Autoimmune regulator deficiency causes sterile epididymitis and impacts male fertility through disruption of inorganic physiology

Autoimmune regulator (AIRE), a transcriptional regulator expressed by medullary thymic epithelial cells, is required for shaping the self-antigen tolerant T cell receptor repertoire. In humans, AIRE mutations caues autoimmune polyglandular syndrome type 1. Among other symptoms, men with autoimmune polyglandular syndrome type 1 commonly experience testicular insufficiency and infertility, but the mechanisms causing infertility are unknown. Using an Aire-deficient mouse model, we demonstrate that male subfertility is caused by sterile epididymitis characterized by immune cell infiltration and extensive fibrosis. In addition, we reveal that the presence of autoreactive immune cells and inflammation in epididymides of Aire-deficient mice are required for iron deposition in the interstitium, which is brought on by macrophages. We further demonstrate that male subfertility is associated with a decrease in metals zinc, copper, and selenium, which serve as cofactors in several antioxidant enzymes. We also show an increase in DNA damage of epididymal sperm of Aire-/- animals as a key contributing factor to subfertility. The absence of Aire results in autoimmune attack of the epididymis leading to fibrosis, iron deposition, and copper, zinc, and selenium imbalance, ultimately resulting in sperm DNA damage and subfertility. These results highlight the requirement of Aire to promote immune tolerance to the epididymis, and that its disruption causes an imbalance of inorganic elements with resulting consequence on male fertility.