T-CELL REACTIVITY TO GAD65 PEPTIDE SEQUENCES SHARED WITH COXSACKIE-VIRUS PROTEIN IN RECENT-ONSET IDDM, POST-ONSET IDDM PATIENTS AND CONTROLSUBJECTS

GAD65 is one of the major autoantigens associated with insulin-depende nt diabetes mellitus (IDDM). The two peptides p17 and p18 of GAD65 tha t share sequence similarity with coxsackie virus (amino acid sequence identity: PEVKEK) appeared to be the major determinants of GAD65 recog nized preferably by T cells from new-onset IDDM patients and their fir st degree relatives. In contrast, in our study unrelated control subje cts frequently recognized the two GAD peptides (55%, 16/29), similar t o first degree relatives (41%, 12/29) and IDDM patients post-onset (68 %, 15/22). However, recent-onset IDDM patients, responded less frequen tly (25%, 4/16) compared with IDDM patients post-onset (p < 0.03) or u nrelated 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 b oth peptides in 13% of all subjects tested (n = 97) (p < 0.001). T-cel l proliferation to GAD p17 was higher than to p18 in recent-onset diab etic 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 resu lts show that T-cell reactivity to GAD65 peptides homologous with coxs ackie protein is very frequently observed, but not primarily associate d with IDDM. The temporary decline of T-cell proliferation is not asso ciated with the beta-cell destruction process, but with clinical manif estation. The positive correlation of reactivity to the two peptides i n the viral motif implicates that PEVKEK is an immunogenic epitope.