The Autoimmune Regulator Prevents Premature Reproductive Senescence in Female Mice1

Abstract

Loss-of-function mutations in the autoimmune regulator (AIRE) gene are responsible for autoimmune polyglandular syndrome type 1 (APS-1), which commonly manifests as infertility in women. AIRE is a transcriptional regulator that promotes expression of tissue-restricted antigens in the thymus, including antigens specific to the ovary. Thymic expression of ovarian genes under AIRE's control may be critical for preventing ovarian autoimmune disease. Because mice lacking Aire are an important APS-1 model, we examined the reproductive properties of female Aire-deficient (Aire(-/-)) mice. Female Aire(-/-) mice on the BALB/c background were examined for reproductive parameters, including fertility, litter sizes, and ovarian follicular reserves. Although delayed puberty was observed in Aire(-/-) mice, all mice entered puberty and exhibited mating behavior. Only 50% of Aire(-/-) females gave an initial litter, and only 16% were able to produce two litters. Ovarian histopathologic examination revealed that 83% of previously bred females lost all ovarian follicular reserves. Among virgin females, follicular depletion was observed in 25% by 8 wk, and by 20 wk, 50%-60% of mice lost all follicles. This was associated with elevated serum follicle-stimulating hormone level and ovarian infiltration of proliferating CD3+ T lymphocytes. Ovulation rates of 6-wk-old Aire(-/-) mice were reduced by 22%, but this difference was not statistically significant. Finally, transplantation experiments revealed that follicular loss depended on factors extrinsic to the ovary. These results suggest that immune-mediated ovarian follicular depletion is a mechanism of infertility in Aire(-/-) mice. The results have important implications in the pathogenesis of ovarian autoimmune disease in women.

Genetic associations with diminished ovarian reserve: a systematic review of the literature

“…One of the known genetic causes of POI, a mutation in the FMR1 gene, has been implicated as a potential cause of DOR. Additionally, many known genetic causes of POI [10] have been implicated as being associated with DOR in mice, including autoimmune regulator gene (Aire) [23], forkhead transcription factor forkhead protein (Foxl2) [24], growth differentiation factor 9 (Gdf9) [25], and bone morphogenetic protein 15 (Bmp15) [26,27]. Here, we focused on DOR to examine the strength of evidence for the association.…”

“…AIRE gene mutations in humans are responsible for Autoimmune Polyglandular Syndrome type 1 (APS-1), which manifests as chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency, and other autoimmune processes including infertility [23]. AIRE is a glycoprotein produced in the medullary thymus where it promotes the expression of tissue-restricted antigens to develop central tolerance, or immunologic tolerance to self.…”

“…Failure to do so permits autoreactive T cells to escape into the peripheral system, which can manifest as an autoimmune disease. Jasti et al [23] studied the reproductive lifespan of Aire knockout mice. Delayed onset of puberty was observed in Aire knockout mice when compared to wild type mice (p=0.0009).…”

“…Next, Jasti et al [23] analyzed the sera of the mice for autoimmune antibodies, specifically anti-ovarian antibodies (AOA). Eighty-three percent of AIRE-deficient mice had positive a AOA, whereas none of the wild type mice displayed positive antibodies.…”

“…Interestingly, wild type ovaries were reimplanted subrenally into knockout mice which resulted in 4/6 mice undergoing complete follicular depletion and lymphocytic infiltration. Jasti et al [23] concluded that infertility and subfertility could be caused by mutations in the Aire gene. These results suggest that the reduced fertility of the mice was due in part to an immunemediated follicular decline supported by the positive autoimmune antibodies and T cell infiltration in transplanted wild type ovaries into Aire knockout mice.…”