Experimental autoimmune insulitis. Induction by T lymphocytes specific for a peptide of proinsulin.
Type I diabetes, an autoimmune disease that occurs in humans and animals, is characterized by the destruction of insulin-secreting islet beta-cells of the pancreas. Antibodies directed toward multiple islet protein can be detected before diagnosis of type I diabetes; however, the identity of the inciting autoantigen(s) that targets beta-cells for destruction has not been defined. Autorecognition of many self-proteins by CD4+ T lymphocytes is restricted by the products of class II immune response genes of the major histocompatibility complex (MHC), and in human type I diabetes such a MHC association has been described. The present study uses a rat MHC class II (RT1.Bl) peptide binding motif to predict potentially autoreactive CD4+ T cell epitopes in two key islet beta-cell constituents: the enzyme glutamic acid decarboxylase (GAD) and the insulin precursor hormone proinsulin (PI). Seventeen-amino-acid-long peptide fragments of GAD and PI containing the binding motif were synthesized and used to generate peptide-specific, MHC class II-restricted, CD4+ T cell lines. Once established, the T cell lines specific for rat islet GAD and PI were adoptively transferred to naive, MHC-compatible rats. At 10 days after transfer, insulitis had developed in rats receiving PI-specific T cells, whereas no insulitis was observed in pancreata of rats receiving GAD-specific T cells. Of particular interest is the finding that the pathogenic T cell epitope identified in PI spans the endogenous cleavage site between the B-chain and C-peptide of insulin. Moreover, the PI-specific T cells were able to react specifically with material produced in vitro by a rat insulinoma cell line. These results demonstrate that pathogenic T cell epitopes can be located in portions of molecules that are subsequently degraded during normal enzymatic processing. As PI is found highest concentrations in the beta-cells of pancreatic islets, it is possible that this molecule and not its individual degradation products (ie, insulin and C-peptide) might serve as an autoantigen in the pathogenesis of type I diabetes.
Griffin
A C
AC
Department of Pathology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
Zhao
W
W
Wegmann
K W
KW
Hickley
W F
WF
D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D000939:Epitopes; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000276:immunology; D007515:Islets of Langerhans / Q000473:pathology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D011384:Proinsulin / Q000235:genetics / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D000939:Epitopes; D010446:Peptide Fragments; D011384:Proinsulin; D005968:Glutamate Decarboxylase