Transglutaminase 4 as a prostate autoantigen in male subfertility

NILS LANDEGREN; DONALD SHARON; ANTHONY K. SHUM; IMRAN S. KHAN; KAYLA J. FASANO; ÅSA HALLGREN; CAROLINE KAMPF; EVA FREYHULT; BRITA ARDESJÖ-LUNDGREN; MOHAMMAD ALIMOHAMMADI; SANDRA RATHSMAN; JONAS F. LUDVIGSSON; DAN LUNDH; RUBEN MOTRICH; RIVERO VE; LAWRENCE FONG; ALEKSANDER GIWERCMAN; JAN GUSTAFSSON; JAAKKO PERHEENTUPA; EYSTEIN S. HUSEBYE; MARK S. ANDERSON; MICHAEL SNYDER; OLLE KÄMPE1

.ScienceTranslational Medicine

AAAS

Año: 2015 vol. 7 p. 292 - 301

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 maleinfertility have remained poorly understood. We performed a proteome-wide autoantibody screen in APS1 patientsera to assess the autoimmune response against the male reproductive organs. By screening human proteinarrays with male and female patient sera and by selecting for gender-imbalanced autoantibody signals, we identifiedtransglutaminase 4 (TGM4) as a male-specific autoantigen. Notably, TGM4 is a prostatic secretory molecule withcritical role in male reproduction. TGM4 autoantibodies were detected in most of the adult male APS1 patients butwere absent in all the young males. Consecutive serum samples further revealed that TGM4 autoantibodies firstpresented during pubertal age and subsequent to prostate maturation. We assessed the animal model for APS1, theAire-deficient mouse, and found spontaneous development of TGM4 autoantibodies specifically in males. Airedeficientmice failed to present TGM4 in the thymus, consistent with a defect in central tolerance for TGM4. Inthe 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 manifestationof APS1 with potential role in male subfertility