Autoimmune Oophoritis with Multiple Molecular Targets Mitigated by Transgenic Expression of Mater

• DOI: 10.1210/en.2011-0022
• Publication Date: 2011-03-30T02:10:23Z
• Authors: Noriyuki Otsuka; Zhi-Bin Tong; Konstantina Vanevski; Wei Tu; Mickie H. Cheng; Lawrence M. Nelson
• Keywords: Male; 0301 basic medicine; Egg Proteins; Oophoritis; Ovary; Histocompatibility Antigens Class II; Mice, Transgenic; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Immune Tolerance; Animals; Humans; Female; Antigens; Polyendocrinopathies, Autoimmune

Primary ovarian insufficiency (POI) resulting from ovarian autoimmunity is a poorly understood clinical condition lacking in effective treatments. Understanding the targets of the autoimmune response and induction of ovarian-specific tolerance would allow development of focused therapies to preserve fertility in an at-risk population. MATER (maternal antigen that embryos require) is a known ovarian autoantigen targeted in autoimmune syndromes of POI. We attempt to induce ovarian-specific tolerance via transgenic expression of the MATER antigen on potentially tolerogenic antigen-presenting cells (APC), which typically present antigen via the major histocompatibility complex (MHC) class II molecule. We hypothesize that expression of MATER in a MHC class II-dependent manner on APC can mediate induction of ovarian tolerance.We utilized a well-characterized murine model of ovarian autoimmunity, whereby oophoritis develops after d 3 neonatal thymectomy (NTx). Wild-type and transgenic mice, carrying an MHC Class II-driven Mater gene (IE-Mater), were subjected to NTx and assessed for evidence of autoimmune oophoritis. After disease induction by NTx, female mice carrying the IE-Mater transgene had significant reductions in histological oophoritis (56%) and circulating ovarian autoantibodies (28%) compared with wild-type females (94% and 82%, respectively). Incidence of other autoimmunity was unaffected as assessed by antinuclear autoantibodies. Transgenic expression of MATER in APC can induce antigen-specific tolerance with a significant reduction in ovarian autoimmunity. Lack of complete disease protection suggests that other antigens may also play a role in autoimmune oophoritis. As a known autoantigen in the human APS1 (autoimmune polyglandular syndrome type 1), which is associated with POI, MATER may represent a relevant target for future diagnostic and therapeutic clinical interventions.