title: Lymphopenia-induced proliferation in the absence of functional Autoimmune regulator (Aire) induces colitis in mice.
abstract: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in Autoimmune regulator (Aire), a transcriptional regulator of negative selection in thymus. However, Aire is also expressed in periphery, but the full range of Aire's peripheral function is unknown. Here, we transferred lymphocytes from wildtype donors into lymphopenic recipients with or without functional Aire. Following cell proliferation thus took place in Aire-sufficient or deficient environment. The wildtype lymphocytes hyperproliferated and induced disease in lymphopenic Aire(-/-) but not in Aire(+/+) recipients. The disease was characterized by diarrhea, inflammation, and colitis, and in some recipients pancreatitis, gastritis, and hepatitis was also found. Our results identify Aire as an important regulator of peripheral T cell homeostasis in gastrointestinal tissues. Given a suitable trigger the absence of peripheral Aire leads to dysregulated T cell proliferation and disease.
authors.affiliation: Haartman Institute, Department of Bacteriology and Immunology, Immunobiology Research Program, University of Helsinki, PB 21, Helsinki 00014, Finland. Electronic address: eliisa.kekalainen@helsinki.fi.
authors.forename: Eliisa
authors.initials: E
authors.lastname: Kekäläinen
authors.affiliation: Haartman Institute, Department of Bacteriology and Immunology, Immunobiology Research Program, University of Helsinki, PB 21, Helsinki 00014, Finland.
authors.forename: Maija-Katri
authors.initials: MK
authors.lastname: Lehto
authors.affiliation: Haartman Institute, Department of Bacteriology and Immunology, Immunobiology Research Program, University of Helsinki, PB 21, Helsinki 00014, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Smeds
authors.affiliation: National Institute for Health and Welfare, Department of Molecular Medicine, Biomedicum, Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
authors.forename: Nora
authors.initials: N
authors.lastname: Pöntynen
authors.affiliation: Haartman Institute, Department of Bacteriology and Immunology, Immunobiology Research Program, University of Helsinki, PB 21, Helsinki 00014, Finland.
authors.forename: Pirkka T
authors.initials: PT
authors.lastname: Pekkarinen
authors.affiliation: National Institute for Health and Welfare, Department of Molecular Medicine, Biomedicum, Helsinki, Finland.
authors.forename: Ismo
authors.initials: I
authors.lastname: Ulmanen
authors.affiliation: HUSLAB Helsinki Central Hospital Laboratory, Division of Clinical Microbiology, Haartmaninkatu 3, 00290 Helsinki, Finland.
authors.forename: Aaro
authors.initials: A
authors.lastname: Miettinen
authors.affiliation: Haartman Institute, Department of Bacteriology and Immunology, Immunobiology Research Program, University of Helsinki, PB 21, Helsinki 00014, Finland.
authors.forename: T Petteri
authors.initials: TP
authors.lastname: Arstila
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015415:Biomarkers; D003092:Colitis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003967:Diarrhea / Q000209:etiology; D004195:Disease Models, Animal; D005260:Female; D016654:Genes, RAG-1; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008231:Lymphopenia / Q000150:complications*; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D000096927:AIRE Protein
chemical_list: D015415:Biomarkers; D014157:Transcription Factors; D000096927:AIRE Protein
keywords: APECED; APS-1; Colitis; Homeostatic proliferation; Intestinal immunity; Tolerance