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Transglutaminase 4 as a prostate autoantigen in male subfertility
Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden / Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Department of Genetics, Stanford University, CA, USA / Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
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2015 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, no 292, 292ra101Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Association for the Advancement of Science , 2015. Vol. 7, no 292, 292ra101
Keyword [en]
Transglutaminase, prostate autoantigen, male subfertility
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Medical sciences
Identifiers
URN: urn:nbn:se:his:diva-11315DOI: 10.1126/scitranslmed.aaa9186ISI: 000356390500008PubMedID: 26084804Scopus ID: 2-s2.0-84931466170OAI: oai:DiVA.org:his-11315DiVA: diva2:843999
Available from: 2015-08-03 Created: 2015-08-03 Last updated: 2016-07-01Bibliographically approved

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