The Experts below are selected from a list of 66 Experts worldwide ranked by ideXlab platform
Rachel R. Caspi - One of the best experts on this subject based on the ideXlab platform.
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Microbiota as Drivers and as Therapeutic Targets in Ocular and Tissue Specific Autoimmunity
Frontiers in cell and developmental biology, 2021Co-Authors: Ryan Salvador, Amy Zhang, Reiko Horai, Rachel R. CaspiAbstract:Autoimmune uveitis is a major cause of blindness in humans. Activation of retina-specific autoreactive T cells by commensal microbiota has been shown to trigger uveitis in mice. Although a culprit microbe and/or its immunogenic antigen remains to be identified, studies from inducible and spontaneous mouse models suggest the potential of microbiota-modulating therapies for treating Ocular Autoimmune Disease. In this review, we summarize recent findings on the contribution of microbiota to T cell-driven, tissue-specific autoimmunity, with an emphasis on Autoimmune uveitis, and analyze microbiota-altering interventions, including antibiotics, probiotics, and microbiota-derived metabolites (e.g. short-chain fatty acids), which have been shown to be effective in other Autoimmune Diseases. We also discuss the need to explore more translational animal models as well as to integrate various datasets (microbiomic, transcriptomic, proteomic, metabolomic, and other cellular measurements) to gain a better understanding of how microbiota can directly or indirectly modulate the immune system and contribute to the onset of Disease. It is hoped that deeper understanding of these interactions may lead to more effective treatment interventions.
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IL-10 has a protective role in experimental Autoimmune uveoretinitis.
International immunology, 1998Co-Authors: Luiz Vicente Rizzo, Chi-chao Chan, Barbara Wiggert, Rachel R. CaspiAbstract:The role of IL-10 in the regulation of Ocular Autoimmune Disease was studied in experimental Autoimmune uveoretinitis (EAU) elicited in mice by immunization with the retinal antigen interphotoreceptor retinoid binding protein. IL-10-deficient mice were susceptible to EAU, indicating that pathogenesis can occur without presence of IL-10. Treatment of normal mice with IL-10 for 5 days after uveitogenic immunization ameliorated subsequent EAU scores, and down-regulated antigen-specific production of tumor necrosis factor-alpha and IFN-gamma. A concomitant treatment with IL-4 further reduced Disease, and resulted in emergence of antigen-specific IL-4 and IL-10 production, as well as in enhancement of the IgG1 antibody isotype. IL-4 by itself was not protective. Only IL-10, but not IL-4, was able to inhibit the function of differentiated uveitogenic T cells in culture. Expression of mRNA for Th1 and Th2 cytokines in the eye during the course of EAU showed that while a Th1 pattern predominated early, IL-10 mRNA expression coincided with down-regulation of the Th1 response and resolution of EAU. Systemic neutralization of IL-10 during the expression phase of EAU resulted in elevated Disease scores. Our results suggest that endogenous IL-10 limits expression of EAU and may play a role in the natural resolution of Disease. The data further suggest that exogenous IL-10 may be useful in therapeutic control of Autoimmune uveitis. While IL-10 by itself is sufficient to suppress Th1 effector development and function, a concomitant administration of IL-4 is required to shift the Autoimmune response towards a non-pathogenic Th2 pathway.
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immunotolerance and prevention of Ocular Autoimmune Disease
Current Eye Research, 1995Co-Authors: Luiz Vicente Rizzo, Rachel R. CaspiAbstract:Immunotherapeutic approaches to Autoimmune Disease have a common goal of inducing antigen-specific, long-lasting tolerance to autoantigens, without otherwise compromising the immune response. Here we review some of the most interesting experimental advances in this area. We discuss the use of T cell targeting drugs that have been reported to induce long lasting tolerance to Ocular antigens. Strategies involving the targeting of idiotypic and clonotypic determinants associated with Ocular autoimmunity, such as idiotypic network manipulation and T cell vaccination, are reviewed. The use of cytokines to promote perturbation of the Th1/Th2 balance with its possible implications for treatment of uveitis, is analysed. Finally, we review tolerogenic strategies based on acquisition of tolerance following presentation of antigen through alternative routes, such as injection of antigen into the anterior chamber, intravenous infusion of antigen, and oral administration of retinal antigens. Special emphasis is placed...
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Immunotolerance and prevention of Ocular Autoimmune Disease.
Current eye research, 1995Co-Authors: Luiz Vicente Rizzo, Rachel R. CaspiAbstract:Immunotherapeutic approaches to Autoimmune Disease have a common goal of inducing antigen-specific, long-lasting tolerance to autoantigens, without otherwise compromising the immune response. Here we review some of the most interesting experimental advances in this area. We discuss the use of T cell targeting drugs that have been reported to induce long lasting tolerance to Ocular antigens. Strategies involving the targeting of idiotypic and clonotypic determinants associated with Ocular autoimmunity, such as idiotypic network manipulation and T cell vaccination, are reviewed. The use of cytokines to promote perturbation of the Th1/Th2 balance with its possible implications for treatment of uveitis, is analysed. Finally, we review tolerogenic strategies based on acquisition of tolerance following presentation of antigen through alternative routes, such as injection of antigen into the anterior chamber, intravenous infusion of antigen, and oral administration of retinal antigens. Special emphasis is placed on the last strategy, since there are ongoing clinical trials using oral tolerance as an immunotherapeutic approach to treat Autoimmune Diseases, among them uveitis.
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Immunogenetic aspects of clinical and experimental uveitis.
Regional immunology, 1992Co-Authors: Rachel R. CaspiAbstract:Genetic association of some immune-mediated human uveitic Diseases with histocompatibility antigens, ethnic origin, familial background, or gender have suggested the presence a hereditary component in susceptibility. Experimental Autoimmune uveoretinitis (EAU) can be induced in inbred rodents by immunization with evolutionarily conserved retinal proteins, and mimics many features of human uveitis. Susceptibility to EAU is genetically controlled, and the model is being used to study mechanisms that might affect susceptibility to Ocular Autoimmune Disease. EAU expression in mice and in rats requires the presence of both a susceptible MHC haplotype and a "permissive" genetic background. MHC control of susceptibility in H-2k mice was tentatively mapped to the I-A subregion (HLA-DR equivalent), implicating epitope recognition as a major mechanism in susceptibility. In contrast, expression of the I-Ek gene product (HLA-DQ equivalent) appeared to have an ameliorating effect on Disease. Susceptible H-2 haplotypes exhibited highest Disease scores on the B10 background, and Disease was reduced, or even absent, on some other (nonpermissive) backgrounds. Factors which may determine "permissiveness" or "nonpermissiveness" of a particular genetic background, as studied in mice and rats, may include regulation of responses to lymphokines, hypothalamic-adrenal-pituitary axis hormones, mast cell/vascular effects, and possibly the T cell repertoire. The data are interpreted to suggest that, in individuals susceptible to uveitis by virtue of their MHC, the final expression of Disease will be determined by the genetic background. These results might help to explain why only a minority of individuals with a susceptible HLA type develop uveitis, as well as the variable incidence of Disease in HLA-identical populations of different ethnic backgrounds.
Pablo Argüeso - One of the best experts on this subject based on the ideXlab platform.
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Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the Ocular surface
Scientific Reports, 2020Co-Authors: Ashley M. Woodward, Antonio Di Zazzo, Stefano Bonini, Pablo ArgüesoAbstract:A growing body of evidence implicates endoplasmic reticulum (ER) stress in the pathogenesis of chronic inflammatory and Autoimmune disorders. Here, we demonstrate that the proinflammatory cytokine TNFα stimulates matrix metalloproteinase 9 (MMP9) at the Ocular surface through a c-Fos-dependent mechanism of ER stress. We found positive reactivity of the molecular chaperone BiP/GRP78 in conjunctival epithelium of patients with Ocular cicatricial pemphigoid and increased levels of BiP/GRP78, sXBP1 and GRP94 in human corneal epithelial cells treated with TNFα. Pharmacological blockade of ER stress in vitro using dexamethasone or the chemical chaperones TUDCA and 4PBA attenuated MMP9 expression and secretion in the presence of TNFα. Moreover, expression analysis of genes associated with inflammation and autoimmunity identified the c-Fos proto-oncogene as a mediator of ER stress responses in epithelial cells. Substantially less TNFα-induced MMP9 expression occurred when c-Fos signaling was suppressed with a function-blocking antibody. Taken together, these results indicate that activation of ER stress contributes to promote inflammation-mediated proteolytic activity and uncovers a target for restoring tissue homeostasis in Ocular Autoimmune Disease.
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Inflammatory Stress Causes N-Glycan Processing Deficiency in Ocular Autoimmune Disease.
The American journal of pathology, 2018Co-Authors: Ashley M. Woodward, Sylvain Lehoux, Flavio Mantelli, Antonio Di Zazzo, Inka Brockhausen, Stefano Bonini, Pablo ArgüesoAbstract:High levels of proinflammatory cytokines have been associated with a loss of tissue function in Ocular Autoimmune Diseases, but the basis for this relationship remains poorly understood. Here we investigate a new role for tumor necrosis factor α in promoting N-glycan-processing deficiency at the surface of the eye through inhibition of N-acetylglucosaminyltransferase expression in the Golgi. Using mass spectrometry, complex-type biantennary oligosaccharides were identified as major N-glycan structures in differentiated human corneal epithelial cells. Remarkably, significant differences were detected between the efficacies of cytokines in regulating the expression of glycogenes involved in the biosynthesis of N-glycans. Tumor necrosis factor α but not IL-1β had a profound effect in suppressing the expression of enzymes involved in the Golgi branching pathway, including N-acetylglucosaminyltransferases 1 and 2, which are required for the formation of biantennary structures. This decrease in gene expression was correlated with a reduction in enzymatic activity and impaired N-glycan branching. Moreover, patients with Ocular mucous membrane pemphigoid were characterized by marginal N-acetylglucosaminyltransferase expression and decreased N-glycan branching in the conjunctiva. Together, these data indicate that proinflammatory cytokines differentially influence the expression of N-glycan-processing enzymes in the Golgi and set the stage for future studies to explore the pathophysiology of Ocular Autoimmune Diseases.
Luiz Vicente Rizzo - One of the best experts on this subject based on the ideXlab platform.
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IL-10 has a protective role in experimental Autoimmune uveoretinitis.
International immunology, 1998Co-Authors: Luiz Vicente Rizzo, Chi-chao Chan, Barbara Wiggert, Rachel R. CaspiAbstract:The role of IL-10 in the regulation of Ocular Autoimmune Disease was studied in experimental Autoimmune uveoretinitis (EAU) elicited in mice by immunization with the retinal antigen interphotoreceptor retinoid binding protein. IL-10-deficient mice were susceptible to EAU, indicating that pathogenesis can occur without presence of IL-10. Treatment of normal mice with IL-10 for 5 days after uveitogenic immunization ameliorated subsequent EAU scores, and down-regulated antigen-specific production of tumor necrosis factor-alpha and IFN-gamma. A concomitant treatment with IL-4 further reduced Disease, and resulted in emergence of antigen-specific IL-4 and IL-10 production, as well as in enhancement of the IgG1 antibody isotype. IL-4 by itself was not protective. Only IL-10, but not IL-4, was able to inhibit the function of differentiated uveitogenic T cells in culture. Expression of mRNA for Th1 and Th2 cytokines in the eye during the course of EAU showed that while a Th1 pattern predominated early, IL-10 mRNA expression coincided with down-regulation of the Th1 response and resolution of EAU. Systemic neutralization of IL-10 during the expression phase of EAU resulted in elevated Disease scores. Our results suggest that endogenous IL-10 limits expression of EAU and may play a role in the natural resolution of Disease. The data further suggest that exogenous IL-10 may be useful in therapeutic control of Autoimmune uveitis. While IL-10 by itself is sufficient to suppress Th1 effector development and function, a concomitant administration of IL-4 is required to shift the Autoimmune response towards a non-pathogenic Th2 pathway.
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immunotolerance and prevention of Ocular Autoimmune Disease
Current Eye Research, 1995Co-Authors: Luiz Vicente Rizzo, Rachel R. CaspiAbstract:Immunotherapeutic approaches to Autoimmune Disease have a common goal of inducing antigen-specific, long-lasting tolerance to autoantigens, without otherwise compromising the immune response. Here we review some of the most interesting experimental advances in this area. We discuss the use of T cell targeting drugs that have been reported to induce long lasting tolerance to Ocular antigens. Strategies involving the targeting of idiotypic and clonotypic determinants associated with Ocular autoimmunity, such as idiotypic network manipulation and T cell vaccination, are reviewed. The use of cytokines to promote perturbation of the Th1/Th2 balance with its possible implications for treatment of uveitis, is analysed. Finally, we review tolerogenic strategies based on acquisition of tolerance following presentation of antigen through alternative routes, such as injection of antigen into the anterior chamber, intravenous infusion of antigen, and oral administration of retinal antigens. Special emphasis is placed...
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Immunotolerance and prevention of Ocular Autoimmune Disease.
Current eye research, 1995Co-Authors: Luiz Vicente Rizzo, Rachel R. CaspiAbstract:Immunotherapeutic approaches to Autoimmune Disease have a common goal of inducing antigen-specific, long-lasting tolerance to autoantigens, without otherwise compromising the immune response. Here we review some of the most interesting experimental advances in this area. We discuss the use of T cell targeting drugs that have been reported to induce long lasting tolerance to Ocular antigens. Strategies involving the targeting of idiotypic and clonotypic determinants associated with Ocular autoimmunity, such as idiotypic network manipulation and T cell vaccination, are reviewed. The use of cytokines to promote perturbation of the Th1/Th2 balance with its possible implications for treatment of uveitis, is analysed. Finally, we review tolerogenic strategies based on acquisition of tolerance following presentation of antigen through alternative routes, such as injection of antigen into the anterior chamber, intravenous infusion of antigen, and oral administration of retinal antigens. Special emphasis is placed on the last strategy, since there are ongoing clinical trials using oral tolerance as an immunotherapeutic approach to treat Autoimmune Diseases, among them uveitis.
Andrew D. Dick - One of the best experts on this subject based on the ideXlab platform.
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TNFα Regulates SIRT1 Cleavage during Ocular Autoimmune Disease
The American journal of pathology, 2015Co-Authors: Peter Gardner, Samia Yazid, Colin J Chu, David A. Copland, Peter Adamson, Andrew D. Dick, Virginia L. CalderAbstract:Elevated tumor necrosis factor (TNF) α levels are associated with chronic Autoimmune Diseases in which effects of TNFα on immune cells are multiple and complex. Analysis of uveitis in mice exhibiting severe Autoimmune inflammation, resulting in a destructive subtotal loss of photoreceptors, revealed the presence of high plasma levels of TNFα and a significant population of CD4 + TNFα + cells in the periphery and the eye at peak Disease (TNFα hi ). We have shown previously by pharmacological activation that the deacetylase Sirtuin 1 (SIRT1) has an anti-inflammatory role in a less severe, TNFα lo model of uveitis. We now show that SIRT1 activation fails to clinically suppress severe TNFα hi Disease, whereas glucocorticoid treatment is successful. TNFα has been reported to mediate cleavage and inactivation of SIRT1 during inflammation, and at peak Disease we observed both full-length and cleaved SIRT1 in draining lymph node cells. In vivo systemic TNFα blockade suppressed severe Ocular Disease and restricted SIRT1 cleavage in the periphery, maintaining full-length active SIRT1 protein. When combining a suboptimal TNFα blockade with SIRT1 activation, a synergistic suppression of severe Disease compared with TNFα blockade alone occurred. Our data suggest a new role for TNFα in exacerbating the severity of Autoimmune Disease by regulating SIRT1 cleavage in draining lymph node effector cells. SIRT1 activation may be effective as an adjunctive treatment for inflammatory conditions not fully controlled by TNFα inhibitors.
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The B subunit of Escherichia coli heat-labile enterotoxin inhibits Th1 but not Th17 cell responses in established experimental Autoimmune uveoretinitis.
Investigative ophthalmology & visual science, 2008Co-Authors: Ben J. E. Raveney, David A. Copland, C. M. Richards, Marie-laure Aknin, Bronwen R. Burton, Emma C. Kerr, Lindsay B. Nicholson, Neil A. Williams, Andrew D. DickAbstract:PURPOSE. To investigate the efficacy of the B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of Ocular Autoimmune Disease. Murine experimental Autoimmune uveoretinitis (EAU) is an animal model of Autoimmune posterior uveitis initiated by retinal antigen-specific Th1 and Th17 CD4 T cells, which activate myeloid cells, inducing retinal damage. EtxB is a potent immune modulator that ameliorates other Th1-mediated Autoimmune Diseases, enhancing regulatory T-cell activity.
Chi-chao Chan - One of the best experts on this subject based on the ideXlab platform.
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Effect of sex hormones on experimental Autoimmune uveoretinitis (EAU).
Immunological investigations, 2003Co-Authors: Ronald Buggage, Dawn M. Matteson, De Fen Shen, Bing Sun, Nadine Tuaillon, Chi-chao ChanAbstract:Purpose: Sex hormones have been associated with the prevalence, susceptibility, and severity of Autoimmune Disease. Although the exact mechanism is unknown, sex hormones are reported to influence cytokine production, specifically by affecting the balance of Th1 and Th2 effector cells. We evaluated the effect of estrogen, progesterone, and testosterone in Autoimmune uveoretinitis (EAU), a rodent model of human Ocular Autoimmune Disease. Methods: Lewis rats implanted with either β‐estradiol (estrogen), 5‐dihydrotestosterone (5‐DHT), norgestrel (progesterone), or estrogen plus progesterone were immunized with the retinal antigen interphotoreceptor retinoid binding protein (IRBP) peptide. Evaluation of EAU was based on histology of the eyes and measurement of peripheral immunological responses of DTH and lymphocyte proliferation to S‐antigen. Quantitative RT‐PCR was used to measure IFN‐γ and IL‐10 mRNA in the eyes. Results: In female rats 5‐DHT significantly decreased, estrogen slightly enhanced, but progeste...
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IL-10 has a protective role in experimental Autoimmune uveoretinitis.
International immunology, 1998Co-Authors: Luiz Vicente Rizzo, Chi-chao Chan, Barbara Wiggert, Rachel R. CaspiAbstract:The role of IL-10 in the regulation of Ocular Autoimmune Disease was studied in experimental Autoimmune uveoretinitis (EAU) elicited in mice by immunization with the retinal antigen interphotoreceptor retinoid binding protein. IL-10-deficient mice were susceptible to EAU, indicating that pathogenesis can occur without presence of IL-10. Treatment of normal mice with IL-10 for 5 days after uveitogenic immunization ameliorated subsequent EAU scores, and down-regulated antigen-specific production of tumor necrosis factor-alpha and IFN-gamma. A concomitant treatment with IL-4 further reduced Disease, and resulted in emergence of antigen-specific IL-4 and IL-10 production, as well as in enhancement of the IgG1 antibody isotype. IL-4 by itself was not protective. Only IL-10, but not IL-4, was able to inhibit the function of differentiated uveitogenic T cells in culture. Expression of mRNA for Th1 and Th2 cytokines in the eye during the course of EAU showed that while a Th1 pattern predominated early, IL-10 mRNA expression coincided with down-regulation of the Th1 response and resolution of EAU. Systemic neutralization of IL-10 during the expression phase of EAU resulted in elevated Disease scores. Our results suggest that endogenous IL-10 limits expression of EAU and may play a role in the natural resolution of Disease. The data further suggest that exogenous IL-10 may be useful in therapeutic control of Autoimmune uveitis. While IL-10 by itself is sufficient to suppress Th1 effector development and function, a concomitant administration of IL-4 is required to shift the Autoimmune response towards a non-pathogenic Th2 pathway.
