Transglutaminase 4 as a prostate autoantigen in male subfertility

Abstract

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.

Autoimmune Polyendocrine Syndromes

“…Many are fairly specific to APS-1, for example NLRP5 (also termed NALP5, an autoantibody expressed in the parathyroid and to some extent in the ovaries), 23 BPI Fold Containing Family B Member 1 (BPIFB1) 24 , the potassium channel regulator KCNRG, 25 expressed in the lung, and transglutaminase-4, expressed solely in the prostate gland. 26 Other autoantibodies observed in APS-1 also appear in more common autoimmune diseases, for example, those targeting glutamic acid decarboxylase-65 in type 1 diabetes, 27 21-hydroxylase in Addison’s disease, 28 and side-chain cleavage enzyme in autoimmune premature ovarian insufficiency 29 pointing to possible commonality in the pathogenesis of these various entities.…”

The prostate-specific protein, transglutaminase 4 (TG4), is an autoantigen associated with male subfertility

“…The male Airedeficient mouse, which is subfertile, exhibits normal testis anatomy and histology, yet the prostate gland is a major target of autoimmune destruction (6). The causes of male infertility have remained unclear until the recent work of Landegren et al published in Science Translational Medicine (7), which reports that the prostate-specific secretory protein transglutaminase 4 (TG4), is a malespecific autoantigen in APS1 patients that could contribute to subfertility.…”

“…Male Aire-deficient mice displayed prostatitis characterized by increased mRNA expression of markers of T helper 1 (Th1) cells (7), which is consistent with Th1 cells being the major contributors to autoimmune pathology in these mice (9). Landegren et al (7) detected Tgm4 mRNA expression in pooled mTECs from wild-type but not Aire-deficient mice, indicating Aire-dependent thymic expression of TG4. This links the lack of tolerance for TG4 in the prostate gland of Aire-deficient mice to its consequent autoimmune destruction.…”

“…What is the effect of TG4 and/or the TG4 enzyme-substrate reaction on male fertility in terms of effects on sperm activity or antigenicity in the female reproductive tract, oocyte fertilization, or post-fertilization events such as implantation? Clearly, there is much yet to be learned about the functional role of TG4 and its substrates in male reproductive physiology and the study by Landegren et al (7) has pointed us in fruitful directions for future research.…”

“…To identify male-specific autoantibodies against antigens specific to male reproductive organs, Landegren et al (7) screened human protein arrays with sera from male and female APS1 patients from Finland, Norway and Sweden, and sex-matched healthy control subjects. Their screen identified one significant target, TG4, which is expressed specifically in the prostate epithelium.…”