Transglutaminase 4 as a prostate autoantigen in male subfertility

TGM4 is a male-specific autoantigen for prostatitis associated with autoimmune polyendocrine syndrome type 1. AIREing out autoimmunity Patients with autoimmune polyendocrine syndrome type 1(APS1) experience dysfunction in multiple endocrine glands due to mutations in the AIRE gene, which helps promote immune tolerance. These patients frequently are infertile; female infertility can be explained by autoimmune ovarian failure, but the causes of male infertility have remained unclear. Now, Landegren et al. report that the prostatic secretory molecule tranglutaminase 4 (TGM4) is a male-specific autoantigen in APS1 patients that could contribute to subfertility. They found autoantibodies to TGM4 in APS1 patients beginning at puberty, and confirmed in AIRE-deficient mice that TGM4 autoantibodies lead to a destructive prostatitis. These data could help explain infertility in male APS1 patients. Autoimmune polyendocrine syndrome type 1 (APS1), a monogenic disorder caused by AIRE gene mutations, features multiple autoimmune disease components. Infertility is common in both males and females with APS1. Although female infertility can be explained by autoimmune ovarian failure, the mechanisms underlying male infertility have remained poorly understood. We performed a proteome-wide autoantibody screen in APS1 patient sera to assess the autoimmune response against the male reproductive organs. By screening human protein arrays with male and female patient sera and by selecting for gender-imbalanced autoantibody signals, we identified transglutaminase 4 (TGM4) as a male-specific autoantigen. Notably, TGM4 is a prostatic secretory molecule with critical role in male reproduction. TGM4 autoantibodies were detected in most of the adult male APS1 patients but were absent in all the young males. Consecutive serum samples further revealed that TGM4 autoantibodies first presented during pubertal age and subsequent to prostate maturation. We assessed the animal model for APS1, the Aire-deficient mouse, and found spontaneous development of TGM4 autoantibodies specifically in males. Aire-deficient mice failed to present TGM4 in the thymus, consistent with a defect in central tolerance for TGM4. In the mouse, we further link TGM4 immunity with a destructive prostatitis and compromised secretion of TGM4. Collectively, our findings in APS1 patients and Aire-deficient mice reveal prostate autoimmunity as a major manifestation of APS1 with potential role in male subfertility.