title: β-cell specific T-lymphocyte response has a distinct inflammatory phenotype in children with Type 1 diabetes compared with adults.
abstract: To examine the hypothesis that the quality, magnitude and breadth of helper T-lymphocyte responses to β cells differ in Type 1 diabetes according to diagnosis in childhood or adulthood.
  
  
  
  We studied helper T-lymphocyte reactivity against β-cell autoantigens by measuring production of the pro-inflammatory cytokine interferon-γ and the anti-inflammatory cytokine interleukin-10, using enzyme-linked immunospot assays in 61 people with Type 1 diabetes (within 3 months of diagnosis, positive for HLA DRB1*0301 and/or *0401), of whom 33 were children/adolescents, and a further 91 were unaffected siblings.
  
  
  
  Interferon-γ responses were significantly more frequent in children with Type 1 diabetes compared with adults (85 vs 61%; P = 0.04). Insulin and proinsulin peptides were preferentially targeted in children (P = 0.0001 and P = 0.04, respectively) and the breadth of the interferon-γ response was also greater, with 70% of children having an interferon-γ response to three or more peptides compared with 14% of adults (P < 0.0001). Islet β-cell antigen-specific interleukin-10 responses were similar in children and adults in terms of frequency, breadth and magnitude, with the exception of responses to glutamic acid decarboxylase 65, which were significantly less frequent in adults.
  
  
  
  At diagnosis of Type 1 diabetes, pro-inflammatory autoreactivity is significantly more prevalent, focuses on a wider range of targets, and is more focused on insulin/proinsulin in children than adults. We interpret this as indicating a more aggressive immunological response in the younger age group that is especially characterized by loss of tolerance to proinsulin. These findings highlight the existence of age-related heterogeneity in Type 1 diabetes pathogenesis that could have relevance to the development of immune-based therapies.
authors.affiliation: Department of Immunobiology, King's College London, London.|JDRF Centre for Diabetes Genes, Autoimmunity and Prevention, University of Cambridge, Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: Arif
authors.affiliation: Department of Immunobiology, King's College London, London.
authors.forename: V B
authors.initials: VB
authors.lastname: Gibson
authors.affiliation: Department of Immunobiology, King's College London, London.
authors.forename: V
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, UK.|JDRF Centre for Diabetes Genes, Autoimmunity and Prevention, University of Cambridge, Cambridge, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Bingley
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.|JDRF Centre for Diabetes Genes, Autoimmunity and Prevention, University of Cambridge, Cambridge, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Todd
authors.affiliation: University Department of Paediatrics, Addenbrooke's Hospital, Cambridge, UK.|JDRF Centre for Diabetes Genes, Autoimmunity and Prevention, University of Cambridge, Cambridge, UK.
authors.forename: C
authors.initials: C
authors.lastname: Guy
authors.affiliation: University Department of Paediatrics, Addenbrooke's Hospital, Cambridge, UK.|JDRF Centre for Diabetes Genes, Autoimmunity and Prevention, University of Cambridge, Cambridge, UK.
authors.forename: D B
authors.initials: DB
authors.lastname: Dunger
authors.affiliation: Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Dayan
authors.affiliation: Department of Diabetes and Endocrinology, Guy's & St Thomas' National Health Service (NHS) Foundation Trust, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Powrie
authors.affiliation: National Institute for Health Research, Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Lorenc
authors.affiliation: Department of Immunobiology, King's College London, London.|JDRF Centre for Diabetes Genes, Autoimmunity and Prevention, University of Cambridge, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Peakman
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging; D001323:Autoantibodies / Q000032:analysis; D001324:Autoantigens / Q000378:metabolism; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism; D059425:Interferon-gamma Release Tests; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D018448:Models, Immunological; D035781:Siblings; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; C508609:IL10 protein, human; D016753:Interleukin-10