Open this publication in new window or tab >>Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA..
Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, SE-17176 Stockholm, Sweden.;Uppsala Univ, Dept Med Sci, Sci Life Lab, SE-75185 Uppsala, Sweden..
Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
Uppsala Univ, Canc Pharmacol & Computat Med, Dept Med Sci Bioinformat Infrastruct Life Sci, Sci Life Lab, SE-75185 Uppsala, Sweden..
Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, SE-17176 Stockholm, Sweden.;Uppsala Univ, Dept Med Sci, Sci Life Lab, SE-75185 Uppsala, Sweden.;Uppsala Univ, Dept Med Sci, SE-75185 Uppsala, Sweden..
Univ Orebro, Dept Lab Med Microbiol, SE-70185 Orebro, Sweden..
Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17176 Stockholm, Sweden..
School of Bioscience, University of Skövde, Skövde, Sweden.
Univ Nacl Cordoba, Fac Ciencias Quim, Dept Bioquim Clin, Ctr Invest Bioquim Clin & Inmunol, RA-5000 Cordoba, Argentina..
Univ Nacl Cordoba, Fac Ciencias Quim, Dept Bioquim Clin, Ctr Invest Bioquim Clin & Inmunol, RA-5000 Cordoba, Argentina..
Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94115 USA..
Lund Univ, Mol Reprod Res, Dept Clin Sci Malmo, SE-20502 Malmo, Sweden..
Uppsala Univ, Dept Womens & Childrens Hlth, SE-75185 Uppsala, Sweden..
Univ Helsinki, Hosp Children & Adolescents, Helsinki 00029, Finland..
Univ Bergen, Dept Clin Sci, N-5020 Bergen, Norway.;Haukeland Hosp, Dept Med, N-5020 Bergen, Norway..
Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA..
Stanford Univ, Dept Genet, Stanford, CA 94305 USA..
Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, SE-17176 Stockholm, Sweden.;Uppsala Univ, Dept Med Sci, Sci Life Lab, SE-75185 Uppsala, Sweden..
Show others...
2015 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, no 292, article id 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
National Category
Cell Biology
Identifiers
urn:nbn:se:hj:diva-45749 (URN)10.1126/scitranslmed.aaa9186 (DOI)000356390500008 ()26084804 (PubMedID)2-s2.0-84931466170 (Scopus ID)
2019-08-292019-08-292019-08-29Bibliographically approved