Similar peptides from two beta cell autoantigens, proinsulin and glutamic acid decarboxylase, stimulate T cells of individuals at risk for insulin-dependent diabetes

• Published in: Molecular medicine (Cambridge, Mass.) Vol. 1; no. 6; pp. 625 - 633
• Main Authors: Rudy, G, Stone, N, Harrison, L C, Colman, P G, McNair, P, Brusic, V, French, M B, Honeyman, M C, Tait, B, Lew, A M
• Format: Journal Article
• Language: English
• Published: England The Feinstein Institute for Medical Research 01-09-1995
• Subjects: Adolescent; Adult; Amino Acid Sequence; Animals; Autoantibodies - blood; Autoantibodies - immunology; Autoantigens - chemistry; Child; Diabetes Mellitus, Type 1 - epidemiology; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Glutamate Decarboxylase - chemistry; Glutamate Decarboxylase - immunology; Glutamate Decarboxylase - pharmacology; Humans; Islets of Langerhans - immunology; Islets of Langerhans - physiology; Lymphocyte Activation - drug effects; Mice; Molecular Sequence Data; Peptide Fragments - chemistry; Peptide Fragments - immunology; Peptide Fragments - pharmacology; Prediabetic State - genetics; Prediabetic State - immunology; Proinsulin - chemistry; Proinsulin - immunology; Proinsulin - pharmacology; Risk Factors; Sequence Homology, Amino Acid; T-Lymphocytes - drug effects; T-Lymphocytes - immunology
• ISSN: 1076-1551; 1528-3658
• DOI: 10.1007/bf03401603

Insulin (1) and glutamic acid decarboxylase (GAD) (2) are both autoantigens in insulin-dependent diabetes mellitus (IDDM), but no molecular mechanism has been proposed for their association. We have identified a 13 amino acid peptide of proinsulin (amino acids 24-36) that bears marked similarity to a peptide of GAD65 (amino acids 506-518) (G. Rudy, unpublished). In order to test the hypothesis that this region of similarity is implicated in the pathogenesis of IDDM, we assayed T cell reactivity to these two peptides in subjects at risk for IDDM.
Subjects at risk for IDDM were islet cell antibody (ICA)-positive, first degree relatives of people with insulin-dependent diabetes. Peripheral blood mononuclear cells from 10 pairs of at-risk and HLA-DR matched control subjects were tested in an in vitro proliferation assay.
Reactivity to both proinsulin and GAD peptides was significantly greater among at-risk subjects than controls (proinsulin; p < 0.008; GAD; p < 0.018). In contrast to reactivity to the GAD peptide, reactivity to the proinsulin peptide was almost entirely confined to the at-risk subjects.
This is the first demonstration of T cell reactivity to a proinsulin-specific peptide. In addition, it is the first example of reactivity to a minimal peptide region shared between two human autoimmune disease-associated self antigens. Mimicry between these similar peptides may provide a molecular basis for the conjoint autoantigenicity of proinsulin and GAD in IDDM.