The Autoimmune Regulator (AIRE) preserves fertility in male and female Balb/c mice

The Autoimmune Regulator (AIRE) contributes to central immune tolerance through the induction of self-antigen expression within the thymus. In humans, a defect in AIRE results in a multi-organ autoimmune disorder known as Autoimmune Polyglandular Syndrome Type-1. Both humans and mice with a deficiency in this gene develop autoreactive CD4+ T cells, serum autoantibodies and elevated rates of infertility. Interestingly, the pathology of autoimmune infertility in Aire-deficient (Aire-KO) mice differs between males and females. Ovarian autoimmunity causing a depletion of follicular reserves is prominent in female Aire-KO mice over 10 weeks of age. However, 50% of mated six-week old female Aire -KO mice demonstrate embryo loss by embryonic day (ED) 7.5 despite having normal follicular reserves. We determined that ovulation (90% KO vs 100% WT; n=11), mating frequency (99% KO vs 100% WT; n>58), progesterone production (p=0.232; n=4) and decidualization are unaffected. However, 60% (9 of 15) of 6-8 week old Aire-KO female mice generated serum autoantibodies against the ovary and more frequently ovulated degenerated oocytes (31% KO vs 2% WT; n>71) When cultured, one-cell embryos from Aire-KO females failed to become 2-cell and blastocyst stage embryos at significantly reduced rate compared to WT controls (47% KO vs 76% WT and 19% KO vs 60% WT; n>67). Finally, embryos from Aire-KO dams are developmentally delayed at ED3.5 with a reduced trophectoderm outgrowth potential after 48 and 96 hours of culture (0mm2 KO vs 7.1 mm2 WT, and 16.5 mm2 KO vs 30.9 mm2 WT; p<0.001, n=4). Alternatively, male Aire-KO mice have greater variability in the autoimmune targets associated with reduced fertility (18% KO vs 80% WT; n=10). Signs of disease included reduced testosterone (p=0.03; n=18), loss of vomeronasal organ-associated glands (86% KO vs 0% WT; n=7), prostatitis (90% KO vs 0% WT; n=20), epididymitis (75% KO vs 0% WT; n=20) and reduced in vitro fertilization rates (9% KO vs 54% WT; n>83 oocytes). Additionally a subset of males (23%; n=22) exhibited oligozoospermia with disruption of the blood-testis barrier. Collectively these results demonstrate the importance of central immune tolerance on fertility preservation by preventing autoimmune disease against the male and female reproductive systems.