Immunoregulation Section

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:

1. 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.
2. 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.
3. 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.
4. 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:

• Annual Report 2013
• Annual Report 2014
• Annual Report 2015

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