T-cell reactivity to GAD65 peptide sequences shared with coxsackie virus protein in recent-onset IDDM, post-onset IDDM patients and control subjects.
GAD65 is one of the major autoantigens associated with insulin-dependent diabetes mellitus (IDDM). The two peptides p17 and p18 of GAD65 that share sequence similarity with coxsackie virus (amino acid sequence identity: PEVKEK) appeared to be the major determinants of GAD65 recognized preferably by T cells from new-onset IDDM patients and their first degree relatives. In contrast, in our study unrelated control subjects frequently recognized the two GAD peptides (55%, 16/29), similar to first degree relatives (41%, 12/29) and IDDM patients post-onset (68%, 15/22). However, recent-onset IDDM patients, responded less frequently (25%, 4/16) compared with IDDM patients post-onset (p < 0.03) or unrelated control subjects (borderline significant) confirming previous observations in humans and NOD mice that T-cell reactivity to GADp17/p18 at diabetes onset is decreased. Moreover, this study demonstrated a positive correlation of T-cell proliferation to GAD p17 (amino acid 247-266) and p18 (amino acid 260-279) with simultaneous responses to both peptides in 13% of all subjects tested (n = 97) (p < 0.001). T-cell proliferation to GAD p17 was higher than to p18 in recent-onset diabetic patients, first degree relatives and unrelated control subjects (p < 0.02, p < 0.004, p < 0.002, respectively). However, in post-onset IDDM patients, the two peptides were recognized equally well. Our results show that T-cell reactivity to GAD65, peptides homologous with coxsackie protein is very frequently observed, but not primarily associated with IDDM. The temporary decline of T-cell proliferation is not associated with the beta-cell destruction process, but with clinical manifestation. The positive correlation of reactivity to the two peptides in the viral motif implicates that PEVKEK is an immunogenic epitope.
Schloot
N C
NC
Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, USA.
Roep
B O
BO
Wegmann
D R
DR
Yu
L
L
Wang
T B
TB
Eisenbarth
G S
GS
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000276:immunology* / Q000494:pharmacology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D004770:Enterovirus / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000032:analysis; D059866:HLA-DQ beta-Chains; D006801:Humans; D007328:Insulin / Q000627:therapeutic use; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors
D001323:Autoantibodies; D001324:Autoantigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D007328:Insulin; D010446:Peptide Fragments; D005968:Glutamate Decarboxylase