Similar peptides from two beta cell autoantigens, proinsulin and glutamic acid decarboxylase, stimulate T cells of individuals at risk for insulin-dependent diabetes.
BACKGROUND
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of proinsulin (amino acids 24-36) that bears marked similarity to a peptide of GAD65 (amino acids 506-518) (G. Rudy, unpublished).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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Rudy
G
G
Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Stone
N
N
Harrison
L C
LC
Colman
P G
PG
McNair
P
P
Brusic
V
V
French
M B
MB
Honeyman
M C
MC
Tait
B
B
Lew
A M
AM
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology*; D011384:Proinsulin / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D012307:Risk Factors; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D001323:Autoantibodies; D001324:Autoantigens; D010446:Peptide Fragments; C024211:islet cell antibody; D011384:Proinsulin; D005968:Glutamate Decarboxylase