The Role of AIRE Deficiency in Infertility and Its Potential Pathogenesis

Abstract

The increasing number of patients with infertility is recognized as an emerging problem worldwide. However, little is known about the cause of infertility. At present, it is believed that infertility may be related to genetic or abnormal immune responses. It has long been indicated that autoimmune regulator (AIRE), a transcription factor, participates in immune tolerance by regulating the expression of thousands of promiscuous tissue-specific antigens in medullary thymic epithelial cells (mTECs), which play a pivotal role in preventing autoimmune diseases. AIRE is also expressed in germ cell progenitors. Importantly, the deletion of AIRE leads to severe oophoritis and age-dependent depletion of follicular reserves and causes altered embryonic development in female mice. AIRE-deficient male mice exhibit altered apoptosis during spermatogenesis and have a significantly decreased breeding capacity. These reports suggest that AIRE deficiency may be responsible for infertility. The causes may be related to the production of autoantibodies against sperm, poor development of germ cells, and abnormal ovarian function, which eventually lead to infertility. Here, we focus on the potential associations of AIRE deficiency with infertility as well as the possible pathogenesis, providing insight into the significance of AIRE in the development of infertility.

Regulation of thymic T regulatory cell differentiation by TECs in health and disease

“…The reason may be related to the production of anti-sperm autoantibodies, dysplasia of germ cells and abnormal ovarian function, which ultimately leads to infertility. 121,122 Some articles have also suggested that infertility caused by a lack of AIRE is not related to developmental defects but is caused by autoimmune diseases. 122 AIRE was found to have no direct role in the degeneration of the uterine membranes.…”

“…This indicates that the lack of AIRE may be one of the causes of infertility. The reason may be related to the production of anti‐sperm autoantibodies, dysplasia of germ cells and abnormal ovarian function, which ultimately leads to infertility 121,122 . Some articles have also suggested that infertility caused by a lack of AIRE is not related to developmental defects but is caused by autoimmune diseases 122 .…”

Molecular mimicry between SARS‐CoV‐2 and the female reproductive system

“…Genetic and abnormal immune responses are often presented as factors that may lead to infertility. 3 Infertility resulting from the effect of autoantibodies (autoAbs) has been a matter of many debates. [4][5][6] Certain autoAbs such as anti-phospholipid, antithyroid (anti-thyroperoxidase and/or anti-thyroglobulin), anti-nuclear, anti-annexin V, anti-prothrombin, anti-laminin, anti-follicle stimulating hormone Abs have been associated with infertility, especially due to premature ovarian insufficiency, in addition to pregnancy loss.…”

Thymic and extrathymic Aire‐expressing cells in maternal‐fetal tolerance*

“…4,5 Indeed, infertility correlates with decreased regulatory T-cell frequency at the maternal-fetal interface in humans, [6][7][8][9] and a variety of autoimmune disorders target the ovary directly or secondarily. [10][11][12][13][14][15] Recently, elegant work has also shown that glycan-mediated B-cell immune suppression may also play a critical role in maintaining maternal-fetal tolerance. 16 Thus, tolerance of pregnancy by the maternal immune system requires a complex and overlapping series of active mechanisms, which begin before implantation and continue throughout and beyond pregnancy.…”