title: Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Patients.
abstract: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autoimmune disease caused by mutations in the AIRE gene. Although mainly an endocrine disease, a substantial fraction of patients have gastrointestinal manifestations. In this study, we have examined the role of anticommensal responses and their regulation. APECED patients had increased levels of Abs against Saccharomyces cerevisiae (p < 0.0001) and against several species of commensal gut bacteria, but not against species predominantly associated with other locations. The anticommensal Ab levels did not correlate with gastrointestinal autoantibodies, neutralizing anti-IL-17 or -IL-22 Abs, or gastrointestinal symptoms, although scarcity of the available clinical data suggests that further study is required. However, the anti-S. cerevisiae Ab levels showed a significant inverse correlation with FOXP3 expression levels in regulatory T cells (Treg), previously shown to be dysfunctional in APECED. The correlation was strongest in the activated CD45RO(+) population (ρ = -0.706; p < 0.01). APECED patients also had decreased numbers of FOXP3(+) cells in gut biopsies. These results show that APECED patients develop early and sustained responses to gut microbial Ags in a pattern reminiscent of Crohn's disease. This abnormal immune recognition of gut commensals is linked to a systemic Treg defect, which is also reflected as a local decrease of gut-associated Treg. To our knowledge, these data are the first to show dysregulated responses to non-self commensal Ags in APECED and indicate that AIRE contributes to the regulation of gut homeostasis, at least indirectly. The data also raise the possibility of persistent microbial stimulation as a contributing factor in the pathogenesis of APECED.
authors.affiliation: Department of Bacteriology and Immunology, University of Helsinki, 00290 Helsinki, Finland; Research Programs Unit, Immunobiology Research Program, University of Helsinki, 00014 Helsinki, Finland; iivo.hetemaki@helsinki.fi.
authors.forename: Iivo
authors.initials: I
authors.lastname: Hetemäki
authors.affiliation: Department of Bacteriology and Immunology, University of Helsinki, 00290 Helsinki, Finland; Research Programs Unit, Immunobiology Research Program, University of Helsinki, 00014 Helsinki, Finland; HUSLAB, Helsinki University Central Hospital, 00029 Helsinki, Finland;
authors.forename: Hanna
authors.initials: H
authors.lastname: Jarva
authors.affiliation: Department of Skin and Allergic Diseases, Skin and Allergy Hospital, Helsinki University Central Hospital, 00250 Helsinki, Finland;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kluger
authors.affiliation: Department of Bacteriology and Immunology, University of Helsinki, 00290 Helsinki, Finland;
authors.forename: Hanna-Mari
authors.identifier: http://orcid.org/0000-0003-0589-697X
authors.initials: HM
authors.lastname: Baldauf
authors.affiliation: Department of Bacteriology and Immunology, University of Helsinki, 00290 Helsinki, Finland;
authors.forename: Sini
authors.identifier: http://orcid.org/0000-0002-0104-2849
authors.initials: S
authors.lastname: Laakso
authors.affiliation: Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway; and.
authors.forename: Eirik
authors.identifier: http://orcid.org/0000-0002-8359-9818
authors.initials: E
authors.lastname: Bratland
authors.affiliation: Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway; and.
authors.forename: Eystein S
authors.initials: ES
authors.lastname: Husebye
authors.affiliation: Institute of General and Molecular Pathology, University of Tartu, Tartu 50411, Estonia.
authors.forename: Kai
authors.initials: K
authors.lastname: Kisand
authors.affiliation: Department of Skin and Allergic Diseases, Skin and Allergy Hospital, Helsinki University Central Hospital, 00250 Helsinki, Finland;
authors.forename: Annamari
authors.initials: A
authors.lastname: Ranki
authors.affiliation: Institute of General and Molecular Pathology, University of Tartu, Tartu 50411, Estonia.
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
authors.affiliation: Department of Bacteriology and Immunology, University of Helsinki, 00290 Helsinki, Finland; Research Programs Unit, Immunobiology Research Program, University of Helsinki, 00014 Helsinki, Finland;
authors.forename: T Petteri
authors.initials: TP
authors.lastname: Arstila
mesh_terms: D000328:Adult; D000368:Aged; D000908:Antibodies, Fungal / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity; D016022:Case-Control Studies; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004386:Duodenum / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000908:Antibodies, Fungal; D001323:Autoantibodies; D016207:Cytokines; D007074:Immunoglobulin G