimulate Innate Immunity by Inducing Different Temporal Patterns of Proinflammatory Cytokine Expression in Macrophages.

    Science.gov (United States)

    Zhong, Ta-Ying; Arancibia, Sergio; Born, Raimundo; Tampe, Ricardo; Villar, Javiera; Del Campo, Miguel; Manubens, Augusto; Becker, María Inés

    2016-06-01

    Hemocyanins induce a potent Th1-dominant immune response with beneficial clinical outcomes when used as a carrier/adjuvant in vaccines and nonspecific immunostimulant in cancer. However, the mechanisms by which hemocyanins trigger innate immune responses, leading to beneficial adaptive immune responses, are unknown. This response is triggered by a proinflammatory signal from various components, of which macrophages are an essential part. To understand how these proteins influence macrophage response, we investigated the effects of mollusks hemocyanins with varying structural and immunological properties, including hemocyanins from Concholepas concholepas, Fissurella latimarginata, and Megathura crenulata (keyhole limpet hemocyanin), on cultures of peritoneal macrophages. Hemocyanins were phagocytosed and slowly processed. Analysis of this process showed differential gene expression along with protein levels of proinflammatory markers, including IL-1β, IL-6, IL-12p40, and TNF-α. An extended expression analysis of 84 cytokines during a 24-h period showed a robust proinflammatory response for F. latimarginata hemocyanin in comparison with keyhole limpet hemocyanin and C. concholepas hemocyanin, which was characterized by an increase in the transcript levels of M1 cytokines involved in leukocyte recruitment. These cytokine genes included chemokines (Cxcl1, Cxcl3, Cxcl5, Ccl2, and Ccl3), ILs (Il1b and Ifng), growth factors (Csf2 and Csf3), and TNF family members (Cd40lg). The protein levels of certain cytokines were increased. However, every hemocyanin maintains downregulated key M2 cytokine genes, including Il4 and Il5 Collectively, our data demonstrate that hemocyanins are able to trigger the release of proinflammatory factors with different patterns of cytokine expression, suggesting differential signaling pathways and transcriptional network mechanisms that lead to the activation of M1-polarized macrophages. Copyright © 2016 by The American Association of

  10. Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses.

    Science.gov (United States)

    Zeelenberg, Ingrid S; Ostrowski, Matias; Krumeich, Sophie; Bobrie, Angélique; Jancic, Carolina; Boissonnas, Alexandre; Delcayre, Alain; Le Pecq, Jean-Bernard; Combadière, Béhazine; Amigorena, Sebastian; Théry, Clotilde

    2008-02-15

    Expression of non-self antigens by tumors can induce activation of T cells in vivo, although this activation can lead to either immunity or tolerance. CD8+ T-cell activation can be direct (if the tumor expresses MHC class I molecules) or indirect (after the capture and cross-presentation of tumor antigens by dendritic cells). The modes of tumor antigen capture by dendritic cells in vivo remain unclear. Here we examine the immunogenicity of the same model antigen secreted by live tumors either in association with membrane vesicles (exosomes) or as a soluble protein. We have artificially addressed the antigen to secreted vesicles by coupling it to the factor VIII-like C1C2 domain of milk fat globule epidermal growth factor-factor VIII (MFG-E8)/lactadherin. We show that murine fibrosarcoma tumor cells that secrete vesicle-bound antigen grow slower than tumors that secrete soluble antigen in immunocompetent, but not in immunodeficient, host mice. This growth difference is due to the induction of a more potent antigen-specific antitumor immune response in vivo by the vesicle-bound than by the soluble antigen. Finally, in vivo secretion of the vesicle-bound antigen either by tumors or by vaccination with naked DNA protects against soluble antigen-secreting tumors. We conclude that the mode of secretion can determine the immunogenicity of tumor antigens and that manipulation of the mode of antigen secretion may be used to optimize antitumor vaccination protocols.

  11. Demodex canis targets TLRs to evade host immunity and induce canine demodicosis.

    Science.gov (United States)

    Kumari, P; Nigam, R; Choudhury, S; Singh, S K; Yadav, B; Kumar, D; Garg, S K

    2018-03-01

    Widespread incidence of Demodex mites throughout the mammalian class and occasional serious and fatal outcomes in dogs warrant an insight into the host-parasite interface especially. Therefore, this study was aimed to unravel the interplay between innate immune response and canine demodicosis. The dogs diagnosed to have natural clinical demodicosis were allocated into two groups; dogs with localized demodicosis (LD) and with generalized demodicosis (GD). The expression of toll-like receptors (TLRs) 2, 4 and 6 genes in peripheral blood mononuclear cells of these dogs was quantified by real-time PCR. Significantly increased TLR2 gene expression, while significantly diminished TLR4 and TLR6 gene expressions were observed in demodicosed dogs (LD and GD) as compared with the healthy ones. Even the expression of TLR2 gene was found to differ significantly between the dogs with LD and GD. Therefore, it can be inferred that clinical demodicosis in dogs is coupled with an up-regulation of TLR2 and down-regulation of TLR4 and TLR6 gene expressions. Overexpression of TLR2 gene might be responsible for Demodex-induced clinical manifestations, while TLR4 and TLR6 gene down-regulations could be the paramount strategy of Demodex mites to elude the host-immune interface. © 2017 John Wiley & Sons Ltd.

  12. Fungal Innate Immunity Induced by Bacterial Microbe-Associated Molecular Patterns (MAMPs

    Directory of Open Access Journals (Sweden)

    Simon Ipcho

    2016-06-01

    Full Text Available Plants and animals detect bacterial presence through Microbe-Associated Molecular Patterns (MAMPs which induce an innate immune response. The field of fungal–bacterial interaction at the molecular level is still in its infancy and little is known about MAMPs and their detection by fungi. Exposing Fusarium graminearum to bacterial MAMPs led to increased fungal membrane hyperpolarization, a putative defense response, and a range of transcriptional responses. The fungus reacted with a different transcript profile to each of the three tested MAMPs, although a core set of genes related to energy generation, transport, amino acid production, secondary metabolism, and especially iron uptake were detected for all three. Half of the genes related to iron uptake were predicted MirA type transporters that potentially take up bacterial siderophores. These quick responses can be viewed as a preparation for further interactions with beneficial or pathogenic bacteria, and constitute a fungal innate immune response with similarities to those of plants and animals.

  13. Humoral Immune Response Induced by PLGA Micro Particle Coupled Newcastle Disease Virus Vaccine in Chickens

    Directory of Open Access Journals (Sweden)

    Sanganagouda K

    2014-02-01

    Full Text Available This experiment was conducted for evaluating the humoral immune responses induced by Poly Lactide-co-Glycolide Acid (PLGA microspheres coupled inactivated Newcastle Disease Virus (NDV vaccine in comparison to an ‘in-house’ prepared inactivated and a live commercial vaccine. PLG microparticles containing inactivated NDV were prepared by a double emulsion technique based on solvent evaporation method. The size of the NDV coupled PLG microparticles was determined by Electron Microscopy. NDV coupled PLG microparticles were spherical having smooth surface, hollow core inside with no pores on the surface. The experiment was conducted in four groups of chickens (n=15. The encapsulation efficiency of NDV coupled PLG microparticles was determined by protein estimation and HA activity in elute. The mean (± SE size of PLG microspheres was found to be 2.409 ± 0.65 µm. The mean percent of encapsulation efficiency of PLG microspheres coupled to NDV was assessed based on the total protein content and HA activity in elute was found to be 8.03 ± 0.50 and 12.5 ± 0.00, respectively. In conclusion, the results of the experiment showed that PLGA coupled NDV vaccine elicited stronger and prolonged humoral immune response in chickens, in comparison to the other tested vaccines, as assessed by haemagglutination inhibition and enzyme linked immuno sorbent asaay titers.

  14. Pathogen-induced maternal effects result in enhanced immune responsiveness across generations.

    Science.gov (United States)

    Rosengaus, Rebeca B; Hays, Nicole; Biro, Colette; Kemos, James; Zaman, Muizz; Murray, Joseph; Gezahegn, Bruck; Smith, Wendy

    2017-05-01

    Parental investment theory postulates that adults can accurately perceive cues from their surroundings, anticipate the needs of future offspring based on those cues, and selectively allocate nongenetic resources to their progeny. Such context-dependent parental contributions can result in phenotypically variable offspring. Consistent with these predictions, we show that bacterially exposed Manduca sexta mothers oviposited significantly more variable embryos (as measured by mass, volume, hatching time, and hatching success) relative to naïve and control mothers. By using an in vivo "clearance of infection" assay, we also show that challenged larvae born to heat-killed- or live- Serratia -injected mothers, supported lower microbial loads and cleared the infection faster than progeny of control mothers. Our data support the notion that mothers can anticipate the future pathogenic risks and immunological needs of their unborn offspring, providing progeny with enhanced immune protection likely through transgenerational immune priming. Although the inclusion of live Serratia into oocytes does not appear to be the mechanism by which mothers confer protection to their young, other mechanisms, including epigenetic modifications in the progeny due to maternal pathogenic stress, may be at play. The adaptive nature of maternal effects in the face of pathogenic stress provides insights into parental investment, resource allocation, and life-history theories and highlights the significant role that pathogen-induced maternal effects play as generators and modulators of evolutionary change.

  15. Binding of human papilloma virus L1 virus-like particles to dendritic cells is mediated through heparan sulfates and induces immune activation

    NARCIS (Netherlands)

    de Witte, Lot; Zoughlami, Younes; Aengeneyndt, Birgit; David, Guido; van Kooyk, Yvette; Gissmann, Lutz; Geijtenbeek, Teunis B. H.

    2007-01-01

    Immunization using human papilloma virus (HPV)-L1 virus-like particles (VLPs) induces a robust and effective immune response, which has recently resulted in the implementation of the HPV-L1 VLP vaccination in health programs. However, during infection, HPV can escape immune surveillance leading to

  16. Interactions of opsonized immune complexes with whole blood cells: binding to erythrocytes restricts complex uptake by leucocyte populations

    DEFF Research Database (Denmark)

    Nielsen, C H; Svehag, S E; Marquart, H V

    1994-01-01

    binding, the main contributors being B cells. E initially inhibited and then later enhanced the IC binding to lymphocytes, suggesting that E promote B cell uptake of C3d,g-covered IC via CR2. Our findings, that E can restrict the IC uptake by circulating leucocytes, and that an IC-induced degranulation...

  17. Pathogens Inactivated by Low-Energy-Electron Irradiation Maintain Antigenic Properties and Induce Protective Immune Responses

    Science.gov (United States)

    Fertey, Jasmin; Bayer, Lea; Grunwald, Thomas; Pohl, Alexandra; Beckmann, Jana; Gotzmann, Gaby; Casado, Javier Portillo; Schönfelder, Jessy; Rögner, Frank-Holm; Wetzel, Christiane; Thoma, Martin; Bailer, Susanne M.; Hiller, Ekkehard; Rupp, Steffen; Ulbert, Sebastian

    2016-01-01

    Inactivated vaccines are commonly produced by incubating pathogens with chemicals such as formaldehyde or β-propiolactone. This is a time-consuming process, the inactivation efficiency displays high variability and extensive downstream procedures are often required. Moreover, application of chemicals alters the antigenic components of the viruses or bacteria, resulting in reduced antibody specificity and therefore stimulation of a less effective immune response. An alternative method for inactivation of pathogens is ionizing radiation. It acts very fast and predominantly damages nucleic acids, conserving most of the antigenic structures. However, currently used irradiation technologies (mostly gamma-rays and high energy electrons) require large and complex shielding constructions to protect the environment from radioactivity or X-rays generated during the process. This excludes them from direct integration into biological production facilities. Here, low-energy electron irradiation (LEEI) is presented as an alternative inactivation method for pathogens in liquid solutions. LEEI can be used in normal laboratories, including good manufacturing practice (GMP)- or high biosafety level (BSL)-environments, as only minor shielding is necessary. We show that LEEI efficiently inactivates different viruses (influenza A (H3N8), porcine reproductive and respiratory syndrome virus (PRRSV), equine herpesvirus 1 (EHV-1)) and bacteria (Escherichia coli) and maintains their antigenicity. Moreover, LEEI-inactivated influenza A viruses elicit protective immune responses in animals, as analyzed by virus neutralization assays and viral load determination upon challenge. These results have implications for novel ways of developing and manufacturing inactivated vaccines with improved efficacy. PMID:27886076

  18. Lentivirus-Induced Dendritic Cells (iDC for Immune-Regenerative Therapies in Cancer and Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Renata Stripecke

    2014-08-01

    Full Text Available Conventional dendritic cells (cDC are ex vivo differentiated professional antigen presenting cells capable of potently stimulating naïve T cells and with vast potential for immunotherapeutic applications. The manufacture of clinical-grade cDC is relatively complex and requires several days for completion. Clinical trials showed poor trafficking of cDC from subcutaneous injection sites to lymph nodes (LN, where DC can optimally stimulate naïve lymphocytes for long-lasting memory responses. We demonstrated in mouse and human systems that a single overnight ex vivo lentiviral (LV gene transfer into DC precursors for production of combination of cytokines and antigens was capable to induce autonomous self-differentiation of antigen-loaded DC in vitro and in vivo. These highly viable induced DC (iDC effectively migrated from the injected skin to LN, where they effectively activated de novo antigen-specific effector memory T cells. Two iDC modalities were validated in relevant animal models and are now in clinical development: Self-differentiated Myeloid-derived Antigen-presenting-cells Reactive against Tumors co-expressing GM-CSF/IL-4/TRP2 for melanoma immunotherapy in the autologous setting (SmartDCtrp2, and Self-differentiated Myeloid-derived Lentivirus-induced against human cytomegalovirus as an allogeneic matched adoptive cell after stem cell transplantation (SmyleDCpp65. The lentiviral vector design and packaging methodology has “evolved” continuously in order to simplify and optimize function and biosafety of in vitro and in vivo genetic reprogramming of iDC. Here, we address the challenges seeking for new creations of genetically programmed iDC and integrase-defective LV vaccines for immune regeneration.

  19. Hapten-Induced Contact Hypersensitivity, Autoimmune Reactions, and Tumor Regression: Plausibility of Mediating Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Dan A. Erkes

    2014-01-01

    Full Text Available Haptens are small molecule irritants that bind to proteins and elicit an immune response. Haptens have been commonly used to study allergic contact dermatitis (ACD using animal contact hypersensitivity (CHS models. However, extensive research into contact hypersensitivity has offered a confusing and intriguing mechanism of allergic reactions occurring in the skin. The abilities of haptens to induce such reactions have been frequently utilized to study the mechanisms of inflammatory bowel disease (IBD to induce autoimmune-like responses such as autoimmune hemolytic anemia and to elicit viral wart and tumor regression. Hapten-induced tumor regression has been studied since the mid-1900s and relies on four major concepts: (1 ex vivo haptenation, (2 in situ haptenation, (3 epifocal hapten application, and (4 antigen-hapten conjugate injection. Each of these approaches elicits unique responses in mice and humans. The present review attempts to provide a critical appraisal of the hapten-mediated tumor treatments and offers insights for future development of the field.

  20. Relationship between renal pathology and the size of circulating immune complexes in patients with systemic lupus erythematosus

    International Nuclear Information System (INIS)

    Wener, M.H.; Mannik, M.; Schwartz, M.M.; Lewis, E.J.

    1987-01-01

    Sera from 35 patients with biopsy-proven diffuse proliferative (WHO class IV) or membranous (WHO class V) lupus nephritis were analyzed for the presence and size of circulating immune complexes. Elevations of the C1q solid-phase assay (C1qSP) for immune complexes were found in sera from all patients with diffuse proliferative nephritis, with a mean +/- 1 SEM of 166.8 +/- 42.0 micrograms/AHG-equivalents/ml serum, and in 71.4% of the patients with membranous nephritis (83.1 +/- 26.7, p = 0.06). Using the WHO criteria for subclasses of membranous lupus nephritis, we also designated renal biopsies as nonproliferative (WHO classes Va and Vb) or proliferative (WHO classes IV and Vc). Employing the latter groupings, we observed significant differences between C1qSP results of patients with nonproliferative (30.3 +/- 8.8) and proliferative (172.8 +/- 36.8, p less than 0.001) lupus nephritis. These data suggest that the presence of C1q-binding material in serum is pathophysiologically related to proliferative glomerular lesions, and that levels of C1qSP binding reflect renal lesions in SLE patients. Sucrose density gradient ultracentrifugation was performed on each serum, and gradient fractions analyzed for C1qSP-binding and total IgG, using techniques to minimize losses of immune complexes. The predominant peak of C1qSP activity sedimented with the 6.6S monomeric IgG. The 6.6S C1q-binding IgG was increased only in 1 of 10 patients with membranous lupus nephritis without proliferative changes, and was elevated in 16 of 25 patients with proliferative lesions (WHO classes IV and Vc)

  1. Effect of plasmapheresis on the immune system in endotoxin-induced sepsis

    DEFF Research Database (Denmark)

    Toft, P; Schmidt, R; Broechner, A C

    2008-01-01

    BACKGROUND: It has been proposed that plasmapheresis is most effective when applied early in Gram-negative sepsis. We therefore studied the effect of early plasmapheresis on immunity in experimental Escherichia coli endotoxin-induced sepsis. METHODS: 20 pigs received 30 microg/kg of E. coli...... endotoxin. 40 min later, half of the pigs were treated with plasmapheresis which lasted 4 h. The adhesion molecules, the oxidative burst, the number of neutrophils in blood and lungs, and cytokines were measured. RESULTS: Infusion of endotoxin was associated with activation of adhesion molecules increased...... oxidative burst, increased concentration of cytokine, and accumulation of granulocytes in lung tissue. Plasmapheresis reduced the oxidative burst, and there was a tendency towards a reduced accumulation of granulocytes in the lung. CONCLUSION: Though plasmapheresis was initiated early after the endotoxin...

  2. PAMP INDUCED EXPRESSION OF IMMUNE RELEVANT GENES IN HEAD KIDNEY LEUKOCYTES OF RAINBOW TROUT (ONCORHYNCHUS MYKISS)

    DEFF Research Database (Denmark)

    Chettri, Jiwan Kumar; Holten-Andersen, Lars; Kania, Per Walter

    mykiss) to different PAMPs mimicking bacterial (flagellin and LPS), viral (poly I:C) and fungal infections (zymosan and ß-glucan). Transcript of cytokines related to inflammation (IL-1ß, IL-6, IL-10 and TNF-a) were highly up-regulated following LPS exposure whereas flagellin or poly I:C induced merely...... of the invader. Phagocytic cells are known to initiate a respiratory burst following an exposure to the pathogen, but the underlying and associated specific elements are poorly elucidated in fish. The present study describes the differential response of head kidney leukocytes from rainbow trout (Oncorhynchus...... of LPS and zymosan became evident after 4 h exposure. This study suggests that rainbow trout leukocytes respond differently to viral, bacterial and fungal PAMPs, which may reflect activation of specific signaling cascades eventually leading to activation of different immune effector molecules....

  3. Three Pairs of Protease-Serpin Complexes Cooperatively Regulate the Insect Innate Immune Responses*

    OpenAIRE

    Jiang, Rui; Kim, Eun-Hye; Gong, Ji-Hee; Kwon, Hyun-Mi; Kim, Chan-Hee; Ryu, Kyoung-Hwa; Park, Ji-Won; Kurokawa, Kenji; Zhang, Jinghai; Gubb, David; Lee, Bok-Luel

    2009-01-01

    Serpins are known to be necessary for the regulation of several serine protease cascades. However, the mechanisms of how serpins regulate the innate immune responses of invertebrates are not well understood due to the uncertainty of the identity of the serine proteases targeted by the serpins. We recently reported the molecular activation mechanisms of three serine protease-mediated Toll and melanin synthesis cascades in a large beetle, Tenebrio molitor. Here, we purified three novel serpins ...

  4. Cell-mediated immune responses in the head-associated lymphoid tissues induced to a live attenuated avian coronavirus vaccine.

    Science.gov (United States)

    Gurjar, Rucha S; Gulley, Stephen L; van Ginkel, Frederik W

    2013-12-01

    Humoral immunity is important for controlling viral diseases of poultry, but recent studies have indicated that cytotoxic T cells also play an important role in the immune response to infectious bronchitis virus (IBV). To better understand the cell mediated immune responses to IBV in the mucosal and systemic immune compartments chickens were ocularly vaccinated with IBV. This induced a lymphocyte expansion in head-associated lymphoid tissues (HALT) and to a lesser extent in the spleen, followed by a rapid decline, probably due to homing of lymphocytes out of these organs and contraction of the lymphocyte population. This interpretation was supported by observations that changes in mononuclear cells were mirrored by that in CD3(+)CD44(+) T cell abundance, which presumably represent T effector cells. Increased interferon gamma (IFN-γ) expression was observed in the mucosal immune compartment, i.e., HALT, after primary vaccination, but shifted to the systemic immune compartment after boosting. In contrast, the expression of cytotoxicity-associated genes, i.e., granzyme A (GZMA) and perforin mRNA, remained associated with the HALT after boosting. Thus, an Ark-type IBV ocular vaccine induces a central memory IFN-γ response in the spleen while the cytotoxic effector memory response, as measured by GZMA and perforin mRNA expression, remains associated with CALT after boosting. Copyright © 2013. Published by Elsevier Ltd.

  5. Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut.

    Science.gov (United States)

    Mantis, N J; Rol, N; Corthésy, B

    2011-11-01

    Secretory IgA (SIgA) serves as the first line of defense in protecting the intestinal epithelium from enteric toxins and pathogenic microorganisms. Through a process known as immune exclusion, SIgA promotes the clearance of antigens and pathogenic microorganisms from the intestinal lumen by blocking their access to epithelial receptors, entrapping them in mucus, and facilitating their removal by peristaltic and mucociliary activities. In addition, SIgA functions in mucosal immunity and intestinal homeostasis through mechanisms that have only recently been revealed. In just the past several years, SIgA has been identified as having the capacity to directly quench bacterial virulence factors, influence composition of the intestinal microbiota by Fab-dependent and Fab-independent mechanisms, promote retro-transport of antigens across the intestinal epithelium to dendritic cell subsets in gut-associated lymphoid tissue, and, finally, to downregulate proinflammatory responses normally associated with the uptake of highly pathogenic bacteria and potentially allergenic antigens. This review summarizes the intrinsic biological activities now associated with SIgA and their relationships with immunity and intestinal homeostasis.

  6. Construction and comparison of gene co-expression networks shows complex plant immune responses

    Directory of Open Access Journals (Sweden)

    Luis Guillermo Leal

    2014-10-01

    Full Text Available Gene co-expression networks (GCNs are graphic representations that depict the coordinated transcription of genes in response to certain stimuli. GCNs provide functional annotations of genes whose function is unknown and are further used in studies of translational functional genomics among species. In this work, a methodology for the reconstruction and comparison of GCNs is presented. This approach was applied using gene expression data that were obtained from immunity experiments in Arabidopsis thaliana, rice, soybean, tomato and cassava. After the evaluation of diverse similarity metrics for the GCN reconstruction, we recommended the mutual information coefficient measurement and a clustering coefficient-based method for similarity threshold selection. To compare GCNs, we proposed a multivariate approach based on the Principal Component Analysis (PCA. Branches of plant immunity that were exemplified by each experiment were analyzed in conjunction with the PCA results, suggesting both the robustness and the dynamic nature of the cellular responses. The dynamic of molecular plant responses produced networks with different characteristics that are differentiable using our methodology. The comparison of GCNs from plant pathosystems, showed that in response to similar pathogens plants could activate conserved signaling pathways. The results confirmed that the closeness of GCNs projected on the principal component space is an indicative of similarity among GCNs. This also can be used to understand global patterns of events triggered during plant immune responses.

  7. Hydrodynamic delivery of plasmid DNA encoding human Fc?R-Ig dimers blocks immune-complex mediated inflammation in mice

    OpenAIRE

    Shashidharamurthy, Rangaiah; Machiah, Deepa; Bozeman, Erica N.; Srivatsan, Sanjay; Patel, Jaina; Cho, Alice; Jacob, Joshy; Selvaraj, Periasamy

    2011-01-01

    Therapeutic use and function of recombinant molecules can be studied by the expression of foreign genes in mice. In this study, we have expressed human Fcgamma receptor ?Ig fusion molecules (Fc?R-Igs) in mice by administering Fc?R-Ig plasmid DNAs hydrodynamically and compared their effectiveness to purified molecules in blocking immune-complex (IC) mediated inflammation in mice. The concentration of hydrodynamically expressed Fc?R-Igs (CD16AF-Ig, CD32AR-Ig and CD32AH-Ig) reached a maximum of ...

  8. Cholesterol level in the circulating immune complexes of subjects suffering from the remote aftereffects of acute radiation sickness

    International Nuclear Information System (INIS)

    Nikitin, G.Yu.; Barabanova, A.V.; Nadezhina, N.M.; Tertov, V.V.; Orekhov, A.N.

    1994-01-01

    The potentiaoity of coronary atherosclerosis was assessed from cholesterol levels in the ciculationg immune complexes (CIC) in 53 subjects who suffered acute radiation sickness in 1986 after the Chernobyl power plant accident. CIC cholesterol levels of the subjects who suffered 3-4 years before acute radiation sickness of the first-second degrees of severity were found elevated as against an adequately matched reference group. Thus, subjects who suffered the second degree of severity acute radiation sickness after the radiation exposure, from 3-4 years later a group at high risk of coronary atherosclerosis

  9. Advice Complexity of the Online Induced Subgraph Problem

    DEFF Research Database (Denmark)

    Komm, Dennis; Královič, Rastislav; Královič, Richard

    2016-01-01

    of the input can influence the solution quality. We evaluate the information in a quantitative way by considering the best possible advice of given size that describes the unknown input. Using a result from Boyar et al. we give a tight trade-off relationship stating that, for inputs of length n, roughly n...... subgraph problem, preemption does not significantly help by giving a lower bound of Omega(n/(c^2\\log c)) on the bits of advice that are needed to obtain competitive ratio c, where c is any increasing function bounded from above by \\sqrt{n/\\log n}. We also give a linear lower bound for c close to 1....... these problems by investigating a generalized problem: for an arbitrary but fixed hereditary property, find some maximal induced subgraph having the property. We investigate this problem from the point of view of advice complexity, i.e. we ask how some additional information about the yet unrevealed parts...

  10. Bifidobacterium longum CECT 7347 modulates immune responses in a gliadin-induced enteropathy animal model.

    Directory of Open Access Journals (Sweden)

    José Moisés Laparra

    Full Text Available Coeliac disease (CD is an autoimmune disorder triggered by gluten proteins (gliadin that involves innate and adaptive immunity. In this study, we hypothesise that the administration of Bifidobacterium longum CECT 7347, previously selected for reducing gliadin immunotoxic effects in vitro, could exert protective effects in an animal model of gliadin-induced enteropathy. The effects of this bacterium were evaluated in newborn rats fed gliadin alone or sensitised with interferon (IFN-γ and fed gliadin. Jejunal tissue sections were collected for histological, NFκB mRNA expression and cytokine production analyses. Leukocyte populations and T-cell subsets were analysed in peripheral blood samples. The possible translocation of the bacterium to different organs was determined by plate counting and the composition of the colonic microbiota was quantified by real-time PCR. Feeding gliadin alone reduced enterocyte height and peripheral CD4+ cells, but increased CD4+/Foxp3+ T and CD8+ cells, while the simultaneous administration of B. longum CECT 7347 exerted opposite effects. Animals sensitised with IFN-γ and fed gliadin showed high cellular infiltration, reduced villi width and enterocyte height. Sensitised animals also exhibited increased NFκB mRNA expression and TNF-α production in tissue sections. B. longum CECT 7347 administration increased NFκB expression and IL-10, but reduced TNF-α, production in the enteropathy model. In sensitised gliadin-fed animals, CD4+, CD4+/Foxp3+ and CD8+ T cells increased, whereas the administration of B. longum CECT 7347 reduced CD4+ and CD4+/Foxp3+ cell populations and increased CD8+ T cell populations. The bifidobacterial strain administered represented between 75-95% of the total bifidobacteria isolated from all treated groups, and translocation to organs was not detected. These findings indicate that B. longum attenuates the production of inflammatory cytokines and the CD4+ T-cell mediated immune response in

  11. Schistosoma mansoni: is acquired immunity induced by highly x-irradiated cercariae dependent on the size of the challenging dose

    International Nuclear Information System (INIS)

    Hsue, S.Y.; Hsue, H.F.; Osborne, J.W.; Johnson, S.C.

    1982-01-01

    A high degree of immunity, as shown by a 91% reduction of the number of worms recovered was found in five groups of mice that were immunized five times with highly X-irradiated cercariae and then challenged with 10, 20, 50, 100, or 500 normal Schistosoma mansoni cercariae. The results indicated that there were no significant differences in worm reduction in immunized mice challenged with different numbers of cercariae; consequently the immunity induced by this immunization method did not appear to be challenge-dose-dependent. However, the results also showed that when immunized mice were challenged with 500, 100, 50, 20, and 10 cercariae, 0, 13, 26, 56, and 68%, respectively, of the experimental animals were free of worms. Thus, the percentage of worm-negative cases increased as the number of challenge cercariae decreased. When viewed in this manner, the acquired immunity may be considered challenge-dose-dependent as well. If this method of vaccination is used for schistosomiasis control, we may anticipate that in both hypo- and hyperendemic areas, the intensity of infection and the severity of the disease will be reduced owing to a reduction in worms burdens, and in hypoendemic areas, there will be a number of worm-free cases

  12. Sex-biased terminal investment in offspring induced by maternal immune challenge in the house wren (Troglodytes aedon).

    Science.gov (United States)

    Bowers, E Keith; Smith, Rebecca A; Hodges, Christine J; Zimmerman, Laura M; Thompson, Charles F; Sakaluk, Scott K

    2012-07-22

    The reproductive costs associated with the upregulation of immunity have been well-documented and constitute a fundamental trade-off between reproduction and self-maintenance. However, recent experimental work suggests that parents may increase their reproductive effort following immunostimulation as a form of terminal parental investment as prospects for future reproduction decline. We tested the trade-off and terminal investment hypotheses in a wild population of house wrens (Troglodytes aedon) by challenging the immune system of breeding females with lipopolysaccharide, a potent but non-lethal antigen. Immunized females showed no evidence of reproductive costs; instead, they produced offspring of higher phenotypic quality, but in a sex-specific manner. Relative to control offspring, sons of immunized females had increased body mass and their sisters exhibited higher cutaneous immune responsiveness to phytohaemagglutinin injection, constituting an adaptive strategy of sex-biased allocation by immune-challenged females to enhance the reproductive value of their offspring. Thus, our results are consistent with the terminal investment hypothesis, and suggest that maternal immunization can induce pronounced transgenerational effects on offspring phenotypes.

  13. Circulating immune complexes, immunoglobulin G, salivary proteins and salivary immunoglobulin A in patients with Sjögren's syndrome

    Directory of Open Access Journals (Sweden)

    Hadži-Mihailović Miloš

    2009-01-01

    Full Text Available Introduction. Sjögren's syndrome (SS is a chronic autoimmune disorder, with its major clinical manifestations resulting from changes in exocrine glands. Objective The aim of this study was to evaluate serum concentrations of circulating immune complexes (CIC and immunoglobulin G (IgG, and salivary proteins (SP and salivary immunoglobulin A (sIgA in 40 patients with SS, and to correlate these values among themselves, as well as with the unstimulated salivary flow rate (USFR and the duration of disease. Methods. The total of 40 patients were included in this research. CIC was determined using the solution of polyethylene glycol and IgG with the standard procedure of radial immunodiffusion. SP was investigated by the method of Lowry and sIgA was separated from the whole saliva using the method of immune chromatography. Results. The values of most of the studied parameters exceeded the normal range in a high degree: CIC 72.5%, IgG 70%, SP 80%. The concentrations of CIC were significantly higher in the patients with the duration of disease less than 10 years. With the decrease of USFR, the concentration of sIgA and IgG were increased with statistical significance. Conclusion The increased prevalence of abnormal values of CIC, IgG and SP indicate that the patients with SS have developed a higher level of immune reactivity. These results could be useful in diagnosis and disease activity monitoring.

  14. The role of recombinant IL-12 in enhancing immune responses induced by hepatitis B vaccine in mice

    International Nuclear Information System (INIS)

    Lu Qun; Zhou Lixia; Zhao Yanrong; Miao Xiaoguang; Jin Jie; Ke Jinshan; Qin Xuliang; He Zheng

    2007-01-01

    Objective: To study the role played by recombinant IL-12 in enhancing the intensity and quality of the immune response to hepatitis B vaccine in mice, and investigate the possibility of adding recombinant IL-12 as adjuvants to hepatitis B therapeutic vaccine. Methods: Recombinant IL-12 was injected together with hepatitis B vaccine into mice and special anti-HBsAb in the mice and the cellular immune responses were examined. Results: Recombinant IL-12 can obviously enhance T lymphocyte multiplication activity, accelerate excretion of cytokines IFN-γ and IL-2, and increase the IgG2a antibody in mice. Conclusion: Recombinant IL-12 can remarkably strengthen the cellular immune responses induced by the hepatitis B vaccine, and modulate the immune responses toward Thl. (authors)

  15. Recombinant Lactobacillus plantarum induces immune responses to cancer testis antigen NY-ESO-1 and maturation of dendritic cells

    Science.gov (United States)

    Mobergslien, Anne; Vasovic, Vlada; Mathiesen, Geir; Fredriksen, Lasse; Westby, Phuong; Eijsink, Vincent GH; Peng, Qian; Sioud, Mouldy

    2015-01-01

    Given their safe use in humans and inherent adjuvanticity, Lactic Acid Bacteria may offer several advantages over other mucosal delivery strategies for cancer vaccines. The objective of this study is to evaluate the immune responses in mice after oral immunization with Lactobacillus (L) plantarum WCFS1 expressing a cell-wall anchored tumor antigen NY-ESO-1. And to investigate the immunostimulatory potency of this new candidate vaccine on human dendritic cells (DCs). L. plantarum displaying NY-ESO-1 induced NY-ESO-1 specific antibodies and T-cell responses in mice. By contrast, L. plantarum displaying conserved proteins such as heat shock protein-27 and galectin-1, did not induce immunity, suggesting that immune tolerance to self-proteins cannot be broken by oral administration of L. plantarum. With respect to immunomodulation, immature DCs incubated with wild type or L. plantarum-NY-ESO-1 upregulated the expression of co-stimulatory molecules and secreted a large amount of interleukin (IL)-12, TNF-α, but not IL-4. Moreover, they upregulated the expression of immunosuppressive factors such as IL-10 and indoleamine 2,3-dioxygenase. Although L. plantarum-matured DCs expressed inhibitory molecules, they stimulated allogeneic T cells in-vitro. Collectively, the data indicate that L. plantarum-NY-ESO-1 can evoke antigen-specific immunity upon oral administration and induce DC maturation, raising the potential of its use in cancer immunotherapies. PMID:26185907

  16. Perturbations in immune responses induced by concurrent subchronic exposure to arsenic and endosulfan

    International Nuclear Information System (INIS)

    Aggarwal, Manoj; Naraharisetti, Suresh Babu; Dandapat, S.; Degen, G.H.; Malik, J.K.

    2008-01-01

    The metalloid arsenic and the chlorinated insecticide endosulfan are common environmental contaminants. Humans, animals, and birds are exposed to these chemicals through water and food. Although health effects due to either arsenic or endosulfan exposure are documented, the toxicological impact of co-exposure to these environmental pollutants is unpredictable and unknown. The present study was undertaken to assess whether concurrent exposure to arsenic and endosulfan induces significant alterations in immunological functions. Day-old chicks were exposed to 3.7 ppm of arsenic via drinking water and to 30 ppm of endosulfan-mixed feed either individually or concurrently for up to 60 days. All the chicks were vaccinated with Ranikhet disease virus (F-strain; RD-F) on days 1 and 30. During the course of study and at term, parameters of cellular and humoral immunity were determined. None of the treatments altered the absolute body weight or body weight gain, except arsenic significantly reduced weight gain on day 60. Absolute, but not the relative, weights of spleen, thymus and bursa of Fabricius were significantly reduced in all the treatment groups. The metalloid and insecticide combination significantly depressed the ability of peripheral blood and splenic lymphocytes to proliferate in response to antigen RD-F and mitogen Con A. The delayed type hypersensitivity response to 2,4-dinitro-1-chlorobenzene or to PHA-P was also significantly decreased. Nitric oxide production by RD-F or lipopolysaccharide-stimulated peripheral blood and splenic mononuclear cells was significantly suppressed following concurrent exposure to arsenic and endosulfan. Furthermore, the combined exposure also decreased the antibody response to RD-F. The suppression of cellular and humoral immune responses was also evident following administration of individual compounds, and it was not exacerbated following concurrent exposure. To our knowledge, this is the first report describing the suppression

  17. Noise-induced polarization switching in complex networks

    Science.gov (United States)

    Haerter, Jan O.; Díaz-Guilera, Albert; Serrano, M. Ángeles

    2017-04-01

    The combination of bistability and noise is ubiquitous in complex systems, from biology to social interactions, and has important implications for their functioning and resilience. Here we use a simple three-state dynamical process, in which nodes go from one pole to another through an intermediate state, to show that noise can induce polarization switching in bistable systems if dynamical correlations are significant. In large, fully connected networks, where dynamical correlations can be neglected, increasing noise yields a collapse of bistability to an unpolarized configuration where the three possible states of the nodes are equally likely. In contrast, increased noise induces abrupt and irreversible polarization switching in sparsely connected networks. In multiplexes, where each layer can have a different polarization tendency, one layer is dominant and progressively imposes its polarization state on the other, offsetting or promoting the ability of noise to switch its polarization. Overall, we show that the interplay of noise and dynamical correlations can yield discontinuous transitions between extremes, which cannot be explained by a simple mean-field description.

  18. 255Gy irradiated tachyzoites of Toxoplasma gondii induce intestinal immune response in C57BL/6J immunized by oral route

    Energy Technology Data Exchange (ETDEWEB)

    Galisteo Junior, Andres Jimenez; Alves, Janaina Baptista [Instituto de Pesquisas Energeticas e Nucleares (IPEN), Sao Paulo, SP (Brazil). Lab. de Biologia Molecular]. E-mail: galisteo@usp.br; Hiramoto, Roberto Mitsuyoshi [Instituto Adolfo Lutz, Sao Paulo, SP (Brazil). Secao de Parasitoses Sistemicas]. E-mail: hiramoto@usp.br; Carmo, Claudia Villano do; Andrade Junior, Heitor Franco de [Instituto de Medicina Tropical de Sao Paulo, Sao Paulo, SP (Brazil). Lab. de Protozoologia]. E-mail: hfandrad@usp.br

    2005-07-01

    Toxoplasmosis, a prevalent widespread infection in man and animals, occurs mainly through ingestion of water and food contaminated with oocyst from cat feces, causing usually benign disease in humans, except in intrauterine fetal infection or in immunodeficient patients. We study the oral route for the development of a vaccine for toxoplasmosis, using parasites irradiated with 60 Cobalt, as an alternative for vaccine development to this worldwide parasitic infection. We evaluated the development of immunity at serum or mucosal levels, and their efficiency in protect the mice against challenge with oral cysts of the ME-49 strain. C57Bl/6j isogenic mice were immunized by oral route with 10{sup 7} 255 Gy irradiated tachyzoites from RH strain, at several protocols using milk as anti-peptic adjuvant and alum hydroxide as antacid. The preparations of irradiated tachyzoites induced production of serum IgG and IgA in immunized mice, as determined by ELISA, with IgG2a as the dominant subclass, similar to chronic infection. Their use with adjuvant allowed the excretion of significant amounts of IgA in stools also IgG, despite a lesser extent. All oral preparations induced some quantitative protection against challenge, which was similar to the parenteral route only isolated alum hydroxide was used as adjuvant. All these data support the possibility of the development of an oral vaccine against toxoplasmosis, using irradiated tachyzoites, which would be possible tool in near future for use in field baits, for immunizing either domestic or wild felids. (author)

  19. 255Gy irradiated tachyzoites of Toxoplasma gondii induce intestinal immune response in C57BL/6J immunized by oral route

    International Nuclear Information System (INIS)

    Galisteo Junior, Andres Jimenez; Alves, Janaina Baptista; Hiramoto, Roberto Mitsuyoshi; Carmo, Claudia Villano do; Andrade Junior, Heitor Franco de

    2005-01-01

    Toxoplasmosis, a prevalent widespread infection in man and animals, occurs mainly through ingestion of water and food contaminated with oocyst from cat feces, causing usually benign disease in humans, except in intrauterine fetal infection or in immunodeficient patients. We study the oral route for the development of a vaccine for toxoplasmosis, using parasites irradiated with 60 Cobalt, as an alternative for vaccine development to this worldwide parasitic infection. We evaluated the development of immunity at serum or mucosal levels, and their efficiency in protect the mice against challenge with oral cysts of the ME-49 strain. C57Bl/6j isogenic mice were immunized by oral route with 10 7 255 Gy irradiated tachyzoites from RH strain, at several protocols using milk as anti-peptic adjuvant and alum hydroxide as antacid. The preparations of irradiated tachyzoites induced production of serum IgG and IgA in immunized mice, as determined by ELISA, with IgG2a as the dominant subclass, similar to chronic infection. Their use with adjuvant allowed the excretion of significant amounts of IgA in stools also IgG, despite a lesser extent. All oral preparations induced some quantitative protection against challenge, which was similar to the parenteral route only isolated alum hydroxide was used as adjuvant. All these data support the possibility of the development of an oral vaccine against toxoplasmosis, using irradiated tachyzoites, which would be possible tool in near future for use in field baits, for immunizing either domestic or wild felids. (author)

  20. Evaluation of humoral and cell-mediated inducible immunity to Haemophilus ducreyi in an animal model of chancroid.

    Science.gov (United States)

    Desjardins, M; Filion, L G; Robertson, S; Kobylinski, L; Cameron, D W

    1996-01-01

    To study the mechanisms of inducible immunity to Haemophilus ducreyi infection in the temperature-dependent rabbit model of chancroid, we conducted passive immunization experiments and characterized the inflammatory infiltrate of chancroidal lesions. Polyclonal immunoglobulin G was purified from immune sera raised against H. ducreyi 35000 whole-cell lysate or a pilus preparation and from naive control rabbits. Rabbits were passively immunized with 24 or 48 mg of purified polyclonal immunoglobulin G intravenously, followed 24 h after infusion by homologous titered infectious challenge. Despite titratable antibody, no significant difference in infection or disease was observed. We then evaluated the immunohistology of lesions produced by homologous-strain challenge in sham-immunized rabbits and those protectively vaccinated by pilus preparation immunization. Immunohistochemical stains for CD5 and CD4 T-lymphocyte markers were performed on lesion sections 4, 10, 15, and 21 days from infection. Lesions of pilus preparation vaccinees compared with those of controls had earlier infiltration with significantly more T lymphocytes (CD5+) and with a greater proportion of CD4+ T lymphocytes at day 4 (33% +/- 55% versus 9.7% +/- 2%; P = 0.002), corroborating earlier sterilization (5.0 +/- 2 versus 13.7 +/- 0.71 days; P < 0.001) and lesion resolution. Intraepithelial challenge of pilus-vaccinated rabbits with 100 micrograms of the pilus preparation alone produced indurated lesions within 48 h with lymphoid and plasmacytoid infiltration, edema, and extravasation of erythrocytes. We conclude that passive immunization may not confer a vaccine effect in this model and that active vaccination with a pilus preparation induces a delayed-type hypersensitivity skin test response and confers protection through cell-mediated immunity seen as an amplified lymphocytic infiltrate and accelerated maturation of the T-lymphocyte response. PMID:8613391

  1. TiO{sub 2} nanoparticle-induced ROS correlates with modulated immune cell function

    Energy Technology Data Exchange (ETDEWEB)

    Maurer-Jones, Melissa A.; Christenson, Jenna R.; Haynes, Christy L., E-mail: chaynes@umn.edu [University of Minnesota, Department of Chemistry (United States)

    2012-12-15

    Design of non-toxic nanoparticles will be greatly facilitated by understanding the nanoparticle-cell interaction mechanism on a cell function level. Mast cells are important cells for the immune system's first line of defense, and we can utilize their exocytotic behavior as a model cellular function as it is a conserved process across cell types and species. Perturbations in exocytosis can also have implications for whole organism health. One proposed mode of toxicity is nanoparticle-induced reactive oxygen species (ROS), particularly for titanium dioxide (TiO{sub 2}) nanoparticles. Herein, we have correlated changes in ROS with the perturbation of the critical cell function of exocytosis, using UV light to induce greater levels of ROS in TiO{sub 2} exposed cells. The primary culture mouse peritoneal mast cells (MPMCs) were exposed to varying concentrations of TiO{sub 2} nanoparticles for 24 h. ROS content was determined using 2,7-dihydrodichlorofluorescein diacetate (DCFDA). Cellular viability was determined with the MTT and Trypan blue assays, and exocytosis was measured by the analytical electrochemistry technique of carbon-fiber microelectrode amperometry. MPMCs exposed to TiO{sub 2} nanoparticles experienced a dose-dependent increase in total ROS content. While there was minimal impact of ROS on cellular viability, there is a correlation between ROS amount and exocytosis perturbation. As nanoparticle-induced ROS increases, there is a significant decrease (45 %) in the number of serotonin molecules being released during exocytosis, increase (26 %) in the amount of time for each exocytotic granule to release, and decrease (28 %) in the efficiency of granule trafficking and docking. This is the first evidence that nanoparticle-induced ROS correlates with chemical messenger molecule secretion, possibly making a critical connection between functional impairment and mechanisms contributing to that impairment.

  2. A Schistosoma japonicum chimeric protein with a novel adjuvant induced a polarized Th1 immune response and protection against liver egg burdens

    Directory of Open Access Journals (Sweden)

    Xue Xiangyang

    2009-05-01

    Full Text Available Abstract Background Schitosomiasis japonica is still a significant public health problem in China. A protective vaccine for human or animal use represents an important strategy for long-term control of this disease. Due to the complex life cycle of schistosomes, different vaccine design approaches may be necessary, including polyvalent subunit vaccines. In this study, we constructed four chimeric proteins (designated SjGP-1~4 via fusion of Sj26GST and four individual paramyosin fragments. We tested these four proteins as vaccine candidates, and investigated the effect of deviating immune response on protection roles in mice. Methods The immunogencity and protection efficacy of chimeric proteins were evaluated in mice. Next, the chimeric protein SjGP-3 was selected and formulated in various adjuvants, including CFA, ISA 206, IMS 1312 and ISA 70M. The titers of antigen-specific IgG, IgE and IgG subclass were measured. The effect of adjuvant on cytokine production and percentages of CD3+CD8-IFN-γ+ cells and CD3+CD8-IL-4+ cells were analyzed at different time points. Worm burdens and liver egg counts in different adjuvant groups were counted to evaluate the protection efficacy against cercarial challenge. Results Immunization of mice with chimeric proteins provided various levels of protection. Among the four proteins, SjGP-3 induced the highest level of protection, and showed enhanced protective efficacy compared with its individual component Sj26GST. Because of this, SjGP-3 was further formulated in various adjuvants to investigate the effect of adjuvant on immune deviation. The results revealed that SjGP-3 formulated in veterinary adjuvant ISA 70M induced a lasting polarized Th1 immune response, whereas the other adjuvants, including CFA, ISA 206 and IMS 1312, generated a moderate mixed Th1/Th2 response after immunization but all except for IMS 1312 shifted to Th2 response after onset of eggs. More importantly, the SjGP-3/70M formulation induced

  3. Neuropsychiatry phenotype in asthma: Psychological stress-induced alterations of the neuroendocrine-immune system in allergic airway inflammation

    Directory of Open Access Journals (Sweden)

    Isao Ohno

    2017-09-01

    Full Text Available Since the recognition of asthma as a syndrome with complex pathophysiological signs and symptoms, recent research has sought to classify asthma phenotypes based on its clinical and molecular pathological features. Psychological stress was first recognized as a potential immune system modulator of asthma at the end of the 19th century. The activation of the central nervous system (CNS upon exposure to psychological stress is integral for the initiation of signal transduction processes. The stress hormones, including glucocorticoids, epinephrine, and norepinephrine, which are secreted following CNS activation, are involved in the immunological alterations involved in psychological stress-induced asthma exacerbation. The mechanisms underlying this process may involve a pathological series of events from the brain to the lungs, which is attracting attention as a conceptually advanced phenotype in asthma pathogenesis. This review presents insights into the critical role of psychological stress in the development and exacerbation of allergic asthma, with a special focus on our own data that emphasizes on the continuity from the central sensing of psychological stress to enhanced eosinophilic airway inflammation.

  4. Assessment of complex water pollution with heavy metals and Pyrethroid pesticides on transcript levels of metallothionein and immune related genes.

    Science.gov (United States)

    Ghazy, Haneen A; Abdel-Razek, Mohamed A S; El Nahas, Abeer F; Mahmoud, Shawky

    2017-09-01

    Alteration of immunological function of an aquatic organism can be used as an indicator for evaluating the direct effect of exposure to pollutants. The aim of this work is to assess the impact of complex water pollution with special reference to Pyrethroid pesticides and heavy metals on mRNA transcript levels of Metallothionine and some immune related genes of Nile tilapia (Oreochromas Niloticus). Residues of six heavy metals and six Pyrethroid were assessed in water as well as fish tissues at three different sites of Lake Burullus, located at Northern Egypt. Variations of water physicochemical properties associated with different levels of heavy metals at the three different sections were recorded. Tissue residues of Fe, Mn and Zn, Cu, Ni exceed water levels in contrast to elevated water level of Pb. All assessed Pyrethroids are detected in fish tissue samples with higher concentration (3-42 folds) than that found in water samples especially Cypermethrin. Significant down-regulation of expression levels of metallothionein (MT) at the three sections of the lake was observed. The expression of immune related genes (IgM) and inflammatory cytokines (TNF, IL.8 and IL.1) were affected. IgM and TNF were significantly down-regulated at eastern and western section of the lake; meanwhile the expression of IL8 is down regulated at the three sections of the lack. IL1 was significantly up-regulated at eastern and middle sections. We conclude that, variable gene expression of MT and immune-related genes at the three sections of the lack impose different response to complex water pollution in relation to variable aquatic environment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Failure of orally administered attenuated goose parvovirus strain B to induce a humoral immune response in adult geese.

    Science.gov (United States)

    Kisary, J; Kelemen, M

    1981-01-01

    Two-month-old geese responded with the production of virus neutralising antibodies against virulent goose parvovirus strain B administered either per os or intramuscularly. They were shedding the virus within a short period after exposure. Humoral immune response in geese of the same age was induced by the attenuated goose parvovirus strain B only by intramuscular injection but not with per os administration.

  6. CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling

    Directory of Open Access Journals (Sweden)

    Matous Hrdinka

    2016-03-01

    Full Text Available Innate immune signaling relies on the deposition of non-degradative polyubiquitin at receptor-signaling complexes, but how these ubiquitin modifications are regulated by deubiquitinases remains incompletely understood. Met1-linked ubiquitin (Met1-Ub is assembled by the linear ubiquitin assembly complex (LUBAC, and this is counteracted by the Met1-Ub-specific deubiquitinase OTULIN, which binds to the catalytic LUBAC subunit HOIP. In this study, we report that HOIP also interacts with the deubiquitinase CYLD but that CYLD does not regulate ubiquitination of LUBAC components. Instead, CYLD limits extension of Lys63-Ub and Met1-Ub conjugated to RIPK2 to restrict signaling and cytokine production. Accordingly, Met1-Ub and Lys63-Ub were individually required for productive NOD2 signaling. Our study thus suggests that LUBAC, through its associated deubiquitinases, coordinates the deposition of not only Met1-Ub but also Lys63-Ub to ensure an appropriate response to innate immune receptor activation.

  7. Detection of immune complexes in sera of dogs with rheumatic and neoplastic diseases by 125I-Clq binding test

    International Nuclear Information System (INIS)

    Terman, D.S.; Moore, D.; Collins, J.; Johnston, B.; Person, D.; Templeton, J.; Poser, R.; Quinby, F.

    1979-01-01

    Some canine rheumatic and neoplastic diseases bear a striking clinical and serological resemblance to their counterparts in man. In the present study, human 125 I-Clq was employed in a radioimmunoassay for detection of immune complexes in sera of normal dogs and those with rheumatic and neoplastic diseases. Human 125 I-Clq showed binding of 16.7 +- 5.73% in a group of normal dog sera with binding of 32.5 +- 17.3% and 43.0 +- 16.0% in sera of dogs with rheumatic and neoplastic diseases. respectively. Human 125 I-Clq bound similar quantities of heat-aggregated canine and human gamma-globulin over a broad range of concentrations and human 125 I-Clq binding in canine sera was effectively inhibited by similar quantities of heat aggregated canine and human gamma-globulin. Seven of 12 dogs with elevated levels of Clq binding had active clinical and serological rheumatic disease (SLE or rheumatoid arthritis), while none of 7 dogs with values within the normal range had active clinical disease. All 5 dogs with widespread osteogenic sarcoma and all 4 dogs with high grade adenocarcinoma of the mammary gland had elevated Clq binding values while 2 animals with low grade malignancies without evident metastases did not. Thus, it appears that human 125 I-Clq may be employed to assay immune complexes in canine sera and may be a valuable technique for the study of dogs with various rheumatic and neoplastic diseases. (author)

  8. Experimentally-induced immune activation in natural hosts of SIV induces significant increases in viral replication and CD4+ T cell depletion

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Ruy M [Los Alamos National Laboratory

    2008-01-01

    Chronically SIVagm-infected African green monkeys (AGMs) have a remarkably stable non-pathogenic disease course, with levels of immune activation in chronic SIVagm infection similar to those observed in uninfected monkeys and stable viral loads (VLs) for long periods of time. In vivo administration of lipopolysaccharide (LPS) or an IL-2/diphtheria toxin fusion protein (Ontak) to chronically SIVagm-infected AGMs triggered increases in immune activation and subsequently of viral replication and depletion of intestinal CD4{sup +} T cells. Our study indicates that circulating microbial products can increase viral replication by inducing immune activation and increasing the number of viral target cells, thus demonstrating that immune activation and T cell prolifeation are key factors in AIDS pathogenesis.

  9. Current Diagnosis and Management of Immune Related Adverse Events (irAEs Induced by Immune Checkpoint Inhibitor Therapy

    Directory of Open Access Journals (Sweden)

    Vivek Kumar

    2017-02-01

    Full Text Available The indications of immune checkpoint inhibitors (ICIs are set to rise further with the approval of newer agent like atezolimumab for use in patients with advanced stage urothelial carcinoma. More frequent use of ICIs has improved our understanding of their unique side effects, which are known as immune-related adverse events (irAEs. The spectrum of irAEs has expanded beyond more common manifestations such as dermatological, gastrointestinal and endocrine effects to rarer presentations involving nervous, hematopoietic and urinary systems. There are new safety data accumulating on ICIs in patients with previously diagnosed autoimmune conditions. It is challenging for clinicians to continuously update their working knowledge to diagnose and manage these events successfully. If diagnosed timely, the majority of events are completely reversible, and temporary immunosuppression with glucocorticoids, infliximab or other agents is warranted only in the most severe grade illnesses. The same principles of management will possibly apply as newer anti- cytotoxic T lymphocytes-associated antigen 4 (CTLA-4 and programmed cell death protein 1 (PD-1/PD-L1 antibodies are introduced. The current focus of research is for prophylaxis and for biomarkers to predict the onset of these toxicities. In this review we summarize the irAEs of ICIs and emphasize their growing spectrum and their management algorithms, to update oncology practitioners.

  10. Bifidobacterium breve alters immune function and ameliorates DSS-induced inflammation in weanling rats.

    Science.gov (United States)

    Izumi, Hirohisa; Minegishi, Mario; Sato, Yohei; Shimizu, Takashi; Sekine, Kazunori; Takase, Mitsunori

    2015-10-01

    Bifidobacterium breve M-16V (M16V) is a probiotic bacterial strain with a long tradition of use in neonatal intensive care units in some countries. Previous study showed that the effects of M16V administration on gene expression were greater during the weaning period than in the neonatal period and were greater in the colon than in the small intestine and spleen, suggesting that M16V has anti-inflammatory effects. In this study, we evaluated the effects of inflammation during the weaning period and the effects of M16V on normal and inflammatory conditions. From postnatal day (PD) 21 to 34, weanling rats were administered of 2.5 × 10(9) of M16V daily, and colitis was induced by administration of 2% dextran sulfate sodium from PD28 to 35. Colitis severity, immune function, and microbiota were investigated. Colitis caused a reduction in body weight gain, colon shortening, poor nutritional status, anemia, changes in blood and spleen lymphocyte populations, spleen T-cell malfunctions, and alterations in colon microbiota. M16V administration improved some but not all of the changes induced by colitis. M16V could suppress inflammation and, therefore, can be considered a safe strain to use not only during the neonatal period but also the weaning period.

  11. Mycobacterium tuberculosis PPD-induced immune biomarkers measurable in vitro following BCG vaccination of UK adolescents by multiplex bead array and intracellular cytokine staining

    Directory of Open Access Journals (Sweden)

    Worth Andrew

    2010-07-01

    Full Text Available Abstract Background The vaccine efficacy reported following Mycobacterium bovis Bacillus Calmette Guerin (BCG administration to UK adolescents is 77% and defining the cellular immune response in this group can inform us as to the nature of effective immunity against tuberculosis. The aim of this study was to identify which cytokines and lymphocyte populations characterise the peripheral blood cellular immune response following BCG vaccination. Results Diluted blood from before and after vaccination was stimulated with Mycobacterium tuberculosis purified protein derivative for 6 days, after which soluble biomarkers in supernatants were assayed by multiplex bead array. Ten out of twenty biomarkers measured were significantly increased (p Mycobacterium tuberculosis purified protein derivative stimulation of PBMC samples from the 12 month group revealed that IFNγ expression was detectable in CD4 and CD8 T-cells and natural killer cells. Polyfunctional flow cytometry analysis demonstrated that cells expressing IFNγ alone formed the majority in each subpopulation of cells. Only in CD4 T-cells and NK cells were there a notable proportion of responding cells of a different phenotype and these were single positive, TNFα producers. No significant expression of the cytokines IL-2, IL-17 or IL-10 was seen in any population of cells. Conclusions The broad array of biomarker responses detected by multiplex bead array suggests that BCG vaccination is capable, in this setting, of inducing a complex immune phenotype. Although polyfunctional T-cells have been proposed to play a role in protective immunity, they were not present in vaccinated adolescents who, based on earlier epidemiological studies, should have developed protection against pulmonary tuberculosis. This may be due to the later sampling time point available for testing or on the kinetics of the assays used.

  12. Immunizing Children

    Directory of Open Access Journals (Sweden)

    Geraldine Jody Macdonald

    2014-11-01

    Full Text Available This article addresses the complex contexts within which Canadian health professionals engage in immunizing children and focuses on the Canadian practice guidelines and current scientific evidence that direct Canadian health professional competencies. The article begins by presenting two current global vaccine initiatives and links these to immunization in Canada. A selected literature review identifies current best immunization practices. With the purpose of promoting quality improvement, three key Canadian immunization competencies for health professional are highlighted: communication with parents, including those who are experiencing vaccine hesitancy; administration of immunizing agents; and documentation of immunizations. Health professionals are encouraged to reflect on immunization competencies and ensure evidence-based practices underpin vaccine delivery in their primary care settings.

  13. Sex-specific consequences of an induced immune response on reproduction in a moth.

    Science.gov (United States)

    Barthel, Andrea; Staudacher, Heike; Schmaltz, Antje; Heckel, David G; Groot, Astrid T

    2015-12-16

    Immune response induction benefits insects in combatting infection by pathogens. However, organisms have a limited amount of resources available and face the dilemma of partitioning resources between immunity and other life-history traits. Since males and females differ in their life histories, sex-specific resource investment strategies to achieve an optimal immune response following an infection can be expected. We investigated immune response induction of females and males of Heliothis virescens in response to the entomopathogenic bacterium Serratia entomophila, and its effects on mating success and the female sexual signal. We found that females had higher expression levels of immune-related genes after bacterial challenge than males. However, males maintained a higher baseline expression of immune-related genes than females. The increased investment in immunity of female moths was negatively correlated with mating success and the female sexual signal. Male mating success was unaffected by bacterial challenge. Our results show that the sexes differed in their investment strategies: females invested in immune defense after a bacterial challenge, indicating facultative immune deployment, whereas males had higher baseline immunity than females, indicating immune maintenance. Interestingly, these differences in investment were reflected in the mate choice assays. As female moths are the sexual signallers, females need to invest resources in their attractiveness. However, female moths appeared to invest in immunity at the cost of reproductive effort.

  14. Circulating immune complexes in the serum in systemic lupus erythematosus and in carriers of hepatitis B antigen: quantitation by binding to radiolabeled Cl/sub q/

    International Nuclear Information System (INIS)

    Nydegger, U.E.; Lambert, P.H.; Gerber, H.; Miescher, P.A.

    1974-01-01

    A sensitive and reproducible procedure fr the detection of souble immune complexes in sera from patients with various immunopathological disorders is reported. Radiolabeled Clq is reacted with sera containing immune complexes. Separation of free from complex bound [ 125 I]Clq is achieved by selective precipitation with polyethylene glycol (PEG). The minimal amount of aggregated immunoglobulins thus detected is about 10 μg and that of soluble human IgG-anti-IgG complexes is about 3 μg of complexed antibody. Some immune complexes formed in large antigen excess (Ag 2 Ab) can still be detected by this radiolabeled Clq bining assay. In a second step, this radiolabeled Clq binding assay was applied to an experimental model of immune complex disease and was shown to be efficient for the detection of in vivo formed immune complexes. Finally, the technique could be applied to the study of sera from patients with systemic lupus erythematosus (SLE) or to carriers of the Hepatitis B antigen (HB-Ag). Particularly high values were seen in active disease, a finding which was confirmed by follow-up studies performed with four SLE patients. No increased [ 125 I]Clq binding was seen in 18 healthy carriers of the HB-Ag; whereas, sera from carriers with hepatitis appear to precipitate increased [ 125 I]Clq percentages: 7/24 cases with acute transient and 4/7 cases with chronic persistent hepatitis were found to increasingly bind [ 125 I]Clq. The results were also used for a correlative study of [ 125 I]Clq binding to IgG levels in the sera but increased [ 125 I]Clq binding could not be attributed to high serum IgG levels which are likely to account for the evaluation of immune complex diseases in human pathology. (U.S.)

  15. Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor

    Science.gov (United States)

    Walterscheid, Jeffrey P.; Nghiem, Dat X.; Kazimi, Nasser; Nutt, Leta K.; McConkey, David J.; Norval, Mary; Ullrich, Stephen E.

    2006-01-01

    Exposure to UV radiation induces skin cancer and suppresses the immune response. To induce immune suppression, the electromagnetic energy of UV radiation must be absorbed by an epidermal photoreceptor and converted into a biologically recognizable signal. Two photoreceptors have been recognized: DNA and trans-urocanic acid (UCA). Trans-UCA is normally found in the outermost layer of skin and isomerizes to the cis isomer upon exposure to UV radiation. Although UCA was identified as a UV photoreceptor years ago, and many have documented its ability to induce immune suppression, its exact mode of action remains elusive. Particularly vexing has been the identity of the molecular pathway by which cis-UCA mediates immune suppression. Here we provide evidence that cis-UCA binds to the serotonin [5-hydroxytryptamine (5-HT)] receptor with relatively high affinity (Kd = 4.6 nM). Anti-cis-UCA antibody precipitates radiolabeled 5-HT, and the binding is inhibited by excess 5-HT and/or excess cis-UCA. Similarly, anti-5-HT antibody precipitates radiolabeled cis-UCA, and the binding is inhibited by excess 5-HT or excess cis-UCA. Calcium mobilization was activated when a mouse fibroblast line, stably transfected with the human 5-HT2A receptor, was treated with cis-UCA. Cis-UCA-induced calcium mobilization was blocked with a selective 5-HT2A receptor antagonist. UV- and cis-UCA-induced immune suppression was blocked by antiserotonin antibodies or by treating the mice with 5-HT2A receptor antagonists. Our findings identify cis-UCA as a serotonin receptor ligand and indicate that the immunosuppressive effects of cis-UCA and UV radiation are mediated by activation of the 5-HT2A receptor. PMID:17085585

  16. Subunit Rotavirus Vaccine Administered Parenterally to Rabbits Induces Active Protective Immunity

    Science.gov (United States)

    Ciarlet, Max; Crawford, Sue E.; Barone, Christopher; Bertolotti-Ciarlet, Andrea; Ramig, Robert F.; Estes, Mary K.; Conner, Margaret E.

    1998-01-01

    Virus-like particles (VLPs) are being evaluated as a candidate rotavirus vaccine. The immunogenicity and protective efficacy of different formulations of VLPs administered parenterally to rabbits were tested. Two doses of VLPs (2/6-, G3 2/6/7-, or P[2], G3 2/4/6/7-VLPs) or SA11 simian rotavirus in Freund’s adjuvants, QS-21 (saponin adjuvant), or aluminum phosphate (AlP) were administered. Serological and mucosal immune responses were evaluated in all vaccinated and control rabbits before and after oral challenge with 103 50% infective doses of live P[14], G3 ALA lapine rotavirus. All VLP- and SA11-vaccinated rabbits developed high levels of rotavirus-specific serum and intestinal immunoglobulin G (IgG) antibodies but not intestinal IgA antibodies. SA11 and 2/4/6/7-VLPs afforded similar but much higher mean levels of protection than 2/6/7- or 2/6-VLPs in QS-21. The presence of neutralizing antibodies to VP4 correlated (P < 0.001, r = 0.55; Pearson’s correlation coefficient) with enhanced protection rates, suggesting that these antibodies are important for protection. Although the inclusion of VP4 resulted in higher mean protection levels, high levels of protection (87 to 100%) from infection were observed in individual rabbits immunized with 2/6/7- or 2/6-VLPs in Freund’s adjuvants. Therefore, neither VP7 nor VP4 was absolutely required to achieve protection from infection in the rabbit model when Freund’s adjuvant was used. Our results show that VLPs are immunogenic when administered parenterally to rabbits and that Freund’s adjuvant is a better adjuvant than QS-21. The use of the rabbit model may help further our understanding of the critical rotavirus proteins needed to induce active protection. VLPs are a promising candidate for a parenterally administered subunit rotavirus vaccine. PMID:9765471

  17. Streptozotocin induced oxidative stress, innate immune system responses and behavioral abnormalities in male mice.

    Science.gov (United States)

    Amiri, Shayan; Haj-Mirzaian, Arya; Momeny, Majid; Amini-Khoei, Hossein; Rahimi-Balaei, Maryam; Poursaman, Simin; Rastegar, Mojgan; Nikoui, Vahid; Mokhtari, Tahmineh; Ghazi-Khansari, Mahmoud; Hosseini, Mir-Jamal

    2017-01-06

    Recent evidence indicates the involvement of inflammatory factors and mitochondrial dysfunction in the etiology of psychiatric disorders such as anxiety and depression. To investigate the possible role of mitochondrial-induced sterile inflammation in the co-occurrence of anxiety and depression, in this study, we treated adult male mice with the intracerebroventricular (i.c.v.) infusion of a single low dose of streptozotocin (STZ, 0.2mg/mouse). Using valid and qualified behavioral tests for the assessment of depressive and anxiety-like behaviors, we showed that STZ-treated mice exhibited behaviors relevant to anxiety and depression 24h following STZ treatment. We observed that the co-occurrence of anxiety and depressive-like behaviors in animals were associated with abnormal mitochondrial function, nitric oxide overproduction and, the increased activity of cytosolic phospholipase A 2 (cPLA 2 ) in the hippocampus. Further, STZ-treated mice had a significant upregulation of genes associated with the innate immune system such as toll-like receptors 2 and 4. Pathological evaluations showed no sign of neurodegeneration in the hippocampus of STZ-treated mice. Results of this study revealed that behavioral abnormalities provoked by STZ, as a cytotoxic agent that targets mitochondria and energy metabolism, are associated with abnormal mitochondrial activity and, consequently the initiation of innate-inflammatory responses in the hippocampus. Our findings highlight the role of mitochondria and innate immunity in the formation of sterile inflammation and behaviors relevant to anxiety and depression. Also, we have shown that STZ injection (i.c.v.) might be an animal model for depression and anxiety disorders based on sterile inflammation. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. Two doses of bovine viral diarrhea virus DNA vaccine delivered by electroporation induce long-term protective immune responses.

    Science.gov (United States)

    van Drunen Littel-van den Hurk, Sylvia; Lawman, Zoe; Snider, Marlene; Wilson, Don; van den Hurk, Jan V; Ellefsen, Barry; Hannaman, Drew

    2013-02-01

    Bovine viral diarrhea virus (BVDV) is a pathogen of major importance in cattle, so there is a need for new effective vaccines. DNA vaccines induce balanced immune responses and are relatively inexpensive and thus promising for both human and veterinary applications. In this study, newborn calves with maternal antibodies were vaccinated intramuscularly (i.m.) with a BVDV E2 DNA vaccine with the TriGrid Delivery System for i.m. delivery (TDS-IM). Two doses of this vaccine spaced 6 or 12 weeks apart were sufficient to induce significant virus-neutralizing antibody titers, numbers of activated T cells, and reduction in viral shedding and clinical presentations after BVDV-2 challenge. In contrast to the placebo-treated animals, the vaccinated calves did not lose any weight, which is an excellent indicator of the well-being of an animal and has a significant economic impact. Furthermore, the interval between the two vaccinations did not influence the magnitude of the immune responses or degree of clinical protection, and a third immunization was not necessary or beneficial. Since electroporation may enhance not only the magnitude but also the duration of immunity after DNA immunization, the interval between vaccination and challenge was extended in a second trial, which showed that two doses of this E2 DNA vaccine again significantly reduced clinical disease against BVDV for several months. These results are promising and support this technology for use against infectious diseases in cattle and large species, including humans, in general.

  19. The potential of immunostimulatory CpG DNA for inducing immunity against genital herpes: opportunities and challenges.

    Science.gov (United States)

    Harandi, Ali M

    2004-07-01

    Herpes simplex virus type 2 (HSV-2) invades human genital tract mucosa and following local replications can be rapidly transmitted via peripheral nerve axons to the sacral ganglia where it can establish latency. Reactivation of the latent viral reservoir results in recurrent ulcers in the genital region. Innate immunity, the first line of defence during both primary and recurrent genital herpes infections, is crucial during the period of acute infection to limit early virus replication and to facilitate the development of an appropriate specific acquired immunity. Recent developments in immunology reveal that the mammalian innate immune systems use Toll-like receptor (TLR) to specifically sense evolutionary conserved molecules such as bacterial DNA in pathogens. Recently, local-vaginal delivery of CpG containing oligodeoxynucleotide (ODN), a synthetic mimic of bacterial DNA, holds substantial promise as a strong inducer of innate immunity against genital herpes infections in the animal models of the disease. These preclinical observations provide a scientific ground work for introduction of this novel intervention strategy to clinic. This review aims to highlight recent developments and future challenges in use of immunostimulatory CpG ODN for inducing immunity against genital herpes infection and disease.

  20. Radiation Therapy Induces Macrophages to Suppress Immune Responses Against Pancreatic Tumors in Mice

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-01-01

    Background & Aims The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. Methods We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Results Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Conclusions Radiation exposure causes macrophages in PDAs

  1. Strain-induced phenomenon in complex oxide thin films

    Science.gov (United States)

    Haislmaier, Ryan

    Complex oxide materials wield an immense spectrum of functional properties such as ferroelectricity, ferromagnetism, magnetoelectricity, optoelectricity, optomechanical, magnetoresistance, superconductivity, etc. The rich coupling between charge, spin, strain, and orbital degrees of freedom makes this material class extremely desirable and relevant for next generation electronic devices and technologies which are trending towards nanoscale dimensions. Development of complex oxide thin film materials is essential for realizing their integration into nanoscale electronic devices, where theoretically predicted multifunctional capabilities of oxides could add tremendous value. Employing thin film growth strategies such as epitaxial strain and heterostructure interface engineering can greatly enhance and even unlock novel material properties in complex oxides, which will be the main focus of this work. However, physically incorporating oxide materials into devices remains a challenge. While advancements in molecular beam epitaxy (MBE) of thin film oxide materials has led to the ability to grow oxide materials with atomic layer precision, there are still major limitations such as controlling stoichiometric compositions during growth as well as creating abrupt interfaces in multi-component layered oxide structures. The work done in this thesis addresses ways to overcome these limitations in order to harness intrinsic material phenomena. The development of adsorption-controlled stoichiometric growth windows of CaTiO3 and SrTiO3 thin film materials grown by hybrid MBE where Ti is supplied using metal-organic titanium tetraisopropoxide material is thoroughly outlined. These growth windows enable superior epitaxial strain-induced ferroelectric and dielectric properties to be accessed as demonstrated by chemical, structural, electrical, and optical characterization techniques. For tensile strained CaTiO3 and compressive strained SrTiO 3 films, the critical effects of

  2. Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function

    Directory of Open Access Journals (Sweden)

    Phillips R

    2006-04-01

    Full Text Available Abstract Background Dendritic cells (DCs are central to the initiation and regulation of the adaptive immune response during infection. Modulation of DC function may therefore allow evasion of the immune system by pathogens. Significant depression of the host's systemic immune response to both concurrent infections and heterologous vaccines has been observed during malaria infection, but the mechanisms underlying this immune hyporesponsiveness are controversial. Results Here, we demonstrate that the blood stages of malaria infection induce a failure of DC function in vitro and in vivo, causing suboptimal activation of T cells involved in heterologous immune responses. This effect on T-cell activation can be transferred to uninfected recipients by DCs isolated from infected mice. Significantly, T cells activated by these DCs subsequently lack effector function, as demonstrated by a failure to migrate to lymphoid-organ follicles, resulting in an absence of B-cell responses to heterologous antigens. Fractionation studies show that hemozoin, rather than infected erythrocyte (red blood cell membranes, reproduces the effect of intact infected red blood cells on DCs. Furthermore, hemozoin-containing DCs could be identified in T-cell areas of the spleen in vivo. Conclusion Plasmodium infection inhibits the induction of adaptive immunity to heterologous antigens by modulating DC function, providing a potential explanation for epidemiological studies linking endemic malaria with secondary infections and reduced vaccine efficacy.

  3. Epicutaneous immunization with type II collagen inhibits both onset and progression of chronic collagen-induced arthritis.

    Directory of Open Access Journals (Sweden)

    Jessica Strid

    Full Text Available Epicutaneous immunization is a potential non-invasive technique for antigen-specific immune-modulation. Topical application of protein antigens to barrier-disrupted skin induces potent antigen-specific immunity with a strong Th2-bias. In this study, we investigate whether the autoimmune inflammatory response of chronic collagen-induced arthritis (CCIA in DBA/1-TCR-beta Tg mice can be modified by epicutaneous immunization. We show that epicutaneous immunization with type II collagen (CII inhibited development and progression of CCIA and, importantly, also ameliorated ongoing disease as indicated by clinical scores of disease severity, paw swelling and joints histology. Treated mice show reduced CII-driven T cell proliferation and IFN-gamma production, as well as significantly lower levels of CII-specific IgG2a serum antibodies. In contrast, CII-driven IL-4 production and IgE antibody levels were increased consistent with skewing of the CII response from Th1 to Th2 in treated mice. IL-4 production in treated mice was inversely correlated with disease severity. Moreover, T cells from treated mice inhibited proliferation and IFN-gamma production by T cells from CCIA mice, suggesting induction of regulatory T cells that actively inhibit effector responses in arthritic mice. The levels of CD4(+CD25(+ T cells were however not increased following epicutaneous CII treatment. Together, these results suggest that epicutaneous immunization may be used as an immune-modulating procedure to actively re-programme pathogenic Th1 responses, and could have potential as a novel specific and simple treatment for chronic autoimmune inflammatory diseases such as rheumatoid arthritis.

  4. Costs and benefits of experimentally induced changes in the allocation of growth versus immune function under differential exposure to ectoparasites.

    Directory of Open Access Journals (Sweden)

    Natalia Pitala

    2010-05-01

    Full Text Available Ecological immunology has focused on the costs of investment in immunocompetence. However, understanding optimal resource allocation to immune defence requires also identification of its benefits, which are likely to occur only when parasites are abundant.We manipulated the abundance of parasitic hen fleas in blue tit (Cyanistes caeruleus nests, and supplemented their hosts, the nestlings, with methionine (a sulphur amino acid enhancing cell-mediated immunity during day 3-6. We found a significant interaction between these two experimental factors on the development of immune defences and growth rates. Only in parasitized nests did methionine supplementation boost immune (PHA response, and did nestling with experimentally increased immunocompetence show a relatively faster growth rate than control nestlings between days 6-9. Hence, the allocation of resources into immune defence and its growth-benefits are apparent only in presence of parasites. The main cost of methionine-induced increased allocation to the immune system was an increase in mortality, independently of ectoparasites. Nestlings in all treatments compensated initial growth reduction and all reached equal body size at day 16 (just prior to fledging, indicating a lack of long-term benefits. In addition, methionine treatment tended (P = 0.09 to lower circulating plasma immunoglobulin levels, possibly indicating a trade-off between the cell-mediated and humoral components of the immune system.We found no strong benefits of an increased investment in immunocompetence in a parasite-rich environment. Any deviation from the growth trajectory (due to changes in allocation induced by methionine is largely detrimental for survival. Hence, while costs are apparent identifying the benefits of investment in immunocompetence during ontogeny is challenging.

  5. Uropathogenic E. coli induce different immune response in testicular and peritoneal macrophages: implications for testicular immune privilege.

    Directory of Open Access Journals (Sweden)

    Sudhanshu Bhushan

    Full Text Available Infertility affects one in seven couples and ascending bacterial infections of the male genitourinary tract by Escherichia coli are an important cause of male factor infertility. Thus understanding mechanisms by which immunocompetent cells such as testicular macrophages (TM respond to infection and how bacterial pathogens manipulate defense pathways is of importance. Whole genome expression profiling of TM and peritoneal macrophages (PM infected with uropathogenic E. coli (UPEC revealed major differences in regulated genes. However, a multitude of genes implicated in calcium signaling pathways was a common feature which indicated a role of calcium-dependent nuclear factor of activated T cells (NFAT signaling. UPEC-dependent NFAT activation was confirmed in both cultured TM and in TM in an in vivo UPEC infectious rat orchitis model. Elevated expression of NFATC2-regulated anti-inflammatory cytokines was found in TM (IL-4, IL-13 and PM (IL-3, IL-4, IL-13. NFATC2 is activated by rapid influx of calcium, an activity delineated to the pore forming toxin alpha-hemolysin by bacterial mutant analysis. Alpha-hemolysin suppressed IL-6 and TNF-α cytokine release from PM and caused differential activation of MAP kinase and AP-1 signaling pathways in TM and PM leading to reciprocal expression of key pro-inflammatory cytokines in PM (IL-1α, IL-1β, IL-6 downregulated and TM (IL-1β, IL-6 upregulated. In addition, unlike PM, LPS-treated TM were refractory to NFκB activation shown by the absence of degradation of IκBα and lack of pro-inflammatory cytokine secretion (IL-6, TNF-α. Taken together, these results suggest a mechanism to the conundrum by which TM initiate immune responses to bacteria, while maintaining testicular immune privilege with its ability to tolerate neo-autoantigens expressed on developing spermatogenic cells.

  6. [Molecular dynamics of immune complex of photoadduct-containing DNA with Fab-Anti-DNA antibody fragment].

    Science.gov (United States)

    Akberova, N I; Zhmurov, A A; Nevzorova, T A; Litvinov, R I

    2016-01-01

    Antibodies to DNA play an important role in the pathogenesis of autoimmune diseases. The elucidation of structural mechanisms of both the antigen recognition and the interaction of anti-DNA antibodies with DNA will help to understand the role of DNA-containing immune complexes in various pathologies and can provide a basis for new treatment modalities. Moreover, the DNA-antibody complex is an analog of specific intracellular DNA-protein interactions. In this work, we used in silico molecular dynamic simulations of bimolecular complexes of the dsDNA segment containing the Fab fragment of an anti-DNA antibody to obtain the detailed thermodynamic and structural characteristics of dynamic intermolecular interactions. Using computationally modified crystal structure of the Fab-DNA complex (PDB ID: 3VW3), we studied the equilibrium molecular dynamics of the 64M-5 antibody Fab fragment associated with the dsDNA fragment containing the thymine dimer, the product of DNA photodamage. Amino acid residues that constitute paratopes and the complementary nucleotide epitopes for the Fab-DNA construct were identified. Stacking and electrostatic interactions were found to play the main role in mediating the most specific antibody-dsDNA contacts, while hydrogen bonds were less significant. These findings may shed light on the formation and properties of pathogenic anti-DNA antibodies in autoimmune diseases, such as systemic lupus erythematosus associated with skin photosensitivity and DNA photodamage.

  7. Effects of Protein-Iron Complex Concentrate Supplementation on Iron Metabolism, Oxidative and Immune Status in Preweaning Calves

    Directory of Open Access Journals (Sweden)

    Robert Kupczyński

    2017-07-01

    Full Text Available The objective of this study was to determine the effects of feeding protein-iron complex (PIC on productive performance and indicators of iron metabolism, hematology parameters, antioxidant and immune status during first 35 days of a calf’s life. Preparation of the complex involved enzymatic hydrolysis of milk casein (serine protease from Yarrowia lipolytica yeast. Iron chloride was then added to the hydrolyzate and lyophilizate. Calves were divided into treated groups: LFe (low iron dose 10 g/day calf of protein-iron complex, HFe (height iron dose 20 g/day calf, and control group. Dietary supplements containing the lower dose of concentrate had a significant positive effect on iron metabolism, while the higher dose of concentrate resulted in increase of total iron binding capacity (TIBC, saturation of transferrin and decrease of and unsaturated iron binding capacity (UIBC, which suggest iron overload. Additionally, treatment with the lower dose of iron remarkably increased the antioxidant parameters, mainly total antioxidant (TAS and glutathione peroxidase activity (GPx. Higher doses of PIC were related to lower total antioxidant status. IgG, IgM, insulin, glucose, TNFα and IGF-1 concentration did not change significantly in either group after supplementation. In practice, the use of protein-iron complex concentrate requires taking into account the iron content in milk replacers and other feedstuffs.

  8. CORRECTION OF IMMUNE STATUS IN CHILDREN WITH FREQUENTLY RECURRENT INFECTIONS WITH COMPLEX PERORAL VACCINE

    Directory of Open Access Journals (Sweden)

    V.V. Chernikov

    2011-01-01

    Full Text Available The market of drugs proposes some new medicines which are labeled by manufacturers as immunomodulating agents. Most of them are not licensed and they have no any evidence of their efficacy. In opposite, non-specific ribosomal modulator (Ribomunyl is the wellstudied drug with good database on its efficacy and safety. The article presents a description of drug’s effect on the immune system of a child for increase of organism’s resistance to the most widespread causative agents of infections of ENT-organs and airways.Key words: children, respiratory infections, recurrent course, immunomodulators, treatment.(Voprosy sovremennoi pediatrii — Current Pediatrics. 2011; 10 (3: 92–96

  9. Interactions of opsonized immune complexes with whole blood cells: binding to erythrocytes restricts complex uptake by leucocyte populations

    DEFF Research Database (Denmark)

    Nielsen, C H; Svehag, S E; Marquart, H V

    1994-01-01

    -binding to granulocytes (PMN), monocytes and lymphocytes was inhibited by up to 46%, 61% and 48%, respectively, depending on the incubation time and the IC-concentration tested. The E-mediated inhibition of the binding to PMN was found to correlate with the average numbers of CR1 per E during the initial 15 min...... to the findings for PMN, the difference between IC-binding to monocytes in the absence and presence of E increased progressively over the 90 min observation period, suggesting that different mechanisms are involved in the late-phase IC uptake by monocytes and PMN. Lymphocytes were heterogeneous with respect to IC...... binding, the main contributors being B cells. E initially inhibited and then later enhanced the IC binding to lymphocytes, suggesting that E promote B cell uptake of C3d,g-covered IC via CR2. Our findings, that E can restrict the IC uptake by circulating leucocytes, and that an IC-induced degranulation...

  10. Tumor-Derived Exosomes and Their Role in Tumor-Induced Immune Suppression

    Directory of Open Access Journals (Sweden)

    Theresa L. Whiteside

    2016-10-01

    Full Text Available Tumor-derived exosomes (TEX are emerging as critical components of an intercellular information network between the tumor and the host. The tumor escapes from the host immune system by using a variety of mechanisms designed to impair or eliminate anti-tumor immunity. TEX carrying a cargo of immunoinhibitory molecules and factors represent one such mechanism. TEX, which are present in all body fluids of cancer patients, deliver negative molecular or genetic signals to immune cells re-programming their functions. Although TEX can also stimulate immune activity, in the microenvironments dominated by the tumor, TEX tend to mediate immune suppression thus promoting tumor progression. The TEX content, in part resembling that of the parent cell, may serve as a source of cancer biomarkers. TEX also interfere with immune therapies. A better understanding of TEX and their contribution to cancer progression and cancer patients’ response to immune therapies represents a challenging new field of investigation.

  11. Vaccination with Recombinant Baculovirus Expressing Ranavirus Major Capsid Protein Induces Protective Immunity in Chinese Giant Salamander, Andrias davidianus

    Directory of Open Access Journals (Sweden)

    Xiaoyuan Zhou

    2017-07-01

    Full Text Available The Chinese giant salamander iridovirus (CGSIV, belonging to the genus Ranavirus in the family Iridoviridae, is the causative agent of an emerging infectious disease causing high mortality of more than 90% and economic losses in Chinese giant salamanders in China. In this study, a recombinant baculovirus-based vaccine expressing the CGSIV major capsid protein (MCP was developed and its protective immunity in Chinese giant salamanders was evaluated. The recombinant Autographa californica nucleopolyhedrosis virus (AcNPV, expressing CGSIV MCP, designated as AcNPV-MCP, was generated with the highest titers of 1 × 108 plaque forming units/mL (PFU/mL and confirmed by Western blot and indirect immunofluorescence (IIF assays. Western blot analysis revealed that the expressed MCP reacted with mouse anti-MCP monoclonal antibodies at the band of about 53 kDa. The results of IIF indicated that the MCP was expressed in the infected Spodoptera frugiperda 9 (Sf9 cells with the recombinant baculovirus, and the Chinese giant salamander muscle cells also transduced with the AcNPV-MCP. Immunization with the recombinant baculovirus of AcNPV-MCP elicited robust specific humoral immune responses detected by ELISA and neutralization assays and potent cellular immune responses in Chinese giant salamanders. Importantly, the effective immunization conferred highly protective immunity for Chinese giant salamanders against CGSIV challenge and produced a relative percent of survival rate of 84%. Thus, the recombinant baculovirus expressing CGSIV MCP can induce significant immune responses involving both humoral and cell-mediated immunity in Chinese giant salamanders and might represent a potential baculovirus based vaccine candidate for Chinese giant salamanders against CGSIV.

  12. Experimental demonstration of a parasite-induced immune response in wild birds: Darwin's finches and introduced nest flies.

    Science.gov (United States)

    Koop, Jennifer A H; Owen, Jeb P; Knutie, Sarah A; Aguilar, Maria A; Clayton, Dale H

    2013-08-01

    Ecological immunology aims to explain variation among hosts in the strength and efficacy of immunological defenses. However, a shortcoming has been the failure to link host immune responses to actual parasites under natural conditions. Here, we present one of the first experimental demonstrations of a parasite-induced immune response in a wild bird population. The recently introduced ectoparasitic nest fly Philornis downsi severely impacts the fitness of Darwin's finches and other land birds in the Galápagos Islands. An earlier study showed that female medium ground finches (Geospiza fortis) had P. downsi-binding antibodies correlating with presumed variation in fly exposure over time. In the current study, we experimentally manipulated fly abundance to test whether the fly does, in fact, cause changes in antibody levels. We manipulated P. downsi abundance in nests and quantified P. downsi-binding antibody levels of medium ground finch mothers, fathers, and nestlings. We also quantified host behaviors, such as preening, which can integrate with antibody-mediated defenses against ectoparasites. Philornis downsi-binding antibody levels were significantly higher among mothers at parasitized nests, compared to mothers at (fumigated) nonparasitized nests. Mothers with higher antibody levels tended to have fewer parasites in their nests, suggesting that antibodies play a role in defense against parasites. Mothers showed no behavioral changes that would enhance the effectiveness of the immune response. Neither adult males, nor nestlings, had P. downsi-induced immunological or behavioral responses that would enhance defense against flies. None of the parasitized nests fledged any offspring, despite the immune response by mothers. Thus, this study shows that, while the immune response of mothers appeared to be defensive, it was not sufficient to rescue current reproductive fitness. This study further shows the importance of testing the fitness consequences of immune

  13. Ocular myasthenia gravis induced by human acetylcholine receptor ϵ subunit immunization in HLA DR3 transgenic mice.

    Science.gov (United States)

    Wu, Xiaorong; Tuzun, Erdem; Saini, Shamsher S; Wang, Jun; Li, Jing; Aguilera-Aguirre, Leopoldo; Huda, Ruksana; Christadoss, Premkumar

    2015-12-01

    Extraocular muscles (EOM) are preferentially involved in myasthenia gravis (MG) and acetylcholine receptor (AChR) antibody positive MG patients may occasionally present with isolated ocular symptoms. Although experimental autoimmune myasthenia gravis (EAMG) induced by whole AChR immunization closely mimics clinical and immunopathological aspects of MG, EOM are usually not affected. We have previously developed an EAMG model, which imitates EOM symptoms of MG by immunization of human leukocyte antigen (HLA) transgenic mice with α or γ-subunits of human AChR (H-AChR). To investigate the significance of the ϵ-subunit in ocular MG, we immunized HLA-DR3 and HLA-DQ8 transgenic mice with recombinant H-AChR ϵ-subunit expressed in Escherichia coli. HLA-DR3 transgenic mice showed significantly higher clinical ocular and generalized MG severity scores and lower grip strength values than HLA-DQ8 mice. H-AChR ϵ-subunit-immunized HLA-DR3 transgenic mice had higher serum anti-AChR antibody (IgG, IgG1, IgG2b, IgG2c and IgM) levels, neuromuscular junction IgG and complement deposit percentages than ϵ-subunit-immunized HLA-DQ8 transgenic mice. Control mice immunized with E. coli extract or complete Freund adjuvant (CFA) did not show clinical and immunopathological features of ocular and generalized EAMG. Lymph node cells of ϵ-subunit-immunized HLA-DR3 mice showed significantly higher proliferative responses than those of ϵ-subunit-immunized HLA-DQ8 mice, crude E. coli extract-immunized and CFA-immunized transgenic mice. Our results indicate that the human AChR ϵ-subunit is capable of inducing myasthenic muscle weakness. Diversity of the autoimmune responses displayed by mice expressing different HLA class II molecules suggests that the interplay between HLA class II alleles and AChR subunits might have a profound impact on the clinical course of MG. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  14. Recombinant Kunjin virus replicon vaccines induce protective T-cell immunity against human papillomavirus 16 E7-expressing tumour

    International Nuclear Information System (INIS)

    Herd, Karen A.; Harvey, Tracey; Khromykh, Alexander A.; Tindle, Robert W.

    2004-01-01

    The persistence of the E7 oncoprotein in transformed cells in human papillomavirus (HPV)-associated cervical cancer provides a tumour-specific antigen to which immunotherapeutic strategies may be directed. Self-replicating RNA (replicon) vaccine vectors derived from the flavivirus Kunjin (KUN) have recently been reported to induce T-cell immunity. Here, we report that inclusion of a CTL epitope of HPV16 E7 protein into a polyepitope encoded by a KUN vector induced E7-directed T-cell responses and protected mice against challenge with an E7-expressing epithelial tumour. We found replicon RNA packaged into virus-like particles to be more effective than naked replicon RNA or plasmid DNA constructed to allow replicon RNA transcription in vivo. Protective immunity was induced although the E7 CTL epitope was subdominant in the context of other CTL epitopes in the polyepitope. The results demonstrate the efficacy of the KUN replicon vector system for inducing protective immunity directed towards a virally encoded human tumour-specific antigen, and for inducing multi-epitopic CTL responses

  15. Immunogenicity is unrelated to protective immunity when induced by soluble and particulate antigens from Nocardia brasiliensis in BALB/c mice.

    Science.gov (United States)

    Salinas-Carmona, Mario C; Ramos, Alma I; Pérez-Rivera, Isabel

    2006-08-01

    Cell-mediated immunity plays a major role in protection against intracellular microbes. Nocardia brasiliensis is a facultative intracellular pathogen that causes chronic actinomycetoma. In this work, we injected BALB/c mice with soluble P24 and particulate antigens from N. brasiliensis. A higher antibody titer and lymphocyte proliferation was induced by the particulate antigen than by the soluble antigen. However, five months after antigen injection, antibody concentration and lymphocyte proliferation were similar. An increase in CD45R and CD4 T cells was unrelated to protective immunity. Active immunization with soluble or particulate antigens induced complete protection during the primary immune response. This protective response was IgM mediated. The higher immunogenicity was not related to protective immunity since the particulate antigen induced protection similar to the soluble antigen. Using particulate antigens for vaccination guarantees a stronger immune response, local and systemic side effects, but not necessarily protection.

  16. Lactose in human breast milk an inducer of innate immunity with implications for a role in intestinal homeostasis.

    Science.gov (United States)

    Cederlund, Andreas; Kai-Larsen, Ylva; Printz, Gordana; Yoshio, Hiroyuki; Alvelius, Gunvor; Lagercrantz, Hugo; Strömberg, Roger; Jörnvall, Hans; Gudmundsson, Gudmundur H; Agerberth, Birgitta

    2013-01-01

    Postpartum, infants have not yet established a fully functional adaptive immune system and are at risk of acquiring infections. Hence, newborns are dependent on the innate immune system with its antimicrobial peptides (AMPs) and proteins expressed at epithelial surfaces. Several factors in breast milk are known to confer immune protection, but which the decisive factors are and through which manner they work is unknown. Here, we isolated an AMP-inducing factor from human milk and identified it by electrospray mass spectrometry and NMR to be lactose. It induces the gene (CAMP) that encodes the only human cathelicidin LL-37 in colonic epithelial cells in a dose- and time-dependent manner. The induction was suppressed by two different p38 antagonists, indicating an effect via the p38-dependent pathway. Lactose also induced CAMP in the colonic epithelial cell line T84 and in THP-1 monocytes and macrophages. It further exhibited a synergistic effect with butyrate and phenylbutyrate on CAMP induction. Together, these results suggest an additional function of lactose in innate immunity by upregulating gastrointestinal AMPs that may lead to protection of the neonatal gut against pathogens and regulation of the microbiota of the infant.

  17. Lactose in human breast milk an inducer of innate immunity with implications for a role in intestinal homeostasis.

    Directory of Open Access Journals (Sweden)

    Andreas Cederlund

    Full Text Available Postpartum, infants have not yet established a fully functional adaptive immune system and are at risk of acquiring infections. Hence, newborns are dependent on the innate immune system with its antimicrobial peptides (AMPs and proteins expressed at epithelial surfaces. Several factors in breast milk are known to confer immune protection, but which the decisive factors are and through which manner they work is unknown. Here, we isolated an AMP-inducing factor from human milk and identified it by electrospray mass spectrometry and NMR to be lactose. It induces the gene (CAMP that encodes the only human cathelicidin LL-37 in colonic epithelial cells in a dose- and time-dependent manner. The induction was suppressed by two different p38 antagonists, indicating an effect via the p38-dependent pathway. Lactose also induced CAMP in the colonic epithelial cell line T84 and in THP-1 monocytes and macrophages. It further exhibited a synergistic effect with butyrate and phenylbutyrate on CAMP induction. Together, these results suggest an additional function of lactose in innate immunity by upregulating gastrointestinal AMPs that may lead to protection of the neonatal gut against pathogens and regulation of the microbiota of the infant.

  18. Toxoplasma gondii vs ionizing radiation: intestinal immunity induced in C57bl/6j mice by irradiated tachyzoites

    International Nuclear Information System (INIS)

    Galisteo Junior, Andres Jimenez.

    2004-01-01

    We study the oral route for the development of a vaccine for toxoplasmosis, using parasites irradiated with 60 Cobalt, as an alternative for vaccine development to this worldwide parasitic infection. We evaluated the development of immunity at serum or mucosal levels, and their efficiency in protect the mice against challenge with oral cysts of the Me-49 strain. C57Bl/6j isogenic mice were immunized by oral route with 107 255 Gy irradiated tachyzoites from RH strain, at several protocols using milk as anti-peptic adjuvant and alum hydroxide as antacid. The preparations of irradiated tachyzoites induced production of serum IgG and IgA in immunized mice, as determined by ELISA, with IgG2a as the dominant subclass, similar to chronic infection. Their use with adjuvant allowed the excretion of significant amounts of IgA in stools also IgG, despite a lesser extent. There are suggestion of tolerance induction at mucosal level, with lower antigen induced proliferation and lower in vitro antibody production by spleen and gut lymphocytes, with the latter doses, specially when milk was used as adjuvant. All oral preparations induced some quantitative protection against challenge, which was similar to the parenteral route only isolated alum hydroxide was used as adjuvant. All these data support the possibility of the development of an oral vaccine against toxoplasmosis, using irradiated tachyzoites, which would be possible tool in near future for use in field baits, for immunizing either domestic or wild felines. (author)

  19. Lactose in Human Breast Milk an Inducer of Innate Immunity with Implications for a Role in Intestinal Homeostasis

    Science.gov (United States)

    Printz, Gordana; Yoshio, Hiroyuki; Alvelius, Gunvor; Lagercrantz, Hugo; Strömberg, Roger; Jörnvall, Hans; Gudmundsson, Gudmundur H.; Agerberth, Birgitta

    2013-01-01

    Postpartum, infants have not yet established a fully functional adaptive immune system and are at risk of acquiring infections. Hence, newborns are dependent on the innate immune system with its antimicrobial peptides (AMPs) and proteins expressed at epithelial surfaces. Several factors in breast milk are known to confer immune protection, but which the decisive factors are and through which manner they work is unknown. Here, we isolated an AMP-inducing factor from human milk and identified it by electrospray mass spectrometry and NMR to be lactose. It induces the gene (CAMP) that encodes the only human cathelicidin LL-37 in colonic epithelial cells in a dose- and time-dependent manner. The induction was suppressed by two different p38 antagonists, indicating an effect via the p38-dependent pathway. Lactose also induced CAMP in the colonic epithelial cell line T84 and in THP-1 monocytes and macrophages. It further exhibited a synergistic effect with butyrate and phenylbutyrate on CAMP induction. Together, these results suggest an additional function of lactose in innate immunity by upregulating gastrointestinal AMPs that may lead to protection of the neonatal gut against pathogens and regulation of the microbiota of the infant. PMID:23326523

  20. Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice

    International Nuclear Information System (INIS)

    Paun, Alexandra; Kunwar, Amit; Haston, Christina K

    2015-01-01

    The lung response to radiation exposure can involve an immediate or early reaction to the radiation challenge, including cell death and an initial immune reaction, and can be followed by a tissue injury response, of pneumonitis or fibrosis, to this acute reaction. Herein, we aimed to determine whether markers of the initial immune response, measured within days of radiation exposure, are correlated with the lung tissue injury responses occurring weeks later. Inbred strains of mice known to be susceptible (KK/HIJ, C57BL/6J, 129S1/SvImJ) or resistant (C3H/HeJ, A/J, AKR/J) to radiation-induced pulmonary fibrosis and to vary in time to onset of respiratory distress post thoracic irradiation (from 10–23 weeks) were studied. Mice were untreated (controls) or received 18 Gy whole thorax irradiation and were euthanized at 6 h, 1d or 7 d after radiation treatment. Pulmonary CD4+ lymphocytes, bronchoalveolar cell profile & cytokine level, and serum cytokine levels were assayed. Thoracic irradiation and inbred strain background significantly affected the numbers of CD4+ cells in the lungs and the bronchoalveolar lavage cell differential of exposed mice. At the 7 day timepoint greater numbers of pulmonary Th1 and Th17 lymphocytes and reduced lavage interleukin17 and interferonγ levels were significant predictors of late stage fibrosis. Lavage levels of interleukin-10, measured at the 7 day timepoint, were inversely correlated with fibrosis score (R = −0.80, p = 0.05), while serum levels of interleukin-17 in control mice significantly correlated with post irradiation survival time (R = 0.81, p = 0.04). Lavage macrophage, lymphocyte or neutrophil counts were not significantly correlated with either of fibrosis score or time to respiratory distress in the six mouse strains. Specific cytokine and lymphocyte levels, but not strain dependent lavage cell profiles, were predictive of later radiation-induced lung injury in this panel of inbred strains. The online version of this

  1. Trivalent Human Papillomavirus (HPV) VLP vaccine covering HPV type 58 can elicit high level of humoral immunity but also induce immune interference among component types.

    Science.gov (United States)

    Zhang, Ting; Xu, Yufei; Qiao, Liang; Wang, Youchun; Wu, Xueling; Fan, Dongsheng; Peng, Qinglin; Xu, Xuemei

    2010-04-26

    Both Human Papillomavirus (HPV) type 16/18 bivalent vaccine and type 16/18/6/11 quadrivalent vaccine have been proved to be safe and effective, and licensed for public use. However, these two vaccines do not quite match the distribution of HPV types in China, Southeast Asia and Latin America, where HPV 58 is highly prevalent. Here we produced three types of virus-like particles (VLPs) in baculovirus expression system, formulated a trivalent vaccine containing HPV 16, 18, and 58 L1 VLPs and examined its in vitro neutralizing titers. This vaccine could induce high level and long-term humoral immunity against the component types. But immune interference was observed when comparing type specific neutralizing antibody levels induced by trivalent vaccine to those by corresponding monovalent vaccines. This kind of interference would become more obvious when formulating more types of VLPs into multivalent vaccines, but could be greatly overcome by decreasing the antigen dosage and adding a proper adjuvant. Copyright 2010 Elsevier Ltd. All rights reserved.

  2. Chronic social stress induces peripheral and central immune activation, blunted mesolimbic dopamine function, and reduced reward-directed behaviour in mice

    Directory of Open Access Journals (Sweden)

    Giorgio Bergamini

    2018-02-01

    Full Text Available Psychosocial stress is a major risk factor for depression, stress leads to peripheral and central immune activation, immune activation is associated with blunted dopamine (DA neural function, DA function underlies reward interest, and reduced reward interest is a core symptom of depression. These states might be inter-independent in a complex causal pathway. Whilst animal-model evidence exists for some specific steps in the pathway, there is currently no animal model in which it has been demonstrated that social stress leads to each of these immune, neural and behavioural states. Such a model would provide important existential evidence for the complex pathway and would enable the study of causality and mediating mechanisms at specific steps in the pathway. Therefore, in the present mouse study we investigated for effects of 15-day resident-intruder chronic social stress (CSS on each of these states. Relative to controls, CSS mice exhibited higher spleen levels of granulocytes, inflammatory monocytes and T helper 17 cells; plasma levels of inducible nitric oxide synthase; and liver expression of genes encoding kynurenine pathway enzymes. CSS led in the ventral tegmental area to higher levels of kynurenine and the microglia markers Iba1 and Cd11b and higher binding activity of DA D1 receptor; and in the nucleus accumbens (NAcc to higher kynurenine, lower DA turnover and lower c-fos expression. Pharmacological challenge with DA reuptake inhibitor identified attenuation of DA stimulatory effects on locomotor activity and NAcc c-fos expression in CSS mice. In behavioural tests of operant responding for sucrose reward validated as sensitive assays for NAcc DA function, CSS mice exhibited less reward-directed behaviour. Therefore, this mouse study demonstrates that a chronic social stressor leads to changes in each of the immune, neural and behavioural states proposed to mediate between stress and disruption of DA-dependent reward processing. The

  3. Periodontitis induced by Porphyromonas gingivalis drives periodontal microbiota dysbiosis and insulin resistance via an impaired adaptive immune response.

    Science.gov (United States)

    Blasco-Baque, Vincent; Garidou, Lucile; Pomié, Céline; Escoula, Quentin; Loubieres, Pascale; Le Gall-David, Sandrine; Lemaitre, Mathieu; Nicolas, Simon; Klopp, Pascale; Waget, Aurélie; Azalbert, Vincent; Colom, André; Bonnaure-Mallet, Martine; Kemoun, Philippe; Serino, Matteo; Burcelin, Rémy

    2017-05-01

    To identify a causal mechanism responsible for the enhancement of insulin resistance and hyperglycaemia following periodontitis in mice fed a fat-enriched diet. We set-up a unique animal model of periodontitis in C57Bl/6 female mice by infecting the periodontal tissue with specific and alive pathogens like Porphyromonas gingivalis ( Pg ), Fusobacterium nucleatum and Prevotella intermedia . The mice were then fed with a diabetogenic/non-obesogenic fat-enriched diet for up to 3 months. Alveolar bone loss, periodontal microbiota dysbiosis and features of glucose metabolism were quantified. Eventually, adoptive transfer of cervical (regional) and systemic immune cells was performed to demonstrate the causal role of the cervical immune system. Periodontitis induced a periodontal microbiota dysbiosis without mainly affecting gut microbiota. The disease concomitantly impacted on the regional and systemic immune response impairing glucose metabolism. The transfer of cervical lymph-node cells from infected mice to naive recipients guarded against periodontitis-aggravated metabolic disease. A treatment with inactivated Pg prior to the periodontal infection induced specific antibodies against Pg and protected the mouse from periodontitis-induced dysmetabolism. Finally, a 1-month subcutaneous chronic infusion of low rates of lipopolysaccharides from Pg mimicked the impact of periodontitis on immune and metabolic parameters. We identified that insulin resistance in the high-fat fed mouse is enhanced by pathogen-induced periodontitis. This is caused by an adaptive immune response specifically directed against pathogens and associated with a periodontal dysbiosis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  4. A downy mildew effector attenuates salicylic acid-triggered immunity in Arabidopsis by interacting with the host mediator complex.

    Directory of Open Access Journals (Sweden)

    Marie-Cécile Caillaud

    2013-12-01

    Full Text Available Plants are continually exposed to pathogen attack but usually remain healthy because they can activate defences upon perception of microbes. However, pathogens have evolved to overcome plant immunity by delivering effectors into the plant cell to attenuate defence, resulting in disease. Recent studies suggest that some effectors may manipulate host transcription, but the specific mechanisms by which such effectors promote susceptibility remain unclear. We study the oomycete downy mildew pathogen of Arabidopsis, Hyaloperonospora arabidopsidis (Hpa, and show here that the nuclear-localized effector HaRxL44 interacts with Mediator subunit 19a (MED19a, resulting in the degradation of MED19a in a proteasome-dependent manner. The Mediator complex of ∼25 proteins is broadly conserved in eukaryotes and mediates the interaction between transcriptional regulators and RNA polymerase II. We found MED19a to be a positive regulator of immunity against Hpa. Expression profiling experiments reveal transcriptional changes resembling jasmonic acid/ethylene (JA/ET signalling in the presence of HaRxL44, and also 3 d after infection with Hpa. Elevated JA/ET signalling is associated with a decrease in salicylic acid (SA-triggered immunity (SATI in Arabidopsis plants expressing HaRxL44 and in med19a loss-of-function mutants, whereas SATI is elevated in plants overexpressing MED19a. Using a PR1::GUS reporter, we discovered that Hpa suppresses PR1 expression specifically in cells containing haustoria, into which RxLR effectors are delivered, but not in nonhaustoriated adjacent cells, which show high PR1::GUS expression levels. Thus, HaRxL44 interferes with Mediator function by degrading MED19, shifting the balance of defence transcription from SA-responsive defence to JA/ET-signalling, and enhancing susceptibility to biotrophs by attenuating SA-dependent gene expression.

  5. Inhalable Andrographolide-β-cyclodextrin Inclusion Complexes for Treatment of Staphylococcus aureus Pneumonia by Regulating Immune Responses.

    Science.gov (United States)

    Zhang, Tongtong; Zhu, Lifei; Li, Miao; Hu, Yuzhen; Zhang, Erfeng; Jiang, Qingcheng; Han, Guang; Jin, Yiguang

    2017-05-01

    Bacterial pneumonia is a serious disease with high mortality if no appropriate and immediate therapy is available. Andrographolide (AG) is an anti-inflammatory agent extracted from a traditional Chinese herb andrographis paniculata. Oral AG tablets and pills are clinically applied for treatment of upper respiratory tract infections. However, the low solubility and bioavailability of AG lead to high doses and long-term therapy. Here we developed an andrographolide-β-cyclodextrin inclusion complex (AG-β-CD) for inhalation therapy of Staphylococcus aureus pneumonia. AG-β-CD was identified with X-ray diffraction and FT-IR. Surprisingly, both AG-β-CD and AG showed little in vitro anti-S. aureus activity. However, pulmonary delivery of AG, AG-β-CD, or penicillin had significant anti-S. aureus pneumonia effects. Leukocytes, neutrophils, white blood cells, total proteins, TNF-α, IL-6, NF-κB p65 expression, and bacterial colonies in the bronchoalveolar lavage fluids were detected. Pulmonary delivery of AG and AG-β-CD led to bacterial inhibition and inflammation alleviation by regulating immune responses, while penicillin only killed bacteria without significant immune regulation. Moreover, the antipneumonia activity of AG-β-CD was much higher than that of AG, probably resulting from locally accelerated AG dissolution due to β-CD inclusion. The aerodynamic diameter of AG-β-CD powders was 2.03 μm, suitable for pulmonary delivery. Inhalable AG-β-CD is a promising antibacterial and anti-inflammatory medicine for the treatment of S. aureus pneumonia by regulating immune responses, and the effect is enhanced by β-CD inclusion. AG and its formulations might be potent weapons against the resistant bacterial pneumonia due to their specific mechanism in the future.

  6. Bombyx mori and Aedes aegypti form multi-functional immune complexes that integrate pattern recognition, melanization, coagulants, and hemocyte recruitment.

    Science.gov (United States)

    Phillips, Dennis R; Clark, Kevin D

    2017-01-01

    The innate immune system of insects responds to wounding and pathogens by mobilizing multiple pathways that provide both systemic and localized protection. Key localized responses in hemolymph include melanization, coagulation, and hemocyte encapsulation, which synergistically seal wounds and envelop and destroy pathogens. To be effective, these pathways require a targeted deposition of their components to provide protection without compromising the host. Extensive research has identified a large number of the effectors that comprise these responses, but questions remain regarding their post-translational processing, function, and targeting. Here, we used mass spectrometry to demonstrate the integration of pathogen recognition proteins, coagulants, and melanization components into stable, high-mass, multi-functional Immune Complexes (ICs) in Bombyx mori and Aedes aegypti. Essential proteins common to both include phenoloxidases, apolipophorins, serine protease homologs, and a serine protease that promotes hemocyte recruitment through cytokine activation. Pattern recognition proteins included C-type Lectins in B. mori, while A. aegypti contained a protein homologous to Plasmodium-resistant LRIM1 from Anopheles gambiae. We also found that the B. mori IC is stabilized by extensive transglutaminase-catalyzed cross-linking of multiple components. The melanization inhibitor Egf1.0, from the parasitoid wasp Microplitis demolitor, blocked inclusion of specific components into the IC and also inhibited transglutaminase activity. Our results show how coagulants, melanization components, and hemocytes can be recruited to a wound surface or pathogen, provide insight into the mechanism by which a parasitoid evades this immune response, and suggest that insects as diverse as Lepidoptera and Diptera utilize similar defensive mechanisms.

  7. Emerging complexities of APOBEC3G action on immunity and viral fitness during HIV infection and treatment

    Directory of Open Access Journals (Sweden)

    Monajemi Mahdis

    2012-04-01

    Full Text Available Abstract The enzyme APOBEC3G (A3G mutates the human immunodeficiency virus (HIV genome by converting deoxycytidine (dC to deoxyuridine (dU on minus strand viral DNA during reverse transcription. A3G restricts viral propagation by degrading or incapacitating the coding ability of the HIV genome. Thus, this enzyme has been perceived as an innate immune barrier to viral replication whilst adaptive immunity responses escalate to effective levels. The discovery of A3G less than a decade ago led to the promise of new anti-viral therapies based on manipulation of its cellular expression and/or activity. The rationale for therapeutic approaches has been solidified by demonstration of the effectiveness of A3G in diminishing viral replication in cell culture systems of HIV infection, reports of its mutational footprint in virions from patients, and recognition of its unusually robust enzymatic potential in biochemical studies in vitro. Despite its effectiveness in various experimental systems, numerous recent studies have shown that the ability of A3G to combat HIV in the physiological setting is severely limited. In fact, it has become apparent that its mutational activity may actually enhance viral fitness by accelerating HIV evolution towards the evasion of both anti-viral drugs and the immune system. This body of work suggests that the role of A3G in HIV infection is more complex than heretofore appreciated and supports the hypothesis that HIV has evolved to exploit the action of this host factor. Here we present an overview of recent data that bring to light historical overestimation of A3G’s standing as a strictly anti-viral agent. We discuss the limitations of experimental systems used to assess its activities as well as caveats in data interpretation.

  8. Improvement effect of gamma-irradiated complex leaf extract of date plum, persimmon and mulberry on UVB-induced skin damage

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Ji Won; Cho, Byoung Ok; Che, Denis Nchang; Shin, Jae Young; Fang, Chong Zhou; Jang, Seon Il [Jeonju University, Jeonju (Korea, Republic of)

    2016-11-15

    This study was conducted to evaluate the improvement effect of gamma-irradiated complex leaf extract of Date Plum, Persimmon and Mulberry (γ-DPME) on UVB induced skin damage. The samples were gamma irradiated at doses of 10 kGy. γ-DPME treatment tended to decrease UVB-induced immune cell infiltration and erthyderma index than the groups treated with non-gamma-irradiated DPME (n-DPME) and L-ascobic acid (AA). In addition, γ-DPME treatment significantly decreased skin thickness, melanin index and mast cell infiltration in UVB-irradiated skin. Moreover, γ-DPME treatment significantly decreased the compound 48/80-induced scratching behavior and immune cell infiltration than n-DPME group. These results show that gamma irradiation can be used to increase the physiological activities of DPME.

  9. C-reactive protein, Rheumatoid factor and circulatory immune complex as markers for monitoring treatment of infective endocarditis

    International Nuclear Information System (INIS)

    Alavi, S.M.; Ahmadi, F.; Nashibi, R.

    2010-01-01

    Objectives: To evaluate the diagnostic usefulness of serum C-reactive protein (CRP), rheumatoid factor (RF) and circulatory immune complex (CIC) determinations in monitoring the outcome of infective endocarditis (IE). Methodology: In this prospective analytic descriptive study CRP, RF and CIC were measured on admission and 4 weeks after initiation of standard antibiotic regimen in 30 hospitalized patients with IE in an educational hospital between 2006 and 2007 in Ahvaz a city south west Iran . Duke criteria were used for diagnosis of IE. CRP and RF were examined using quantitative neflometry (Binding site kit, UK) and CIC was detected by semi quantitative immune diffusion (Baharafshan SIRD kit, Iran). Data were evaluated using statistical analyses in SPSS (version 12, USA) software for windows. Results: The fall in serum C-reactive protein or RF was significant (P= 0.05). Only two of the 30 patients, who had elevated CRP, RF and CIC week four failed to response and one needed cardiac surgery. Conclusions: The C-reactive protein proved to be a good tool for monitoring the treatment of IE. Also RF proved useful in the assessment of patients with IE, but the value of CIC was negligible. (author)

  10. Noise-immune complex correlation for vasculature imaging based on standard and Jones-matrix optical coherence tomography

    Science.gov (United States)

    Makita, Shuichi; Kurokawa, Kazuhiro; Hong, Young-Joo; Li, En; Miura, Masahiro; Yasuno, Yoshiaki

    2016-03-01

    A new optical coherence angiography (OCA) method, called correlation mapping OCA (cmOCA), is presented by using the SNR-corrected complex correlation. An SNR-correction theory for the complex correlation calculation is presented. The method also integrates a motion-artifact-removal method for the sample motion induced decorrelation artifact. The theory is further extended to compute more reliable correlation by using multi- channel OCT systems, such as Jones-matrix OCT. The high contrast vasculature imaging of in vivo human posterior eye has been obtained. Composite imaging of cmOCA and degree of polarization uniformity indicates abnormalities of vasculature and pigmented tissues simultaneously.

  11. The genome of obligately intracellular Ehrlichia canis revealsthemes of complex membrane structure and immune evasion strategies

    Energy Technology Data Exchange (ETDEWEB)

    Mavromatis, K.; Kuyler Doyle, C.; Lykidis, A.; Ivanova, N.; Francino, P.; Chain, P.; Shin, M.; Malfatti, S.; Larimer, F.; Copeland,A.; Detter, J.C.; Land, M.; Richardson, P.M.; Yu, X.J.; Walker, D.H.; McBride, J.W.; Kyrpides, N.C.

    2005-09-01

    Ehrlichia canis, a small obligately intracellular, tick-transmitted, gram-negative, a-proteobacterium is the primary etiologic agent of globally distributed canine monocytic ehrlichiosis. Complete genome sequencing revealed that the E. canis genome consists of a single circular chromosome of 1,315,030 bp predicted to encode 925 proteins, 40 stable RNA species, and 17 putative pseudogenes, and a substantial proportion of non-coding sequence (27 percent). Interesting genome features include a large set of proteins with transmembrane helices and/or signal sequences, and a unique serine-threonine bias associated with the potential for O-glycosylation that was prominent in proteins associated with pathogen-host interactions. Furthermore, two paralogous protein families associated with immune evasion were identified, one of which contains poly G:C tracts, suggesting that they may play a role in phase variation and facilitation of persistent infections. Proteins associated with pathogen-host interactions were identified including a small group of proteins (12) with tandem repeats and another with eukaryotic-like ankyrin domains (7).

  12. Sustained and transient oscillations and chaos induced by delayed antiviral immune response in an immunosuppressive infection model.

    Science.gov (United States)

    Shu, Hongying; Wang, Lin; Watmough, James

    2014-01-01

    Sustained and transient oscillations are frequently observed in clinical data for immune responses in viral infections such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus. To account for these oscillations, we incorporate the time lag needed for the expansion of immune cells into an immunosuppressive infection model. It is shown that the delayed antiviral immune response can induce sustained periodic oscillations, transient oscillations and even sustained aperiodic oscillations (chaos). Both local and global Hopf bifurcation theorems are applied to show the existence of periodic solutions, which are illustrated by bifurcation diagrams and numerical simulations. Two types of bistability are shown to be possible: (i) a stable equilibrium can coexist with another stable equilibrium, and (ii) a stable equilibrium can coexist with a stable periodic solution.

  13. Dynamic expression of leukocyte innate immune genes in whole blood from horses with lipopolysaccharide-induced acute systemic inflammation

    DEFF Research Database (Denmark)

    Vinther, Anne Mette L.; Skovgaard, Kerstin; Heegaard, Peter M. H.

    2015-01-01

    Background: In horses, insights into the innate immune processes in acute systemic inflammation are limited even though these processes may be highly important for future diagnostic and therapeutic advances in high-mortality disease conditions as the systemic inflammatory response syndrome (SIRS......) and sepsis. Therefore, the aim of this study was to investigate the expression of 31 selected blood leukocyte immune genes in an equine model of acute systemic inflammation to identify significantly regulated genes and to describe their expression dynamics during a 24-h experimental period. Systemic...... expressions in blood leukocytes during equine acute LPS-induced systemic inflammation thoroughly characterized a highly regulated and dynamic innate immune response. These results provide new insights into the molecular mechanisms of equine systemic inflammation....

  14. Inducible nitric-oxide synthase plays a minimal role in lymphocytic choriomeningitis virus-induced, T cell-mediated protective immunity and immunopathology

    DEFF Research Database (Denmark)

    Bartholdy, C; Nansen, A; Christensen, Jeanette Erbo

    1999-01-01

    -mediated immune response was found to be unaltered in iNOS-deficient mice compared with wild-type C57BL/6 mice, and LCMV- induced general immunosuppression was equally pronounced in both strains. In vivo analysis revealed identical kinetics of virus clearance, as well as unaltered clinical severity of systemic......By using mice with a targetted disruption in the gene encoding inducible nitric-oxide synthase (iNOS), we have studied the role of nitric oxide (NO) in lymphocytic choriomeningitis virus (LCMV)-induced, T cell-mediated protective immunity and immunopathology. The afferent phase of the T cell...... LCMV infection in both strains. Concerning the outcome of intracerebral infection, no significant differences were found between iNOS-deficient and wild-type mice in the number or composition of mononuclear cells found in the cerebrospinal fluid on day 6 post-infection. Likewise, NO did not influence...

  15. Public speaking stress-induced neuroendocrine responses and circulating immune cell redistribution in irritable bowel syndrome.

    Science.gov (United States)

    Elsenbruch, Sigrid; Lucas, Ayscha; Holtmann, Gerald; Haag, Sebastian; Gerken, Guido; Riemenschneider, Natalie; Langhorst, Jost; Kavelaars, Annemieke; Heijnen, Cobi J; Schedlowski, Manfred

    2006-10-01

    Augmented neuroendocrine stress responses and altered immune functions may play a role in the manifestation of functional gastrointestinal (GI) disorders. We tested the hypothesis that IBS patients would demonstrate enhanced psychological and endocrine responses, as well as altered stress-induced redistribution of circulating leukocytes and lymphocytes, in response to an acute psychosocial stressor when compared with healthy controls. Responses to public speaking stress were analyzed in N = 17 IBS patients without concurrent psychiatric conditions and N = 12 healthy controls. At baseline, immediately following public speaking, and after a recovery period, state anxiety, acute GI symptoms, cardiovascular responses, serum cortisol and plasma adrenocorticotropic hormone (ACTH) were measured, and numbers of circulating leukocytes and lymphocyte subpopulations were analyzed by flow cytometry. Public speaking led to significant cardiovascular activation, a significant increase in ACTH, and a redistribution of circulating leukocytes and lymphocyte subpopulations, including significant increases in natural killer cells and cytotoxic/suppressor T cells. IBS patients demonstrated significantly greater state anxiety both at baseline and following public speaking. However, cardiovascular and endocrine responses, as well as the redistribution of circulating leukocytes and lymphocyte subpopulations after public speaking stress, did not differ for IBS patients compared with controls. In IBS patients without psychiatric comorbidity, the endocrine response as well as the circulation pattern of leukocyte subpopulations to acute psychosocial stress do not differ from healthy controls in spite of enhanced emotional responses. Future studies should discern the role of psychopathology in psychological and biological stress responses in IBS.

  16. A recombinant canine distemper virus expressing a modified rabies virus glycoprotein induces immune responses in mice.

    Science.gov (United States)

    Li, Zhili; Wang, Jigui; Yuan, Daoli; Wang, Shuang; Sun, Jiazeng; Yi, Bao; Hou, Qiang; Mao, Yaping; Liu, Weiquan

    2015-06-01

    Canine distemper virus (CDV) and rabies virus (RV) are two important pathogens of the dog. CDV, a member of the morbillivirus genus, has shown promise as an expression vector. The glycoprotein from RV is a main contributor to protective immunity and capable of eliciting the production of virus-neutralizing antibodies. In this study, we recovered an attenuated strain of canine distemper virus and constructed a recombinant virus, rCDV-RV-G, expressing a modified (R333Q) rabies virus glycoprotein (RV-G) of RV Flury strain LEP. RV-G expression by the recombinant viruses was confirmed. Furthermore, G was proved to be incorporated into the surface of CDV particles. While replication of the recombinant virus was slightly reduced compared with the parental CDV, it stably expressed the RV-G over ten serial passages. Inoculation of mice induced specific neutralizing antibodies against both RV-G and CDV. Therefore, the rCDV-RV-G has the potential as a vaccine that may be used to control rabies virus infection in dogs and other animals.

  17. The habitat disruption induces immune-suppression and oxidative stress in honey bees

    Science.gov (United States)

    Morimoto, Tomomi; Kojima, Yuriko; Toki, Taku; Komeda, Yayoi; Yoshiyama, Mikio; Kimura, Kiyoshi; Nirasawa, Keijiro; Kadowaki, Tatsuhiko

    2011-01-01

    The honey bee is a major insect used for pollination of many commercial crops worldwide. Although the use of honey bees for pollination can disrupt the habitat, the effects on their physiology have never been determined. Recently, honey bee colonies have often collapsed when introduced in greenhouses for pollination in Japan. Thus, suppressing colony collapses and maintaining the number of worker bees in the colonies is essential for successful long-term pollination in greenhouses and recycling of honey bee colonies. To understand the physiological states of honey bees used for long-term pollination in greenhouses, we characterized their gene expression profiles by microarray. We found that the greenhouse environment changes the gene expression profiles and induces immune-suppression and oxidative stress in honey bees. In fact, the increase of the number of Nosema microsporidia and protein carbonyl content was observed in honey bees during pollination in greenhouses. Thus, honey bee colonies are likely to collapse during pollination in greenhouses when heavily infested with pathogens. Degradation of honey bee habitat by changing the outside environment of the colony, during pollination services for example, imposes negative impacts on honey bees. Thus, worldwide use of honey bees for crop pollination in general could be one of reasons for the decline of managed honey bee colonies. PMID:22393496

  18. Effect of immunomodifier on radiation-induced antitumor immunity following local irradiation to tumor, 2

    International Nuclear Information System (INIS)

    Mukae, Shiro; Norimura, Toshiyuki; Tsuchiya, Takehiko

    1988-01-01

    This study was carried out to clarify whether or not the antitumor cell-mediated immunity of host is more effectively induced by the combined use of mouse interferon-α/β (MuIFN-α/β) with local irradiation than by simple local irradiation to tumor. C3H/He female mice, MM46 tumor cells and mouse interferon-α/β (MuIFN-α/β) were used in the experiment. Antitumor activity in mice was evaluated by the inhibition of tumor growth and mean survival days after treatment. Spleen cell killing activity to MM46 tumor cells was measured to evaluate the antitumor activity in vitro. In the case of single use of MuIFN-α/β, tumor growth was more rapid than in the non-treated group (control) in vivo. The mean survival days were also reduced. There was no siginificant difference in tumor growth inhibition between combined therapy using X-irradiation and MuIFN-α/β, and single therapy by local irradiation. However, in the case of administration of MuIFN-α/β after irradiation, the mean survival days was significantly increased compared with the group receiving X-ray irradiation only. (author)

  19. Effects of Experimental Sarcocystis neurona-Induced Infection on Immunity in an Equine Model

    Directory of Open Access Journals (Sweden)

    S. Rochelle Lewis

    2014-01-01

    Full Text Available Sarcocystis neurona is the most common cause of Equine Protozoal Myeloencephalitis (EPM, affecting 0.5–1% horses in the United States during their lifetimes. The objective of this study was to evaluate the equine immune responses in an experimentally induced Sarcocystis neurona infection model. Neurologic parameters were recorded prior to and throughout the 70-day study by blinded investigators. Recombinant SnSAG1 ELISA for serum and CSF were used to confirm and track disease progression. All experimentally infected horses displayed neurologic signs after infection. Neutrophils, monocytes, and lymphocytes from infected horses displayed significantly delayed apoptosis at some time points. Cell proliferation was significantly increased in S. neurona-infected horses when stimulated nonspecifically with PMA/I but significantly decreased when stimulated with S. neurona compared to controls. Collectively, our results suggest that horses experimentally infected with S. neurona manifest impaired antigen specific response to S. neurona, which could be a function of altered antigen presentation, lack of antigen recognition, or both.

  20. Effects of Experimental Sarcocystis neurona-Induced Infection on Immunity in an Equine Model.

    Science.gov (United States)

    Lewis, S Rochelle; Ellison, Siobhan P; Dascanio, John J; Lindsay, David S; Gogal, Robert M; Werre, Stephen R; Surendran, Naveen; Breen, Meghan E; Heid, Bettina M; Andrews, Frank M; Buechner-Maxwell, Virginia A; Witonsky, Sharon G

    2014-01-01

    Sarcocystis neurona is the most common cause of Equine Protozoal Myeloencephalitis (EPM), affecting 0.5-1% horses in the United States during their lifetimes. The objective of this study was to evaluate the equine immune responses in an experimentally induced Sarcocystis neurona infection model. Neurologic parameters were recorded prior to and throughout the 70-day study by blinded investigators. Recombinant SnSAG1 ELISA for serum and CSF were used to confirm and track disease progression. All experimentally infected horses displayed neurologic signs after infection. Neutrophils, monocytes, and lymphocytes from infected horses displayed significantly delayed apoptosis at some time points. Cell proliferation was significantly increased in S. neurona-infected horses when stimulated nonspecifically with PMA/I but significantly decreased when stimulated with S. neurona compared to controls. Collectively, our results suggest that horses experimentally infected with S. neurona manifest impaired antigen specific response to S. neurona, which could be a function of altered antigen presentation, lack of antigen recognition, or both.

  1. Lymphoid tissue inducer cells: pivotal cells in the evolution of CD4 immunity and tolerance?

    Directory of Open Access Journals (Sweden)

    Peter John Lane

    2012-02-01

    Full Text Available Phylogeny suggests that the evolution of placentation in mammals was accompanied by substantial changes in the mammalian immune system: in particular lymph nodes and CD4 high affinity memory antibody responses co-evolved during the same period. Lymphoid tissue inducer cells (LTi are members of an emerging family of innate lymphoid cells (ILCs that are crucial for lymph node development, but our studies have indicated that they also play a pivotal role in the long-term maintenance of memory CD4 T cells in adult mammals through their expression of the tumor necrosis family members, OX40- and CD30-ligands. Additionally, our studies have shown that these two molecules are also key operators in CD4 effector function, as their absence obviates the need for the FoxP3-dependent regulatory T cells (Tregs that prevent CD4 driven autoimmune responses. In this perspective article, we summarize findings from our group over the last 10 years, and focus specifically on the role of LTi in thymus. We suggest that like memory CD4 T cells, LTi also play a role in the selection and maintenance of the Tregs that under normal circumstances are absolutely required to regulate CD4 effector cells.

  2. Diet-Induced Dysbiosis of the Intestinal Microbiota and the Effects on Immunity and Disease

    Directory of Open Access Journals (Sweden)

    Deanna L. Gibson

    2012-08-01

    Full Text Available The gastrointestinal (GI microbiota is the collection of microbes which reside in the GI tract and represents the largest source of non-self antigens in the human body. The GI tract functions as a major immunological organ as it must maintain tolerance to commensal and dietary antigens while remaining responsive to pathogenic stimuli. If this balance is disrupted, inappropriate inflammatory processes can result, leading to host cell damage and/or autoimmunity. Evidence suggests that the composition of the intestinal microbiota can influence susceptibility to chronic disease of the intestinal tract including ulcerative colitis, Crohn’s disease, celiac disease and irritable bowel syndrome, as well as more systemic diseases such as obesity, type 1 diabetes and type 2 diabetes. Interestingly, a considerable shift in diet has coincided with increased incidence of many of these inflammatory diseases. It was originally believed that the composition of the intestinal microbiota was relatively stable from early childhood; however, recent evidence suggests that diet can cause dysbiosis, an alteration in the composition of the microbiota, which could lead to aberrant immune responses. The role of the microbiota and the potential for diet-induced dysbiosis in inflammatory conditions of the GI tract and systemic diseases will be discussed.

  3. Applying Statistical and Complex Network Methods to Explore the Key Signaling Molecules of Acupuncture Regulating Neuroendocrine-Immune Network

    Directory of Open Access Journals (Sweden)

    Kuo Zhang

    2018-01-01

    Full Text Available The mechanisms of acupuncture are still unclear. In order to reveal the regulatory effect of manual acupuncture (MA on the neuroendocrine-immune (NEI network and identify the key signaling molecules during MA modulating NEI network, we used a rat complete Freund’s adjuvant (CFA model to observe the analgesic and anti-inflammatory effect of MA, and, what is more, we used statistical and complex network methods to analyze the data about the expression of 55 common signaling molecules of NEI network in ST36 (Zusanli acupoint, and serum and hind foot pad tissue. The results indicate that MA had significant analgesic, anti-inflammatory effects on CFA rats; the key signaling molecules may play a key role during MA regulating NEI network, but further research is needed.

  4. Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System.

    Science.gov (United States)

    Santaguida, Stefano; Richardson, Amelia; Iyer, Divya Ramalingam; M'Saad, Ons; Zasadil, Lauren; Knouse, Kristin A; Wong, Yao Liang; Rhind, Nicholas; Desai, Arshad; Amon, Angelika

    2017-06-19

    Aneuploidy, a state of karyotype imbalance, is a hallmark of cancer. Changes in chromosome copy number have been proposed to drive disease by modulating the dosage of cancer driver genes and by promoting cancer genome evolution. Given the potential of cells with abnormal karyotypes to become cancerous, do pathways that limit the prevalence of such cells exist? By investigating the immediate consequences of aneuploidy on cell physiology, we identified mechanisms that eliminate aneuploid cells. We find that chromosome mis-segregation leads to further genomic instability that ultimately causes cell-cycle arrest. We further show that cells with complex karyotypes exhibit features of senescence and produce pro-inflammatory signals that promote their clearance by the immune system. We propose that cells with abnormal karyotypes generate a signal for their own elimination that may serve as a means for cancer cell immunosurveillance. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Genotoxicity induced by Taenia solium and its reduction by immunization with calreticulin in a hamster model of taeniosis.

    Science.gov (United States)

    Salazar, Ana María; Mendlovic, Fela; Cruz-Rivera, Mayra; Chávez-Talavera, Oscar; Sordo, Monserrat; Avila, Guillermina; Flisser, Ana; Ostrosky-Wegman, Patricia

    2013-06-01

    Genotoxicity induced by neurocysticercosis has been demonstrated in vitro and in vivo in humans. The adult stage of Taenia solium lodges in the small intestine and is the main risk factor to acquire neurocysticercosis, nevertheless its carcinogenic potential has not been evaluated. In this study, we determined the genotoxic effect of T. solium infection in the hamster model of taeniosis. In addition, we assessed the effect of oral immunization with recombinant T. solium calreticulin (rTsCRT) plus cholera toxin as adjuvant on micronuclei induction, as this protein has been shown to induce 33-44% protection in the hamster model of taeniosis. Blood samples were collected from the orbital venous plexus of noninfected and infected hamsters at different days postinfection, as well as from orally immunized animals, to evaluate the frequency of micronucleated reticulocytes as a measure of genotoxicity induced by parasite exposure and rTsCRT vaccination. Our results indicate that infection with T. solium caused time-dependent DNA damage in vivo and that rTsCRT immunization reduced the genotoxic damage induced by the presence of the tapeworms. Copyright © 2013 Wiley Periodicals, Inc.

  6. Serratia marcescens Induces Apoptotic Cell Death in Host Immune Cells via a Lipopolysaccharide- and Flagella-dependent Mechanism*

    Science.gov (United States)

    Ishii, Kenichi; Adachi, Tatsuo; Imamura, Katsutoshi; Takano, Shinya; Usui, Kimihito; Suzuki, Kazushi; Hamamoto, Hiroshi; Watanabe, Takeshi; Sekimizu, Kazuhisa

    2012-01-01

    Injection of Serratia marcescens into the blood (hemolymph) of the silkworm, Bombyx mori, induced the activation of c-Jun NH2-terminal kinase (JNK), followed by caspase activation and apoptosis of blood cells (hemocytes). This process impaired the innate immune response in which pathogen cell wall components, such as glucan, stimulate hemocytes, leading to the activation of insect cytokine paralytic peptide. S. marcescens induced apoptotic cell death of silkworm hemocytes and mouse peritoneal macrophages in vitro. We searched for S. marcescens transposon mutants with attenuated ability to induce apoptosis of silkworm hemocytes. Among the genes identified, disruption mutants of wecA (a gene involved in lipopolysaccharide O-antigen synthesis), and flhD and fliR (essential genes in flagella synthesis) showed reduced motility and impaired induction of mouse macrophage cell death. These findings suggest that S. marcescens induces apoptosis of host immune cells via lipopolysaccharide- and flagella-dependent motility, leading to the suppression of host innate immunity. PMID:22859304

  7. Pathogen exploitation of an abscisic acid- and jasmonate-inducible MAPK phosphatase and its interception by Arabidopsis immunity.

    Science.gov (United States)

    Mine, Akira; Berens, Matthias L; Nobori, Tatsuya; Anver, Shajahan; Fukumoto, Kaori; Winkelmüller, Thomas M; Takeda, Atsushi; Becker, Dieter; Tsuda, Kenichi

    2017-07-11

    Phytopathogens promote virulence by, for example, exploiting signaling pathways mediated by phytohormones such as abscisic acid (ABA) and jasmonate (JA). Some plants can counteract pathogen virulence by invoking a potent form of immunity called effector-triggered immunity (ETI). Here, we report that ABA and JA mediate inactivation of the immune-associated MAP kinases (MAPKs), MPK3 and MPK6, in Arabidopsis thaliana ABA induced expression of genes encoding the protein phosphatases 2C (PP2Cs), HAI1 , HAI2 , and HAI3 through ABF/AREB transcription factors. These three HAI PP2Cs interacted with MPK3 and MPK6 and were required for ABA-mediated MPK3/MPK6 inactivation and immune suppression. The bacterial pathogen Pseudomonas syringae pv. tomato ( Pto ) DC3000 activates ABA signaling and produces a JA-mimicking phytotoxin, coronatine (COR), that promotes virulence. We found that Pto DC3000 induces HAI1 through COR-mediated activation of MYC2, a master transcription factor in JA signaling. HAI1 dephosphorylated MPK3 and MPK6 in vitro and was necessary for COR-mediated suppression of MPK3/MPK6 activation and immunity. Intriguingly, upon ETI activation, A. thaliana plants overcame the HAI1-dependent virulence of COR by blocking JA signaling. Finally, we showed conservation of induction of HAI PP2Cs by ABA and JA in other Brassicaceae species. Taken together, these results suggest that ABA and JA signaling pathways, which are hijacked by the bacterial pathogen, converge on the HAI PP2Cs that suppress activation of the immune-associated MAPKs. Also, our data unveil interception of JA-signaling activation as a host counterstrategy against the bacterial suppression of MAPKs during ETI.

  8. Strains of bacterial species induce a greatly varied acute adaptive immune response: The contribution of the accessory genome.

    Directory of Open Access Journals (Sweden)

    Uri Sela

    2018-01-01

    Full Text Available A fundamental question in human susceptibility to bacterial infections is to what extent variability is a function of differences in the pathogen species or in individual humans. To focus on the pathogen species, we compared in the same individual the human adaptive T and B cell immune response to multiple strains of two major human pathogens, Staphylococcus aureus and Streptococcus pyogenes. We found wide variability in the acute adaptive immune response induced by various strains of a species, with a unique combination of activation within the two arms of the adaptive response. Further, this was also accompanied by a dramatic difference in the intensity of the specific protective T helper (Th response. Importantly, the same immune response differences induced by the individual strains were maintained across multiple healthy human donors. A comparison of isogenic phage KO strains, demonstrated that of the pangenome, prophages were the major contributor to inter-strain immune heterogeneity, as the T cell response to the remaining "core genome" was noticeably blunted. Therefore, these findings extend and modify the notion of an adaptive response to a pathogenic bacterium, by implying that the adaptive immune response signature of a bacterial species should be defined either per strain or alternatively to the species' 'core genome', common to all of its strains. Further, our results demonstrate that the acquired immune response variation is as wide among different strains within a single pathogenic species as it is among different humans, and therefore may explain in part the clinical heterogeneity observed in patients infected with the same species.

  9. Necrotizing herpetic retinopathies. A spectrum of herpes virus-induced diseases determined by the immune state of the host.

    Science.gov (United States)

    Guex-Crosier, Y; Rochat, C; Herbort, C P

    1997-12-01

    Necrotizing herpetic retinopathies (NHR), a new spectrum of diseases induced by viruses of the herpes family (herpes simplex virus, varicella-zoster virus and cytomegalovirus), includes acute retinal necrosis (ARN) occurring in apparently immunocompetent patients and progressive outer retinal necrosis (PORN) described in severely immuno-compromised patients. Signs of impaired cellular immunity were seen in 16% of ARN patients in a review of 216 reported cases, indicating that immune dysfunction is not only at the origin of PORN but might also be at the origin of ARN. The aim of this study was to correlate clinical findings in NHR patients with their immunologic parameters. Charts from patients with the diagnosis of ARN or PORN seen from 1990 to 1995 were reviewed. Clinical characteristics and disease patterns were correlated with immunological parameters taking into account CD4 lymphocyte rate in AIDS patients and blood-lymphocyte subpopulation determination by flow cytometry, cutaneous delayed type hypersensitivity testing and lymphocytic proliferation rate to seven antigens in HIV-negative patients. During the period considered, 11 patients and 7 patients fulfilled the criteria of ARN and PORN respectively. Immune dysfunctions were identified in most patients. Mild type of ARN and classical ARN were associated with discrete immune dysfunctions, ARN with features of PORN was seen in more immunodepressed patients and classical PORN was always seen in severely immunodepressed HIV patients. Our findings suggest that NHR is a continuous spectrum of diseases induced by herpes viruses, whose clinical expression depends on the immune state of the host going from mild or classical ARN at one end in patients with non-detectable or slight immune dysfunction to PORN in severely immunodepressed patients at the other end and with intermediary forms between these extremes.

  10. Adaptive immunity to leukemia is inhibited by cross-reactive induced regulatory T cells

    OpenAIRE

    Manlove, Luke S.; Berquam-Vrieze, Katherine E.; Pauken, Kristen E.; Williams, Richard T.; Jenkins, Marc K.; Farrar, Michael A.

    2015-01-01

    BCR-ABL+ acute lymphoblastic leukemia patients have transient responses to current therapies. However, the fusion of BCR to ABL generates a potential leukemia-specific antigen that could be a target for immunotherapy. We demonstrate that the immune system can limit BCR-ABL+ leukemia progression although ultimately this immune response fails. To address how BCR-ABL+ leukemia escapes immune surveillance, we developed a peptide: MHC-II tetramer that labels endogenous BCR-ABL-specific CD4+ T cell...

  11. Beta-Glucan induced immune modulation of wound healing in common carp (Cyprinus carpio)

    OpenAIRE

    Jiménez, Natalia Ivonne Vera; Nielsen, Michael Engelbrecht; Lindenstrøm, Thomas

    2012-01-01

    Immune modulators are compounds capable to interact with the immune system and to modify the host response. This interaction enhances non-specific defense mechanisms, improving health and promoting survival. β-glucans are glucose polysaccharides present in sea weed, bacteria, fungi and cereal but not in animals. β-glucans are commonly used as immune modulators, but the mechanisms through which the modulation is achieved remains to be understood. Wound healing and tissue regeneration are essen...

  12. PF-1355, a mechanism-based myeloperoxidase inhibitor, prevents immune complex vasculitis and anti-glomerular basement membrane glomerulonephritis.

    Science.gov (United States)

    Zheng, Wei; Warner, Roscoe; Ruggeri, Roger; Su, Chunyan; Cortes, Christian; Skoura, Athanasia; Ward, Jessica; Ahn, Kay; Kalgutkar, Amit; Sun, Dexue; Maurer, Tristan S; Bonin, Paul D; Okerberg, Carlin; Bobrowski, Walter; Kawabe, Thomas; Zhang, Yanwei; Coskran, Timothy; Bell, Sammy; Kapoor, Bhupesh; Johnson, Kent; Buckbinder, Leonard

    2015-05-01

    Small vessel vasculitis is a life-threatening condition and patients typically present with renal and pulmonary injury. Disease pathogenesis is associated with neutrophil accumulation, activation, and oxidative damage, the latter being driven in large part by myeloperoxidase (MPO), which generates hypochlorous acid among other oxidants. MPO has been associated with vasculitis, disseminated vascular inflammation typically involving pulmonary and renal microvasculature and often resulting in critical consequences. MPO contributes to vascular injury by 1) catabolizing nitric oxide, impairing vasomotor function; 2) causing oxidative damage to lipoproteins and endothelial cells, leading to atherosclerosis; and 3) stimulating formation of neutrophil extracellular traps, resulting in vessel occlusion and thrombosis. Here we report a selective 2-thiouracil mechanism-based MPO inhibitor (PF-1355 [2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide) and demonstrate that MPO is a critical mediator of vasculitis in mouse disease models. A pharmacokinetic/pharmacodynamic response model of PF-1355 exposure in relation with MPO activity was derived from mouse peritonitis. The contribution of MPO activity to vasculitis was then examined in an immune complex model of pulmonary disease. Oral administration of PF-1355 reduced plasma MPO activity, vascular edema, neutrophil recruitment, and elevated circulating cytokines. In a model of anti-glomerular basement membrane disease, formerly known as Goodpasture disease, albuminuria and chronic renal dysfunction were completely suppressed by PF-1355 treatment. This study shows that MPO activity is critical in driving immune complex vasculitis and provides confidence in testing the hypothesis that MPO inhibition will provide benefit in treating human vasculitic diseases. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  13. Characterization of DNA antigens from immune complexes deposited in the skin of patients with systemic lupus erythematosus

    Institute of Scientific and Technical Information of China (English)

    曾凡钦; 尹若菲; 谭国珍; 郭庆; 许德清

    2004-01-01

    Background Skin lesions are common manifestations in systemic lupus erythematosus (SLE). It is still unknown what the definite pathogenesis of skin involvement was and whether DNA participated in it. Our study was designed to explore the pathogenetic role and nature of nuclear antigen (DNA) deposited in the skin lesions of patients with SLE.Methods Thirty skin samples from patients with SLE and 2 normal skin samples were studied. Extracellular DNA was evaluated by indirect immunofluorescence methods. The deposited immune complexes were extracted by cryoprecipitation, and DNA was then isolated with phenol and chloroform. DNA fragment sizes were detected by agarose gel electrophoresis. Finally, 8 different probes were used to analyze the origin of these DNA molecules using Dot hybridization.Results Extracellular DNA staining was found only in skin lesions, mainly those located in the basement membrane zone, vascular wall, and hair follicle wall. Normal skin and non-lesion SLE skin showed no fluorescence at locations outside the nuclei. There were no differences in the rate and intensity of extracellular DNA staining when comparing active phase to remission phase patients. No relationship was found between extracellular DNA and circulating anti-dsDNA antibodies. Deposited DNA fragments clustered into four bands of somewhat discrete sizes: 20 000 bp, 1300 bp, 800-900 bp, 100-200 bp. Small sized fragments (100-200 bp) were positively correlated with disease activity (P<0.05, r=0.407). Dot hybridization showed significant homology of the various extracellular DNA fragments examined with human genomic DNA, but not with DNA from the microorganisms and viruses we examined. There were also homologies between DNA samples from different individuals.Conclusions DNA and its immune complexes may contribute to the pathogenesis of skin lesions in SLE. These DNA molecules range in size from 100 bp to 20 kb and may be endogenous in origin.

  14. Three-dimensional induced polarization data inversion for complex resistivity

    Energy Technology Data Exchange (ETDEWEB)

    Commer, M.; Newman, G.A.; Williams, K.H.; Hubbard, S.S.

    2011-03-15

    The conductive and capacitive material properties of the subsurface can be quantified through the frequency-dependent complex resistivity. However, the routine three-dimensional (3D) interpretation of voluminous induced polarization (IP) data sets still poses a challenge due to large computational demands and solution nonuniqueness. We have developed a flexible methodology for 3D (spectral) IP data inversion. Our inversion algorithm is adapted from a frequency-domain electromagnetic (EM) inversion method primarily developed for large-scale hydrocarbon and geothermal energy exploration purposes. The method has proven to be efficient by implementing the nonlinear conjugate gradient method with hierarchical parallelism and by using an optimal finite-difference forward modeling mesh design scheme. The method allows for a large range of survey scales, providing a tool for both exploration and environmental applications. We experimented with an image focusing technique to improve the poor depth resolution of surface data sets with small survey spreads. The algorithm's underlying forward modeling operator properly accounts for EM coupling effects; thus, traditionally used EM coupling correction procedures are not needed. The methodology was applied to both synthetic and field data. We tested the benefit of directly inverting EM coupling contaminated data using a synthetic large-scale exploration data set. Afterward, we further tested the monitoring capability of our method by inverting time-lapse data from an environmental remediation experiment near Rifle, Colorado. Similar trends observed in both our solution and another 2D inversion were in accordance with previous findings about the IP effects due to subsurface microbial activity.

  15. Immunization against Leishmania major infection using LACK- and IL-12-expressing Lactococcus lactis induces delay in footpad swelling.

    Directory of Open Access Journals (Sweden)

    Felix Hugentobler

    Full Text Available BACKGROUND: Leishmania is a mammalian parasite affecting over 12 million individuals worldwide. Current treatments are expensive, cause severe side effects, and emerging drug resistance has been reported. Vaccination is the most cost-effective means to control infectious disease but currently there is no vaccine available against Leishmaniasis. Lactococcus lactis is a non-pathogenic, non-colonizing Gram-positive lactic acid bacterium commonly used in the dairy industry. Recently, L. lactis was used to express biologically active molecules including vaccine antigens and cytokines. METHODOLOGY/PRINCIPAL FINDINGS: We report the generation of L. lactis strains expressing the protective Leishmania antigen, LACK, in the cytoplasm, secreted or anchored to the bacterial cell wall. L. lactis was also engineered to secrete biologically active single chain mouse IL-12. Subcutaneous immunization with live L. lactis expressing LACK anchored to the cell wall and L. lactis secreting IL-12 significantly delayed footpad swelling in Leishmania major infected BALB/c mice. The delay in footpad swelling correlated with a significant reduction of parasite burden in immunized animals compared to control groups. Immunization with these two L. lactis strains induced antigen-specific multifunctional T(H1 CD4(+ and CD8(+ T cells and a systemic LACK-specific T(H1 immune response. Further, protection in immunized animals correlated with a Leishmania-specific T(H1 immune response post-challenge. L. lactis secreting mouse IL-12 was essential for directing immune responses to LACK towards a protective T(H1 response. CONCLUSIONS/SIGNIFICANCE: This report demonstrates the use of L. lactis as a live vaccine against L. major infection in BALB/c mice. The strains generated in this study provide the basis for the development of an inexpensive and safe vaccine against the human parasite Leishmania.

  16. A leukocyte activation test identifies food items which induce release of DNA by innate immune peripheral blood leucocytes.

    Science.gov (United States)

    Garcia-Martinez, Irma; Weiss, Theresa R; Yousaf, Muhammad N; Ali, Ather; Mehal, Wajahat Z

    2018-01-01

    Leukocyte activation (LA) testing identifies food items that induce a patient specific cellular response in the immune system, and has recently been shown in a randomized double blinded prospective study to reduce symptoms in patients with irritable bowel syndrome (IBS). We hypothesized that test reactivity to particular food items, and the systemic immune response initiated by these food items, is due to the release of cellular DNA from blood immune cells. We tested this by quantifying total DNA concentration in the cellular supernatant of immune cells exposed to positive and negative foods from 20 healthy volunteers. To establish if the DNA release by positive samples is a specific phenomenon, we quantified myeloperoxidase (MPO) in cellular supernatants. We further assessed if a particular immune cell population (neutrophils, eosinophils, and basophils) was activated by the positive food items by flow cytometry analysis. To identify the signaling pathways that are required for DNA release we tested if specific inhibitors of key signaling pathways could block DNA release. Foods with a positive LA test result gave a higher supernatant DNA content when compared to foods with a negative result. This was specific as MPO levels were not increased by foods with a positive LA test. Protein kinase C (PKC) inhibitors resulted in inhibition of positive food stimulated DNA release. Positive foods resulted in CD63 levels greater than negative foods in eosinophils in 76.5% of tests. LA test identifies food items that result in release of DNA and activation of peripheral blood innate immune cells in a PKC dependent manner, suggesting that this LA test identifies food items that result in release of inflammatory markers and activation of innate immune cells. This may be the basis for the improvement in symptoms in IBS patients who followed an LA test guided diet.

  17. Immunization against Leishmania major Infection Using LACK- and IL-12-Expressing Lactococcus lactis Induces Delay in Footpad Swelling

    Science.gov (United States)

    Hugentobler, Felix; Yam, Karen K.; Gillard, Joshua; Mahbuba, Raya; Olivier, Martin; Cousineau, Benoit

    2012-01-01

    Background Leishmania is a mammalian parasite affecting over 12 million individuals worldwide. Current treatments are expensive, cause severe side effects, and emerging drug resistance has been reported. Vaccination is the most cost-effective means to control infectious disease but currently there is no vaccine available against Leishmaniasis. Lactococcus lactis is a non-pathogenic, non-colonizing Gram-positive lactic acid bacterium commonly used in the dairy industry. Recently, L. lactis was used to express biologically active molecules including vaccine antigens and cytokines. Methodology/Principal findings We report the generation of L. lactis strains expressing the protective Leishmania antigen, LACK, in the cytoplasm, secreted or anchored to the bacterial cell wall. L. lactis was also engineered to secrete biologically active single chain mouse IL-12. Subcutaneous immunization with live L. lactis expressing LACK anchored to the cell wall and L. lactis secreting IL-12 significantly delayed footpad swelling in Leishmania major infected BALB/c mice. The delay in footpad swelling correlated with a significant reduction of parasite burden in immunized animals compared to control groups. Immunization with these two L. lactis strains induced antigen-specific multifunctional TH1 CD4+ and CD8+ T cells and a systemic LACK-specific TH1 immune response. Further, protection in immunized animals correlated with a Leishmania-specific TH1 immune response post-challenge. L. lactis secreting mouse IL-12 was essential for directing immune responses to LACK towards a protective TH1 response. Conclusions/Significance This report demonstrates the use of L. lactis as a live vaccine against L. major infection in BALB/c mice. The strains generated in this study provide the basis for the development of an inexpensive and safe vaccine against the human parasite Leishmania. PMID:22348031