HLA-DR4-associated T and B cell responses to specific determinants on the IA-2 autoantigen in type 1 diabetes

McLaughlin, Kerry A., Gulati, Kavita, Richardson, Carolyn C. , Morgan, Diana, Bodansky, H. Jonathan, Feltbower, Richard G. and Christie, Michael (2014) HLA-DR4-associated T and B cell responses to specific determinants on the IA-2 autoantigen in type 1 diabetes. Journal of Immunology, 193 (9). pp. 4448-4456. ISSN 0022-1767

Full content URL: http://www.jimmunol.org/content/193/9/4448

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Item Type:Article
Item Status:Live Archive


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 CD45ROhi 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. Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved.

Keywords:autoantibody, autoantigen, CD45RO antigen, epitope, gamma interferon, HLA DR4 antigen, IA 2 autoantibody, interleukin 10, protein IA 2, transcription factor FOXP3, transcription factor GATA 3, transcription factor T bet, unclassified drug, peptide, PTPRN protein, human, receptor like protein tyrosine phosphatase, adolescent, adult, antigen presentation, Article, B lymphocyte, child, controlled study, cytokine release, female, human, human cell, insulin dependent diabetes mellitus, major clinical study, male, memory T lymphocyte, protein expression, T lymphocyte, Th1 cell, Th2 cell, allele, biosynthesis, chemistry, genetics, immunology, immunophenotyping, metabolism, phenotype, young adult, Adolescent, Alleles, Autoantibodies, Autoantigens, B-Lymphocytes, Diabetes Mellitus, Type 1, Epitopes, HLA-DR4 Antigen, Humans, Interleukin-10, Peptides, Receptor-Like Protein Tyrosine Phosphatases, Class 8, T-Lymphocytes, Young Adult, JCOpen
Subjects:C Biological Sciences > C550 Immunology
Divisions:College of Science > School of Life Sciences
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ID Code:18110
Deposited On:31 Jul 2015 08:51

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