title: Suppressive effect of glutamic acid decarboxylase 65-specific autoimmune B lymphocytes on processing of T cell determinants located within the antibody epitope.
abstract: Type 1 diabetes is a T cell-mediated disease in which B cells serve critical Ag-presenting functions. In >95% of type 1 diabetic patients the B cell response to the glutamic acid decarboxylase 65 (GAD65) autoantigen is exclusively directed at conformational epitopes residing on the surface of the native molecule. We have examined how the epitope specificity of Ag-presenting autoimmune B cell lines, derived from a type 1 diabetic patient, affects the repertoire of peptides presented to DRB1*0401-restricted T cell hybridomas. The general effect of GAD65-specific B cells was to enhance Ag capture and therefore Ag presentation. The enhancing effect was, however, restricted to T cell determinants located outside the B cell epitope region, because processing/presentation of T cell epitopes located within the autoimmune B cell epitope were suppressed in a dominant fashion. A similar effect was observed when soluble Abs formed immune complexes with GAD65 before uptake and processing by splenocytes. Thus, GAD65-specific B cells and the Abs they secrete appear to modulate the autoimmune T cell repertoire by down-regulating T cell epitopes in an immunodominant area while boosting epitopes in distant or cryptic regions.
authors.affiliation: Diabetes Center, Department of Medicine, Division of Endocrinology and Metabolism, Department of Veterans Affairs Medical Center and University of California, San Francisco, CA 94143, USA.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Jaume
authors.forename: Sarah Louise
authors.initials: SL
authors.lastname: Parry
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Madec
authors.forename: Grete
authors.initials: G
authors.lastname: Sønderstrup
authors.forename: Steinunn
authors.initials: S
authors.lastname: Baekkeskov
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D001666:Binding Sites, Antibody / Q000276:immunology; D002461:Cell Line, Transformed; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D018985:Epitopes, B-Lymphocyte / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007527:Isoenzymes / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D001324:Autoantigens; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D011947:Receptors, Antigen, B-Cell; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2