T cell autoreactivity to insulin in diabetic and related non-diabetic individuals.
T cell autoreactivity to insulin in type I diabetic and related non-diabetic individuals was analyzed. Peripheral T lymphocytes from both insulin-treated diabetic and untreated non-diabetic members of four families were found to proliferate in vitro in response to human insulin. T cell autoreactivity to insulin therefore does not appear to be diagnostic of the onset of type I diabetes. Highest T cell responses to human insulin were usually detected in insulin-dependent type I diabetes patients treated with a mixture of beef and pork insulin than with self insulin, the greater the dose of animal insulin the higher the T cell response. The T cell repertoires for self insulin appear to be similar in diabetics and non-diabetics based on their patterns of T cell reactivity to beef insulin, port insulin, human insulin, and various peptide of human insulin. The autoreactive T cells analyzed recognize two conformational epitopes of human insulin formed by interactions between A chain and B chain residues. One epitope is associated with the A chain loop and is present in the A1-A14/B1-B16 peptide, and the other epitope consists mainly of B chain residues located in the A16-A21/B10-B25 peptide. These two epitopes are present in amphipathic alpha-helical regions of insulin. HLA-DR (DR3, DR4, and DR5) and HLA-DQ (DQw2/DQw3) Ag can restrict these T cell responses to human insulin epitopes. The ability to detect insulin-specific autoreactive T cells in healthy non-diabetic individuals supports the hypothesis that autoreactive lymphocytes do not necessarily elicit autoimmune disease if present in an environment in which their activity is immunoregulated.
D000818:Animals; D002417:Cattle / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007328:Insulin / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D010446:Peptide Fragments / Q000276:immunology; D011487:Protein Conformation; D013045:Species Specificity; D013552:Swine / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000939:Epitopes; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D007328:Insulin; D010446:Peptide Fragments