title: HLA-DR4-associated T and B cell responses to specific determinants on the IA-2 autoantigen in type 1 diabetes.
abstract: Autoantibodies to IA-2 in type 1 diabetes are associated with HLA-DR4, suggesting influences of HLA-DR4-restricted T cells on IA-2-specific B cell responses. The aim of this study was to investigate possible T-B cell collaboration by determining whether autoantibodies to IA-2 epitopes are associated with T cell responses to IA-2 peptides presented by DR4. T cells secreting the cytokines IFN-γ and IL-10 in response to seven peptides known to elicit T cell responses in type 1 diabetes were quantified by cytokine ELISPOT in HLA-typed patients characterized for Abs to IA-2 epitopes. T cell responses were detected to all peptides tested, but only IL-10 responses to 841-860 and 853-872 peptides were associated with DR4. Phenotyping by RT-PCR of FACS-sorted CD45RO(hi) T cells secreting IL-10 in response to these two peptides indicated that these expressed GATA-3 or T-bet, but not FOXP3, consistent with these being Th2 or Th1 memory T cells rather than of regulatory phenotype. T cell responses to the same two peptides were also associated with specific Abs: those to 841-860 peptide with Abs to juxtamembrane epitopes, which appear early in prediabetes, and those to peptide 853-872 with Abs to an epitope located in the 831-862 central region of the IA-2 tyrosine phosphatase domain. Abs to juxtamembrane and central region constructs were both DR4 associated. This study identifies a region of focus for B and T cell responses to IA-2 in HLA-DR4 diabetic patients that may explain HLA associations of IA-2 autoantibodies, and this region may provide a target for future immune intervention to prevent disease.
authors.affiliation: Division of Diabetes and Nutritional Sciences, Guy's Campus, King's College London, London SE1 1UL, United Kingdom; and.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: McLaughlin
authors.affiliation: Division of Diabetes and Nutritional Sciences, Guy's Campus, King's College London, London SE1 1UL, United Kingdom; and.
authors.forename: Kavita
authors.initials: K
authors.lastname: Gulati
authors.affiliation: Division of Diabetes and Nutritional Sciences, Guy's Campus, King's College London, London SE1 1UL, United Kingdom; and.
authors.forename: Carolyn C
authors.initials: CC
authors.lastname: Richardson
authors.affiliation: Division of Epidemiology, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Diana
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Division of Epidemiology, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: H Jonathan
authors.initials: HJ
authors.lastname: Bodansky
authors.affiliation: Division of Epidemiology, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Feltbower
authors.affiliation: Division of Diabetes and Nutritional Sciences, Guy's Campus, King's College London, London SE1 1UL, United Kingdom; and michael.christie@kcl.ac.uk.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Christie
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis; D008297:Male; D010455:Peptides / Q000276:immunology; D010641:Phenotype; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D015804:HLA-DR4 Antigen; D010455:Peptides; D016753:Interleukin-10; C516862:PTPRN protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8