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 interferon-γ and interleukin-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 characterised for antibodies to IA-2 epitopes. T-cell responses were detected to all peptides tested, but only interleukin-10 responses to 841-860 and 853-872 peptides were associated with DR4. Phenotyping by RT-PCR of FACS-sorted CD45ROhi T-cells secreting interleukin-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 antibodies; those to 841-860 peptide with antibodies to juxtamembrane epitopes, which appear early in pre-diabetes, and those to peptide 853-872 with antibodies to an epitope located in the 831-862 central region of the IA-2 tyrosine phosphatase domain. Antibodies 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.

Relation ofHLA-DRB1to IgG4 autoantibody and cytokine production in muscle-specific tyrosine kinase myasthenia gravis (MuSK-MG)

“…Cytokines such as IL-10, interferon (IFN)-γ and IL-4 can affect B cell differentiation [33][34][35]. In a recent study in type 1 diabetes, HLA association has been shown to have an effect on the autoantibody titres to IA-2 and on the IL-10 cytokine levels [18]. In a recent study in type 1 diabetes, HLA association has been shown to have an effect on the autoantibody titres to IA-2 and on the IL-10 cytokine levels [18].…”

“…IgM-positive B cells switch to IgG4 or IgE in the presence of added IL-4 [36], and IL-10 also indirectly contributes to IgG4 class switching [37]. In a recent study in type 1 diabetes, HLA association has been shown to have an effect on the autoantibody titres to IA-2 and on the IL-10 cytokine levels [18]. In the present study, higher IL-10 and lower IL-17A levels were detected in DRB1*14 (+) MuSK-MG patients than in DRB1*14 (-) DRB1*16 (-) patients.…”

“…HLA associations are detected with many autoimmune diseases, as in MG. Efforts to explain the role of HLA in disease pathogenesis have been focused on the antigenpresenting functions of these molecules to T cells [18]. The regulation of autoantibody production has also been shown to be related to HLA associations in rheumatoid arthritis (RA) [19,20].…”

Immunological Hypoglycemia Associated with Insulin Antibodies Induced by Exogenous Insulin in 11 Chinese Patients with Diabetes

“…The genetic basis of IAb-associated immunological hypoglycemia was not fully understood. Human leukocyte antigen (HLA) was reported to play a role and individuals with HLA-DR4 genotype were susceptible to develop IAb-associated immunological hypoglycemia [ 27 , 28 ], resembling that of a patient with insulin autoimmune syndrome (IAS) [ 8 , 29 ], type 1 diabetes mellitus [ 30 , 31 ], or rheumatoid arthritis [ 32 , 33 ]. However, HLA typing was not performed in this retrospective study.…”

Direct Analysis of Insulin-Specific T Cells Provides New Insights

“…To date, relatively few studies have correlated autoreactive T cell and antibody responses. McLaughlin et al (14) observed modest correlations between T cell responses to IA-2 841-860 and IA-2 juxtamembrane domain antibodies. Acevedo-Calado et al (15) identified T cell and antibody responses to newly described antigenic determinants within the amino terminus of IA-2.…”