Non-infectious forms of uveitis represent a significant cause of blindness and understanding the underlying mechanisms by which they occur is critical for their prevention and treatment. The long term objectives of this project are to better understand the mechanisms by which autoimmune uveitis occurs in a unique animal model that we have developed. Our model involves mice that are deficient for the Autoimmune Regulator (Aire) gene which has been shown to be the defective gene in the clinical disorder Autoimmune Polyglandular Syndrome Type 1 (APS1). Importantly, both APS1 patients and Aire-deficient mice have been demonstrated to spontaneously develop autoimmune uveitis. Thus, unraveling how a single gene defect in Aire can lead to uveitis can give us important clues into its pathogenesis. Aire appears to play a major role in controlling the promiscuous expression of a wide variety of self-antigens with the thymus, including several eye-specific antigens. We have recently developed novel reagents to further detect and measure eye-specific T cells that are negatively selected within the thymus in an Aire-dependent fashion. In addition, because the autoimmune response to the eye in our model appears to proceed in antigen-specific manner we are also interested in preventing uveitis with antigen-specific tolerance protocols. Three major goals are therefore envisioned: (1) understand mechanisms by which uveitogenic T cells are selected in the thymus in Aire-deficient mice;(2) preventing spontaneous uveitis with antigen-specific tolerance;(3) enforcing tolerance to the eye with extrathymic Aire-expressing cells. Because our animal model occurs spontaneously, it affords the opportunity to explore novel pathways that are involved in the induction of uveitis and also in the prevention and treatment of this disease. In addition, because many of the details on how Aire protects against autoimmunity remained to be unraveled our findings could also have broad implications for our understanding of immune tolerance.

Public Health Relevance

A significant case of blindness is caused by non-infectious forms of uveitis, many of which are thought to be autoimmune in nature. Autoimmune uveitis is thought to result from a defect in immune tolerance to the eye and understanding how tolerance to the eye is maintained is essential to treating and preventing the disease. In this proposal we will address the role of an important transcription factor called Aire (for Autoimmune Regulator) in controlling immune tolerance to the eye and its relevance to disease is clear as both humans and mice that have defects in Aire can develop uveitis.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016408-09
Application #
8494049
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mckie, George Ann
Project Start
2005-06-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$352,260
Indirect Cost
$124,260
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
Metzger, Todd C; Anderson, Mark S (2011) Control of central and peripheral tolerance by Aire. Immunol Rev 241:89-103
Taniguchi, Ruth T; Anderson, Mark S (2011) The role of Aire in clonal selection. Immunol Cell Biol 89:40-4
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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