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Transglutaminase 4 as a prostate autoantigen in male subfertility.

Landegren, Nils; Sharon, Donald; Shum, Anthony K; Khan, Imran S; Fasano, Kayla J; Hallgren, Åsa; Kampf, Caroline; Freyhult, Eva; Ardesjö-Lundgren, Brita and Alimohammadi, Mohammad, et al. (2015) In Science Translational Medicine 7(292). p.101-292
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... (More)
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. (Less)
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Science Translational Medicine
volume
7
issue
292
pages
101 - 292
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:26084804
  • wos:000356390500008
  • scopus:84931466170
ISSN
1946-6242
DOI
10.1126/scitranslmed.aaa9186
language
English
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yes
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40051bac-c7e7-47ea-9a36-b87edf4a4ea2 (old id 7485067)
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http://www.ncbi.nlm.nih.gov/pubmed/26084804?dopt=Abstract
date added to LUP
2015-07-08 18:53:53
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2017-11-12 03:03:32
@article{40051bac-c7e7-47ea-9a36-b87edf4a4ea2,
  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.},
  author       = {Landegren, Nils and Sharon, Donald and Shum, Anthony K and Khan, Imran S and Fasano, Kayla J and Hallgren, Åsa and Kampf, Caroline and Freyhult, Eva and Ardesjö-Lundgren, Brita and Alimohammadi, Mohammad and Rathsman, Sandra and Ludvigsson, Jonas F and Lundh, Dan and Motrich, Ruben and Rivero, Virginia and Fong, Lawrence and Giwercman, Aleksander and Gustafsson, Jan and Perheentupa, Jaakko and Husebye, Eystein S and Anderson, Mark S and Snyder, Michael and Kämpe, Olle},
  issn         = {1946-6242},
  language     = {eng},
  number       = {292},
  pages        = {101--292},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Translational Medicine},
  title        = {Transglutaminase 4 as a prostate autoantigen in male subfertility.},
  url          = {http://dx.doi.org/10.1126/scitranslmed.aaa9186},
  volume       = {7},
  year         = {2015},
}