Skip to Content
Merck

Transglutaminase 4 as a prostate autoantigen in male subfertility.

Science translational medicine (2015-06-19)
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, Virginia Rivero, Lawrence Fong, Aleksander Giwercman, Jan Gustafsson, Jaakko Perheentupa, Eystein S Husebye, Mark S Anderson, Michael Snyder, Olle Kämpe
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ethanol, JIS special grade, 94.8-95.8%
Sigma-Aldrich
Duolink® In Situ PLA® Probe Anti-Goat PLUS
Sigma-Aldrich
L-Thyroxine sodium salt pentahydrate, ≥98% (HPLC), powder
Sigma-Aldrich
L-Thyroxine sodium salt pentahydrate, γ-irradiated, powder, BioXtra, suitable for cell culture
Sigma-Aldrich
Ethanol Fixative 80% v/v, suitable for fixing solution (blood films)
Sigma-Aldrich
Ethanol, JIS first grade, 94.8-95.8%
Sigma-Aldrich
Ethanol, ≥99.5%, suitable for HPLC
Sigma-Aldrich
Ethanol, ≥99.5%, SAJ super special grade
Sigma-Aldrich
Ethanol, ≥99.5%, suitable for absorption spectrum analysis
Sigma-Aldrich
Ethanol, JIS 300, ≥99.5%, for residue analysis
Sigma-Aldrich
Anti-TGM4 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Ethanol, JIS 1000, ≥99.5%, for residue analysis
Sigma-Aldrich
Ethyl alcohol, Pure, 200 proof, anhydrous, ≥99.5%
Sigma-Aldrich
Ethyl alcohol, Pure, 190 proof, ACS spectrophotometric grade, 95.0%
Sigma-Aldrich
Ethyl alcohol, Pure, 190 proof, meets USP testing specifications
Sigma-Aldrich
Hematoxylin
Sigma-Aldrich
Hematoxylin, certified by the Biological Stain Commission
Supelco
Ethanol standards 10% (v/v), 10 % (v/v) in H2O, analytical standard
Sigma-Aldrich
DAPI, for nucleic acid staining
Sigma-Aldrich
Ethanol, ≥99.5%
Sigma-Aldrich
Ethanol, ≥99.5%, suitable for fluorescence