Building 10, Room 10N22, 10 Center Drive , Bethesda, MD 20892
The Section’s interest is in cellular and molecular mechanisms involved in immune and autoimmune responses affecting the eye and vision. Vision can be compromised by an inflammatory autoimmune disease known as uveitis. We aim to understand the basic mechanisms that trigger and drive the disease. Vision can also be compromised by damage to the surface of the eye. A separate line of investigation addresses mucosal immune responses at the ocular surface. The goal is to use the knowledge gained from these studies for designing novel and rational strategies for immunotherapy. This Section is part of the Laboratory of Immunology.
The Section’s interest is in cellular and molecular mechanisms involved in immune and autoimmune responses affecting the eye and vision. The ability to see is precious and once lost, it is difficult or impossible to restore. Vision can be compromised by an inflammatory autoimmune disease known as uveitis, which destroyes the neuroretina and is a major cause of blindness. We aim to understand the basic mechanisms that trigger and drive the disease. The studies center on development and maintenance of self-tolerance to immunologically privileged retinal antigens, on defining the natural triggers that lead to their pathological breakdown, and on experimental modulation of the pathogenic responses that follow. Vision can also be compromised by damage to the surface of the eye. A separate line of investigation addresses mucosal immune responses at the ocular surface, which constitute a barrier between the eye and the environment. Approaches and conclusions are generalizable to other immunologically driven diseases. The goal is to use the knowledge gained from these studies for designing novel and rational strategies for immunotherapy. The experimental approaches utilize animal models in order to dissect at the cellular and molecular level the local and systemic immune responses involved in disease. Experimental autoimmune uveoretinitis (EAU) is elicited in mice by immunization with retinal antigens or their fragments. Spontaneous uveitis develops in gene-manipulated mice that have increased numbers of lymphocytes capable of recognizing retinal antigens. Cellular, molecular and bioinformatic approaches are used to dissect factors that affect susceptibility to disease. Pathogenic lymphocytes are studied functionally and phenotypically using protein, metabolic and transcriptome analyses. Genetically engineered mice are used to evaluate the role of various components of the immune system in the immunopathogenesis of uveitis. Strategies to induce long-lasting immunological tolerance to retinal antigens are explored as immunotherapy. Related autoimmune diseases, e.g., experimental autoimmune encephalomyelitis (EAE), are used to compare, generalize, or to confirm, the findings obtained in the uveitis models. EAU also serves as a template for the preclinical evaluation of new drugs and compounds as to their effects on the various stages of immunopathogenesis and disease expression. Mucosa commensal l immunology of the ocular surface is studied in normal and genetically engineered mice. The surface of the eye is exposed to the environment provides a barrier against entry of irritants and pathogens. The innate and adaptive immune elements that participate in this barrier function, and their interaction with microorganisms at the ocular surface are studied using cellular, molecular and bioinformatic approaches. Recent and ongoing subjects under study include:
- Basic mechanisms in maintenance and breakdown of tolerance to retina. This includes questions related to immune privilege of the eye, central and peripheral tolerance to retinal antigens and the role of microbiota.
- Pathogenesis and immunotherapy of uveitis Studies address the role of innate and adaptive responses in pathogenesis of uveitis and their interplay. This includes natural triggers of uveitis (e.g., microbiota), the instructive effects of the innate milieu (adjuvant) on the resultant adaptive T cell response, roles of Th1 and Th17 responses and their associated cytokines in induced and spontaneous uveitis, and finally the role of regulatory cells of various flavors and their induction by various immunoregulatory regimens, including oral tolerance and antigen-specific genetic therapy. The goal is to harness the natural regulatory mechanisms to achieve prevention or long lasting remission of disease.
- Pre-clinical studies of uveitis using humanized mice and patient samples. Studies address HLA-restricted responses to uveitis-associated antigens and the role of HLA in susceptibility to uveitis. HLA-A29 (relative risk of uveitis = 245) has been of particular interest.
- Mucosal immunology of the ocular surface. We are characterizing the responses of the conjunctiva-associated lymphoid tissue to environmental stimuli and the role of commensal microbiota in maintaining host defense and promoting ocular surface homeostasis.
Specific information on the recent and current work of the Section can be found in the NIH Annual Reports database: Specific information on our recent and current can be found in the NIH Annual Reports database:
- R. R. Caspi, F.G. Roberge and R.B.Nussenblatt: Organ-resident nonlymphoid cells suppress autoimmune T-helper lymphocytes. Science 237:1029-1032, 1987. (PubMed)(link is external)
- R. R. Caspi, et al. A new model of autoimmune disease:experimental autoimmune uveoretinitis induced in mice with two different retinal antigens. J. Immunol. 140:1490-1495,1988. (PubMed)(link is external)
- L. V. Rizzo et al., Interleukin-2 treatment potentiates induction of oral tolerance. J.Clin. Invest. 94:1668-1672, 1994. (PubMed)(link is external)
- L. S. Jones et al., Interferon gamma-deficient mice develop experimental autoimmune uveitis in the context of a deviant effector response. J. Immunol. 158:5997-6005, 1997. (PubMed)(link is external)
- T. K. Tarrant et al., Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide,and apoptosis. J Exp Med 189:219-230 (1999). (PubMed)(link is external)
- H. Xu et al., Transgenic expression of an immunologically privileged retinal antigen extraocularly reduces susceptibility to experimental autoimmune uveitis. Eur. J. Immunol. 30:272-278 (2000) (PubMed)(link is external)
- R. K. Agarwal et al., Retroviral Gene transfer of an immunoglobulin-antigenfusion construct protects from Experimental autoimmune uveitis. J.Clin. Invest. 106:245-252, 2000. (PubMed)(link is external)
- G. Pennesi et al., A humanized model ofexperimental autoimmune uveitis in HLA class II-transgenic mice. J.Clin Invest. 111:1171-1180, 2003. (PubMed)(link is external)
- D. Avichezer et al., An Immunologically Privileged Retinal Antigen Elicits Tolerance: Major Role for Central Selection Mechanisms J. Exp. Med.,198:1665-1676, 2003. (PubMed)(link is external)
- R. S. Grajewski et al., Endogenous IRBP can be dispensable for generation of natural CD4+CD25+ T-regs that protect from IRBP-induced retinal autoimmunity. J. Exp. Med.203:851-856, 2006. (PubMed)(link is external)
- J. Tang et al., A new model of retinal autoimmunity: autoimmune uveitis elicited with antigen-pulsed dendritic cells is driven by unique effector mechanisms. J. Immunol. 2007 J. Immunol. 178:5578-5587, 2007 (PubMed)(link is external)
- P. B. Phyllis B. Silver et al., Hydrodynamic Vaccination with DNA encoding an immunologically privileged retinal antigen protects from anti-retinal autoimmunity through induction of regulatory T cells. J. Immunol.,179:5146-58, 2007 (PubMed)(link is external)
- D. Luger et al., Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J. Exp. Med. 205:799-810, 2008. (PubMed)(link is external)
- R. Zhou, R. Horai, M. J. Mattapallil, R. R. Caspi, A new look at immune privilege of the eye: dual role for the vision-related molecule retinoic acid. J Immunol 187, 4170-4177 (2011). (PubMed)(link is external)
- R. Zhou et al., The living eye “disarms” uncommitted autoreactive T cells by converting them to Foxp3(+) regulatory cells following local antigen recognition. J Immunol 188, 1742-1750 (2012). (PubMed)(link is external)
- R. Horai et al., Breakdown of immune privilege and spontaneous autoimmunity in mice expressing a transgenic T cell receptor specific for a retinal autoantigen. J Autoimmun 44, 21-33 (2013).(PubMed)(link is external)
- P. Silver et al., Retina-specific T regulatory cells bring about resolution and maintain remission of autoimmune uveitis. J Immunol194, 3011-3019 (2015). (PubMed)(link is external)
- Wai Po Chong, Nicolas van Panhuys, Jun Chen, Phyllis B Silver, Chi-Chao Chan, Ronald N. Germain, Rachel R Caspi. NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-γ/IL-27 axis. J Exp Med. 212:1739-52. (2015).(PubMed)(link is external)
- Horai R, Zárate-Bladés CR, Dillenburg-Pilla P, Chen J, Kielczewski JL, Silver PB, Jittayasothorn Y, Chan CC, Yamane H, Honda K, Caspi RR. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site. Immunity. 43(2):343-53. 2015.(PubMed)
|Rachel Caspi, Ph.D.
|Phyllis Silver, B.S.||Biologistemail@example.com|
|Biying Xu, Ph.D.||Biologistfirstname.lastname@example.org|
|Anthony St.Leger, Ph.D.||Postdoctoral Fellowemail@example.com|
|Reiko Horai, Ph.D.||Staff Scientist||hreiko@mail.NIH.gov|
|Mary Mattapallil, DVM, Ph.D.||Staff Scientistfirstname.lastname@example.org|
|So Jin Bing, DVM||Ph.D. Candidateemail@example.com|
|WiaPo Chong, Ph.D.||Postdoctoral Fellowfirstname.lastname@example.org|
|Sophia Jeon, Ph.D.||Postdoctoral Fellowemail@example.com|
|Jennifer Kielczewski, Ph.D.||Postdoctoral Fellowfirstname.lastname@example.org|
|Yingyos (Ed) Jittayasothorn||Research Fellowemail@example.com|
Staff of the NEI’s Immunoregulation Section. February 2016. Front row (left to right): Reiko Horai, Sophia Jeon, Rachel Caspi, Jennifer Kielczewski, Phyllis Silver. Back row (left to right): Mary Mattapallil, So Jin Bing, Ed Jittayasothorn, Wai Po Chong, Anthony St.Leger.