Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Patients

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Hetemaki , I , Jarva , H , Kluger , N , Baldauf , H-M , Laakso , S , Bratland , E , Husebye , E S , Kisand , K , Ranki , A , Peterson , P & Arstila , T P 2016 , ' Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Patients ' , Journal of Immunology , vol. 196 , no. 7 , pp. 2955-2964 . https://doi.org/10.4049/jimmunol.1500301

Title: Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Patients
Author: Hetemaki, Iivo; Jarva, Hanna; Kluger, Nicolas; Baldauf, Hanna-Mari; Laakso, Sini; Bratland, Eirik; Husebye, Eystein S.; Kisand, Kai; Ranki, Annamari; Peterson, Part; Arstila, T. Petteri
Other contributor: University of Helsinki, Research Programs Unit
University of Helsinki, Medicum
University of Helsinki, Department of Dermatology, Allergology and Venereology
University of Helsinki, Department of Bacteriology and Immunology
University of Helsinki, Research Programs Unit
University of Helsinki, Clinicum
University of Helsinki, Medicum






Date: 2016-04-01
Language: eng
Number of pages: 10
Belongs to series: Journal of Immunology
ISSN: 0022-1767
DOI: https://doi.org/10.4049/jimmunol.1500301
URI: http://hdl.handle.net/10138/223925
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 (rho = 20.706; 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.
Subject: SYNDROME TYPE-I
INFLAMMATORY-BOWEL-DISEASE
CHRONIC MUCOCUTANEOUS CANDIDIASIS
CROHNS-DISEASE
APECED SYNDROME
DENDRITIC CELLS
IPEX SYNDROME
AUTOANTIBODIES
AIRE
ANTIBODIES
3111 Biomedicine
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