Autoantibodies and associated T-cell responses to determinants within the 831–860 region of the autoantigen IA-2 in Type 1 diabetes

Abstract B-cells influence T-cell reactivity by facilitating antigen presentation, but the role of autoantibody-secreting B-cells in regulating T-cell responses in Type 1 diabetes is poorly defined. The aims of this study were to characterise epitopes on the IA-2 autoantigen for three monoclonal ant...

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Veröffentlicht in:Journal of autoimmunity 2009-09, Vol.33 (2), p.147-154
Hauptverfasser: Weenink, S.M, Lo, J, Stephenson, C.R, McKinney, P.A, Ananieva-Jordanova, R, Rees Smith, B, Furmaniak, J, Tremble, J.M, Bodansky, H.J, Christie, M.R
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Sprache:eng
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Zusammenfassung:Abstract B-cells influence T-cell reactivity by facilitating antigen presentation, but the role of autoantibody-secreting B-cells in regulating T-cell responses in Type 1 diabetes is poorly defined. The aims of this study were to characterise epitopes on the IA-2 autoantigen for three monoclonal antibodies from diabetic patients by amino acid substitutions of selected residues of IA-2, establish contributions of these epitopes to binding of serum antibodies in Type 1 diabetes and relate B- and T-cell responses to overlapping determinants on IA-2. The monoclonal antibodies recognised overlapping epitopes, with residues within the 831–860 region of IA-2 contributing to binding; substitution of Glu836 inhibited binding of all three antibodies. Monoclonal antibody Fab fragments and substitution of residues within the 831–836 region blocked serum antibody binding to an IA-2 643–937 construct. IL-10-secreting T-cells responding to peptides within the 831–860 region were detected by cytokine-specific ELISPOT in diabetic patients and responses to 841–860 peptide were associated with antibodies to the region of IA-2 recognised by the monoclonal antibodies. The study identifies a region of IA-2 frequently recognised by antibodies in Type 1 diabetes and demonstrates that these responses are associated with T-cells secreting IL-10 in response to a neighbouring determinant.
ISSN:0896-8411
1095-9157
DOI:10.1016/j.jaut.2009.04.002