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: Noriyuki Otsuka, Zhi-Bin Tong, Konstantina Vanevski, Wei Tu, Mickie H Cheng, Lawrence M Nelson
• Journal: Endocrinology (Endocrinology) Vol. 152 Issue 6 Pg. 2465-73 (Jun 2011) ISSN: 1945-7170 [Electronic] United States
• PMID: 21447630 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Antigens
• Egg Proteins
• Histocompatibility Antigens Class II
• Nalp5 protein, mouse

Topics

• Animals
• Antigens (genetics, immunology, pharmacology)
• Disease Models, Animal
• Egg Proteins (genetics, immunology, pharmacology)
• Female
• Histocompatibility Antigens Class II (genetics, immunology)
• Humans
• Immune Tolerance
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Oophoritis (drug therapy, genetics, immunology)
• Ovary (immunology)
• Polyendocrinopathies, Autoimmune (drug therapy, genetics, immunology)