title: Autoimmune oophoritis with multiple molecular targets mitigated by transgenic expression of mater.
abstract: 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.
authors: University of California San Francisco Diabetes Center, San Francisco, California 94143, USA.
authors: Noriyuki
authors: N
authors: Otsuka
authors: Zhi-Bin
authors: ZB
authors: Tong
authors: Konstantina
authors: K
authors: Vanevski
authors: Wei
authors: W
authors: Tu
authors: Mickie H
authors: MH
authors: Cheng
authors: Lawrence M
authors: LM
authors: Nelson
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics* / Q000276:immunology* / Q000494:pharmacology; D004195:Disease Models, Animal; D004527:Egg Proteins / Q000235:genetics* / Q000276:immunology* / Q000494:pharmacology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009869:Oophoritis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D010053:Ovary / Q000276:immunology; D016884:Polyendocrinopathies, Autoimmune / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*
chemical_list: D000941:Antigens; D004527:Egg Proteins; D000949:Histocompatibility Antigens Class II; C416503:Nalp5 protein, mouse