Understanding Autoimmune Uveitis through Animal Models The Friedenwald Lecture

For more than 20 years, my research interests have concentrated on the cellular, molecular, and genetic mechanisms involved in the breakdown of self tolerance to immunologically privileged antigens found in the retina of the eye and in the subsequent pathologic processes that ultimately manifest as autoimmune uveitis. Although my work has emphasized autoimmune uveitis, many of the mechanisms are applicable to other ocular inflammatory diseases, as well as to autoimmune and inflammatory diseases affecting other organs. The eye has a special relationship with the immune system, known as ocular immune privilege, which we believe to have evolved to protect vision from damage caused by day-to-day inflammatory insults.1,2 One of the convincing and medically important manifestations of ocular immune privilege is the extraordinary success of corneal grafts.2 However, despite ocular immune privilege, we develop autoimmune uveitis. This is seemingly a paradox that should be reconciled with what we know, or what we think we know, about immune privilege of the eye. Autoimmune uveitis in humans is not a single entity, but rather is a group of diseases that can differ in presentation and clinical course. The eye may be the only organ involved, or uveitis may be part of a syndrome involving multiple tissues.3 Lymphocytes from peripheral blood of uveitis patients often respond to antigenic proteins expressed in the retina, and it is felt that these responses play a central role in the pathogenesis of autoimmune uveitic disease. Together, these diseases are estimated to affect 2 million Americans and to underlie at least 10% of the severe visual handicap.4 Because the etiology is usually obscure and because studies on clinical material are hampered by strict ethical considerations and limited availability of tissue samples, it is necessary to use animal models to unravel the basic mechanisms of disease.