title: Transglutaminase 4 as a prostate autoantigen in male subfertility.
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.
authors.affiliation: 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.
authors.forename: Nils
authors.initials: N
authors.lastname: Landegren
authors.affiliation: Department of Genetics, Stanford University, Stanford 94305, CA, USA. Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Sharon
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Shum
authors.affiliation: Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Imran S
authors.initials: IS
authors.lastname: Khan
authors.affiliation: Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Kayla J
authors.initials: KJ
authors.lastname: Fasano
authors.affiliation: 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.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Hallgren
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala SE 751 85, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kampf
authors.affiliation: 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.
authors.forename: Eva
authors.initials: E
authors.lastname: Freyhult
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala SE 750 07, Sweden.
authors.forename: Brita
authors.initials: B
authors.lastname: Ardesjö-Lundgren
authors.affiliation: 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.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alimohammadi
authors.affiliation: Department of Laboratory Medicine/Microbiology, Örebro University Hospital, Örebro SE 701 85, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rathsman
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE 171 76, Sweden.
authors.forename: Jonas F
authors.initials: JF
authors.lastname: Ludvigsson
authors.affiliation: School of Bioscience, University of Skövde, Skövde SE 541 28, Sweden.
authors.forename: Dan
authors.initials: D
authors.lastname: Lundh
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina.
authors.forename: Ruben
authors.initials: R
authors.lastname: Motrich
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina.
authors.forename: Virginia
authors.initials: V
authors.lastname: Rivero
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
authors.affiliation: Molecular Reproduction Research, Department of Clinical Sciences Malmö, Lund University, Malmö SE 205 02, Sweden.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Giwercman
authors.affiliation: Department of Women's and Children's Health, Uppsala University, Uppsala SE 751 85, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Gustafsson
authors.affiliation: The Hospital for Children and Adolescents, University of Helsinki, Helsinki 00029, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Perheentupa
authors.affiliation: Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital, Bergen 5020, Norway.
authors.forename: Eystein S
authors.initials: ES
authors.lastname: Husebye
authors.affiliation: Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
authors.affiliation: Department of Genetics, Stanford University, Stanford 94305, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: 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.
authors.forename: Olle
authors.initials: O
authors.lastname: Kämpe
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D006801:Humans; D007248:Infertility, Male / Q000201:enzymology* / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D016884:Polyendocrinopathies, Autoimmune / Q000201:enzymology / Q000276:immunology; D011467:Prostate / Q000201:enzymology*; D011472:Prostatitis / Q000473:pathology; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D011627:Puberty; D013950:Thymus Gland / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism*; D000096927:AIRE Protein
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D020543:Proteome; D014157:Transcription Factors; D011503:Transglutaminases; D000096927:AIRE Protein; C418702:transglutaminase 4