Antigenic targets in Aire-mediated ovarian autoimmunity (44.41)

Abstract Ovarian autoimmunity is a poorly understood cause of premature ovarian failure and infertility among women. Diagnosis of autoimmune ovarian disease (AOD) is challenging due to the lack of specific and sensitive autoantibody tests, and the disease pathogenesis and antigens targeted in AOD remain largely unknown. We have established a novel mouse model of AOD using the Aire-deficient mouse. Like APS1 patients that lack AIRE, Aire-deficient mice develop disease of multiple organs, including the ovary, due to a breakdown in central tolerance. Aire-deficient female mice develop autoimmune oophoritis manifested by 100% incidence of histologic disease and frequent oligoclonal autoantibodies to ovarian tissue, presenting a valuable spontaneous disease model in which to identify ovarian antigens. Initial investigations have identified putative antigenic targets, including a 60 kd ovarian antigen that is targeted early in AOD. Analysis of ovarian infiltrates in Aire-deficient females indicates a central role for Th1 CD4+ T cells in mediating disease. Similar autoantibody profiles and immune infiltrates have also been reported in women with premature ovarian failure, suggesting that common ovarian antigens may be shared. Understanding of antigens and disease pathogenesis in Aire-mediated AOD will define the mechanism by which tolerance is broken in the ovary and will have potential for translation to patients in a significant cause of human ovarian failure and infertility.