title: Th1/Th17 plasticity is a marker of advanced β cell autoimmunity and impaired glucose tolerance in humans.
abstract: Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late stage of preclinical diabetes in children with β cell autoimmunity and impaired glucose tolerance, but not in children with early β cell autoimmunity. We found an increased ratio of IFN-γ/IL-17 expression in Th17 cells in children with advanced β cell autoimmunity, which correlated with HbA1c and plasma glucose concentrations in an oral glucose tolerance test, and thus impaired β cell function. Low expression of Helios was seen in Th17 cells, suggesting that Th1/Th17 cells are not converted thymus-derived regulatory T cells. Our results suggest that the development of Th1/Th17 plasticity may serve as a biomarker of disease progression from β cell autoantibody positivity to type 1 diabetes. These data in human type 1 diabetes emphasize the role of Th1/Th17 plasticity as a potential contributor to tissue destruction in autoimmune conditions.
authors.affiliation: Department of Vaccination and Immune Protection, National Institute for Health and Welfare, 00271 Helsinki, Finland;
authors.forename: Linnea
authors.initials: L
authors.lastname: Reinert-Hartwall
authors.affiliation: Department of Vaccination and Immune Protection, National Institute for Health and Welfare, 00271 Helsinki, Finland;
authors.forename: Jarno
authors.initials: J
authors.lastname: Honkanen
authors.affiliation: Department of Vaccination and Immune Protection, National Institute for Health and Welfare, 00271 Helsinki, Finland;
authors.forename: Harri M
authors.initials: HM
authors.lastname: Salo
authors.affiliation: Department of Vaccination and Immune Protection, National Institute for Health and Welfare, 00271 Helsinki, Finland;
authors.forename: Janne K
authors.initials: JK
authors.lastname: Nieminen
authors.affiliation: Department of Vaccination and Immune Protection, National Institute for Health and Welfare, 00271 Helsinki, Finland; Children's Hospital, University of Helsinki and Helsinki University Central Hospital, 00281 Helsinki, Finland;
authors.forename: Kristiina
authors.initials: K
authors.lastname: Luopajärvi
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, 00281 Helsinki, Finland;
authors.forename: Taina
authors.initials: T
authors.lastname: Härkönen
authors.affiliation: Department of Pediatrics, Medical Research Center, Oulu University Hospital and University of Oulu, 90014 Oulu, Finland;
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.affiliation: Department of Pediatrics, University of Turku, 20520 Turku, Finland;
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.affiliation: Immunogenetics Laboratory, University of Turku, 20520 Turku, Finland; Department of Clinical Microbiology, University of Eastern Finland, 70211 Kuopio, Finland;
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.affiliation: Department of Pediatrics, University of Tartu and Children's Clinic of Tartu University Hospital, Tartu 51014, Estonia;
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Peet
authors.affiliation: Department of Pediatrics, University of Tartu and Children's Clinic of Tartu University Hospital, Tartu 51014, Estonia;
authors.forename: Vallo
authors.initials: V
authors.lastname: Tillmann
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, 00281 Helsinki, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland; Diabetes and Obesity Research Program, University of Helsinki, 00290 Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, 33521 Tampere, Finland; and.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, 00281 Helsinki, Finland; Respiratory, Inflammatory and Autoimmune Diseases, Innovative Medicine, AstraZeneca, 43183 Mölndal, Sweden outi.vaarala@helsinki.fi.
authors.forename: Outi
authors.initials: O
authors.lastname: Vaarala
mesh_terms: D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D018149:Glucose Intolerance / Q000276:immunology*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000096:biosynthesis; D050417:Insulin-Secreting Cells / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D016906:Interleukin-9 / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; C111431:IKZF2 protein, human; C508607:IL9 protein, human; D020381:Interleukin-17; D016906:Interleukin-9; D051740:Ikaros Transcription Factor; D007371:Interferon-gamma