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Sci Transl Med. 2015 Jun 17;7(292):292ra101. doi: 10.1126/scitranslmed.aaa9186.

Transglutaminase 4 as a prostate autoantigen in male subfertility.

Author information

1
Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet, Stockholm SE 171 76, Sweden. Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala SE 751 85, Sweden. nils.landegren@ki.se.
2
Department of Genetics, Stanford University, Stanford 94305, CA, USA. Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
3
Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
4
Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
5
Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet, Stockholm SE 171 76, Sweden. Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala SE 751 85, Sweden.
6
Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala SE 751 85, Sweden.
7
Cancer Pharmacology and Computational Medicine, Department of Medical Sciences, Bioinformatics Infrastructure for Life Sciences, Science for Life Laboratory, Uppsala University, Uppsala SE 751 85, Sweden.
8
Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala SE 750 07, Sweden.
9
Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet, Stockholm SE 171 76, Sweden. Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala SE 751 85, Sweden. Department of Medical Sciences, Uppsala University, Uppsala SE 751 85, Sweden.
10
Department of Laboratory Medicine/Microbiology, Örebro University Hospital, Örebro SE 701 85, Sweden.
11
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE 171 76, Sweden.
12
School of Bioscience, University of Skövde, Skövde SE 541 28, Sweden.
13
Centro de Investigaciones en Bioquímica Clínica e Inmunología, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina.
14
University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USA.
15
Molecular Reproduction Research, Department of Clinical Sciences Malmö, Lund University, Malmö SE 205 02, Sweden.
16
Department of Women's and Children's Health, Uppsala University, Uppsala SE 751 85, Sweden.
17
The Hospital for Children and Adolescents, University of Helsinki, Helsinki 00029, Finland.
18
Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital, Bergen 5020, Norway.
19
Department of Genetics, Stanford University, Stanford 94305, CA, USA.

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.

PMID:
26084804
DOI:
10.1126/scitranslmed.aaa9186
[Indexed for MEDLINE]

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