The long term objectives of this project are to better understand the mechanisms by which autoimmune uveitis occurs in a novel spontaneous animal model of the disease. Our new model involves mice that are deficient for the Autoimmune Regulator (Aire) gene, which was identified by positional cloning efforts on patients with a polyglandular autoimmune syndrome called APECED (Autoimmune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy). Both Aire-deficient mice and humans develop an autoimmune attack directed against the eye and the mice provide the first spontaneously occurring model of autoimmune eye disease. In addition, previous work by our group and others has shown that Aire helps regulate the ectopic expression of many self-antigens in the thymus gland and studies here will help to further clarify the link between the thymus and the generation of autoimmune disease in the eye. The general strategy is to utilize aire-deficient mice as a tool to unravel how uveitis occurs in these animals. Aire-deficient mice generate an autoimmune attack directed against the eye that is characterized by both a mononuclear infiltrate in the retina and by serum autoantibodies directed against the photoreceptor layer of the retina. The autoantibodies and eye-reactive lymphocytes present in aire-deficient mice can be utilized to identify those antigens in the eye that are being targeted by the autoimmune response.
The specific aims are to tightly define the key aspects of the autoimmune response against the eye in aire-deficient mice. Three major goals are envisioned: (1) define and purify the retinal antigens targeted by autoantibodies and T cells in aire-deficient mice; (2) determine the key effector populations of lymphocytes responsible for aire-deficient uveitis; (3) determine the regulation of the thymic expression of retinal autoantigens by aire and their impact on thymocyte selection. Previous work involving animal models of autoimmune uveitis has relied on the induction of disease by immunization with inciting antigens. Because our animal model occurs spontaneously, it affords the opportunity to potentially identify new autoantigens associated with uveitis and also those that are more tightly linked to disease. Aire appears to regulate the expression of many self-antigens in the thymus and studies here will help expand our knowledge of which eye antigens are regulated in the thymus and how tolerance to these antigens may be broken in its absence. These studies have important implications for understanding how autoimmunity in the eye occurs and have a direct link to the clinical realm, as patients with a defective Aire gene also develop uveitis.
|Proekt, Irina; Miller, Corey N; Jeanne, Marion et al. (2016) LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity. J Clin Invest 126:3758-3771|
|Cheng, Mickie H; Anderson, Mark S (2013) Insights into type 1 diabetes from the autoimmune polyendocrine syndromes. Curr Opin Endocrinol Diabetes Obes 20:271-8|
|Su, Maureen A; Davini, Dan; Cheng, Philip et al. (2012) Defective autoimmune regulator-dependent central tolerance to myelin protein zero is linked to autoimmune peripheral neuropathy. J Immunol 188:4906-12|
|Taniguchi, Ruth T; DeVoss, Jason J; Moon, James J et al. (2012) Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection. Proc Natl Acad Sci U S A 109:7847-52|
|Taniguchi, Ruth T; Anderson, Mark S (2011) The role of Aire in clonal selection. Immunol Cell Biol 89:40-4|
|Metzger, Todd C; Anderson, Mark S (2011) Control of central and peripheral tolerance by Aire. Immunol Rev 241:89-103|
|Anderson, Mark S; Su, Maureen A (2011) Aire and T cell development. Curr Opin Immunol 23:198-206|
|DeVoss, Jason J; LeClair, Norbert P; Hou, Yafei et al. (2010) An autoimmune response to odorant binding protein 1a is associated with dry eye in the Aire-deficient mouse. J Immunol 184:4236-46|
|Husebye, Eystein S; Anderson, Mark S (2010) Autoimmune polyendocrine syndromes: clues to type 1 diabetes pathogenesis. Immunity 32:479-87|
|Waterfield, Michael; Anderson, Mark S (2010) Clues to immune tolerance: the monogenic autoimmune syndromes. Ann N Y Acad Sci 1214:138-55|
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