T-cell reactivity to GAD65 peptide sequences shared with coxsackie virus protein in recent-onset IDDM, post-onset IDDM patients and control subjects

Diabetologia. 1997 Mar;40(3):332-8. doi: 10.1007/s001250050683.


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.

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Amino Acid Sequence
  • Animals
  • Autoantibodies / blood*
  • Autoantigens / immunology*
  • Autoantigens / pharmacology
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / immunology*
  • Enterovirus / immunology*
  • Glutamate Decarboxylase / immunology*
  • HLA-DQ Antigens / analysis
  • HLA-DQ beta-Chains
  • Humans
  • Insulin / therapeutic use
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred NOD
  • Peptide Fragments / immunology*
  • Peptide Fragments / pharmacology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Time Factors


  • Autoantibodies
  • Autoantigens
  • HLA-DQ Antigens
  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • Insulin
  • Peptide Fragments
  • Glutamate Decarboxylase