T-cell reactivity to GAD65 peptide sequences shared with coxsackie virus protein in recent-onset IDDM, post-onset IDDM patients and control subjects |
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| Authors: | N. C. Schloot B. O. Roep D. R. Wegmann L. Yu T. B. Wang G. S. Eisenbarth |
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| Affiliation: | (1) Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, Colorado, USA, US;(2) Department of Immunohematology and Bloodbank, Leiden, The Netherlands, NL |
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| Abstract: | Summary 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. [Diabetologia (1997) 40: 332–338] Received: 29 July 1996 and in revised form: 21 November 1996 |
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| Keywords: | Autoreactivity autoimmunity human T-cells GAD65 GAD autoantibodies insulin-dependent diabetes molecular mimicry. |
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