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Transglutaminase 4 as a prostate autoantigen in male subfertility
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
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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
2015. Vol. 7, no 292, 292ra101
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
URN: urn:nbn:se:uu:diva-258338DOI: 10.1126/scitranslmed.aaa9186ISI: 000356390500008PubMedID: 26084804OAI: oai:DiVA.org:uu-258338DiVA: diva2:841606
Swedish Research CouncilSwedish Research Council Formas
Available from: 2015-07-14 Created: 2015-07-13 Last updated: 2016-01-13Bibliographically approved
In thesis
1. Biomarker Discovery in Tissue-specific Autoimmune Disease
Open this publication in new window or tab >>Biomarker Discovery in Tissue-specific Autoimmune Disease
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Autoimmune diseases encompass a diverse group of disorders that collectively affect 5% of the population. Despite large clinical variability, autoimmune disorders share a common etiology in that they all develop from immune responses against self. T-cell receptors and antibodies recognize distinct self-molecules and direct destructive effector mechanisms to the target organs. Characterization of autoimmune targets can help in the understanding autoimmune disease features and is of additional importance for subsequent use in clinical diagnosis.

Rare monogenic disorder can provide an access to the study and understanding of mechanisms underlying common and more complex diseases. Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder caused by mutations in the AIRE gene, and is a valuable model of tissue-specific autoimmune disease. APS1 patients develop multiple autoimmune disease manifestations and display autoantibodies against the affected tissues.

Recent development in protein array technology has opened a novel avenue for explorative biomarker studies in autoimmune disorders. Present-day protein arrays contain many thousands of full-length human proteins and enable autoantibody screens at the proteome-scale.

In the current work I have utilized proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Survey of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of 9000 proteins we further identified three novel, major autoantigens. Our findings revealed a marked enrichment for tissue-specific immune targets and further suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1. This work identifies prostatic transglutaminase 4 as novel male-specific autoantigen. In the mouse model of APS1 we could link TGM4 immunity with a tissue-destructive prostatitis, a compromised prostatic secretion of TGM4 and with defect in the establishment of central immune tolerance for TGM4. Our findings suggest prostate autoimmunity is a major manifestation in male APS1 patients with potential role in development of subfertility. In this doctoral work we also report on collecting duct autoantibodies in APS1 patients with interstitial nephritis and on the identification of aquaporin 2 as a collecting duct autoantigen. Collectively, the present investigations provide an overview-perspective on the autoimmune target repertoire in APS1 and identify novel autoimmune manifestations of the syndrome.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 56 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1153
National Category
Basic Medicine
urn:nbn:se:uu:diva-265284 (URN)978-91-554-9391-2 (ISBN)
Public defence
2015-12-17, Enghoffsalen, Ing. 50, UAS, Uppsala, 09:15 (Swedish)
Available from: 2015-11-26 Created: 2015-10-26 Last updated: 2016-02-09

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Landegren, NilsHallgren, ÅsaKampf, CarolineFreyhult, EvaAlimohammadi, MohammadGustafsson, JanKämpe, Olle
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