Intermolecular antigen spreading occurs during the preclinical period of human type 1 diabetes.
Intra- and intermolecular spreading of T cell responses to autoantigens has been implicated in the pathogenesis of autoimmune diseases. Therefore, we questioned whether T cell responses from subjects identified as at-risk (positive for autoantibody reactivity to islet proteins) for the development of type 1 diabetes, a cell-mediated autoimmune disease, would demonstrate intermolecular Ag spreading of T cell responses to islet cell proteins. Previously, we have demonstrated that by the time subjects develop type 1 diabetes, they have T cell responses to numerous islet proteins, whereas T cells from normal controls respond to a limited number of islet proteins. Initial testing of PBMC responses from 25 nondiabetic at-risk subjects demonstrated that 16 of the 25 subjects have PBMC responses to islet proteins similar to controls. Fourteen of these 16 subjects were available for follow-up. Eleven of the 14 developed T cell responses to increasing numbers of islet proteins, and 6 of these subjects developed type 1 diabetes. In the nine subjects who already demonstrated T cell Ag spreading at the initial visit, four were available for follow-up. Of these four, two had increases in T cell reactivity to islet proteins, while two maintained their initial levels of T cell reactivity. We also observed Ag spreading in autoantibody reactivity to islet proteins in nine of the 18 at-risk subjects available for follow-up. Our data strongly support the conclusion that intermolecular spreading of T cell and Ab responses to islet proteins occurs during the preclinical period of type 1 diabetes.
Brooks-Worrell
B
B
Department of Medicine, University of Washington, Seattle, WA 98195, USA. bbrooks@u.washington.edu
Gersuk
V H
VH
Greenbaum
C
C
Palmer
J P
JP
D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology*; D002478:Cells, Cultured; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D005260:Female; D005500:Follow-Up Studies; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D007330:Insulin Antibodies / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000201:enzymology / Q000276:immunology; D007527:Isoenzymes / Q000276:immunology; D008137:Longitudinal Studies; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D008875:Middle Aged; D011236:Prediabetic State / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D001323:Autoantibodies; D001324:Autoantigens; D007330:Insulin Antibodies; D007527:Isoenzymes; D008565:Membrane Proteins; C024211:islet cell antibody; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2