title: Gastrointestinal Autoimmunity Associated With Loss of Central Tolerance to Enteric α-Defensins.
abstract: OBJECTIVE
  Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autoimmune disorder characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency, but patients also develop intestinal disorders. APECED is an autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE, which regulates immune tolerance) that allow self-reactive T cells to enter the periphery. Enteric α-defensins are antimicrobial peptides secreted by Paneth cells. Patients with APECED frequently have gastrointestinal symptoms and seroreactivity against secretory granules of Paneth cells. We investigated whether enteric α-defensins are autoantigens in humans and mice with AIRE deficiency.
  
  
  METHODS
  We analyzed clinical data, along with serum and stool samples and available duodenal biopsies from 50 patients with APECED collected from multiple centers in Europe. Samples were assessed for expression of defensins and other molecules by quantitative reverse transcription polymerase chain reaction and flow cytometry; levels of antibodies and other proteins were measured by immunohistochemical and immunoblot analyses. Histologic analyses were performed on biopsy samples. We used Aire(-/-) mice as a model of APECED, and studied the effects of transferring immune cells from these mice to athymic mice.
  
  
  RESULTS
  Enteric defensins were detected in extraintestinal tissues of patients with APECED, especially in medullary thymic epithelial cells. Some patients with APECED lacked Paneth cells and were seropositive for defensin-specific autoantibodies; the presence of autoantibodies correlated with frequent diarrhea. Aire(-/-) mice developed defensin-specific T cells. Adoptive transfer of these T cells to athymic mice resulted in T-cell infiltration of the gut, loss of Paneth cells, microbial dysbiosis, and the induction of T-helper 17 cell-mediated autoimmune responses resembling those observed in patients with APECED.
  
  
  CONCLUSIONS
  In patients with APECED, loss of AIRE appears to cause an autoimmune response against enteric defensins and loss of Paneth cells. Aire(-/-) mice developed defensin-specific T cells that cause intestinal defects similar to those observed in patients with APECED. These findings provide a mechanism by which loss of AIRE-mediated immune tolerance leads to intestinal disorders in patients with APECED.
authors.affiliation: Laboratory of Immunobiology, Institute of Molecular Genetics of the AS CR, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Dobeš
authors.affiliation: Laboratory of Immunobiology, Institute of Molecular Genetics of the AS CR, Prague, Czech Republic.
authors.forename: Aleš
authors.initials: A
authors.lastname: Neuwirth
authors.affiliation: Laboratory of Immunobiology, Institute of Molecular Genetics of the AS CR, Prague, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Dobešová
authors.affiliation: Laboratory of Immunobiology, Institute of Molecular Genetics of the AS CR, Prague, Czech Republic.
authors.forename: Matouš
authors.initials: M
authors.lastname: Vobořil
authors.affiliation: Laboratory of Immunobiology, Institute of Molecular Genetics of the AS CR, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Balounová
authors.affiliation: Laboratory of Immunobiology, Institute of Molecular Genetics of the AS CR, Prague, Czech Republic.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Ballek
authors.affiliation: Department of Pediatrics, 2(nd) Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Lebl
authors.affiliation: Pediatric Clinic II, Ospedale Microcitemico and Department of Biomedical and Biotechnological Science, University of Cagliari, Cagliari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Meloni
authors.affiliation: Clinical Research Institute HUCH, Helsinki, Finland; Department of Dermatology and Allergology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Kai
authors.initials: K
authors.lastname: Krohn
authors.affiliation: Department of Dermatology and Allergology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kluger
authors.affiliation: Department of Dermatology and Allergology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Annamari
authors.initials: A
authors.lastname: Ranki
authors.affiliation: Laboratory of Immunobiology, Institute of Molecular Genetics of the AS CR, Prague, Czech Republic. Electronic address: dominik.filipp@img.cas.cz.
authors.forename: Dominik
authors.initials: D
authors.lastname: Filipp
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015551:Autoimmunity; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007422:Intestines / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D016884:Polyendocrinopathies, Autoimmune / Q000150:complications / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult; D023084:alpha-Defensins / Q000276:immunology*; D000096927:AIRE Protein
chemical_list: D014157:Transcription Factors; D023084:alpha-Defensins; D000096927:AIRE Protein
keywords: DEFA; Intestinal Crypt; Microbiota; Mouse Model