MOLECULAR MIMICRY IN DIABETES-MELLITUS - THE HOMOLOGOUS DOMAIN IN COXSACKIE-B VIRUS PROTEIN-2C AND ISLET AUTOANTIGEN GAD(65) IS HIGHLY CONSERVED IN THE COXSACKIE-B-LIKE ENTEROVIRUSES AND BINDS TO THE DIABETES-ASSOCIATED HLA-DR3 MOLECULE

It has been proposed that molecular mimicry between protein 2C (p2C) o f coxsackie virus B4 and the autoantigen glutamic acid decarboxylase ( GAD(65)) plays a role in the pathogenesis of insulin-dependent diabete s mellitus (IDDM). Tn this study we show that the amino acid sequence of p2C which shares homology with a sequence in GAD(65) (PEVKER), is h ighly conserved in coxsackie virus B4 isolates as well as in different viruses of the subgroup of coxsackie B-like enteroviruses. These are the most prevalent enteroviruses and therefore exposure to the mimicry motif will be a frequent event throughout life. Presentation ol the h omologous peptides by HLA molecules is essential for T-cell reactivity . Therefore, we tested whether the PEVKEK motif can bind to the IDDM-a ssociated HLA-DR1, -DR3 and -DR4 molecules. Synthetic peptides with se quences derived from p2C and GAD(65) diet bind to HLA-DR3 but not to H LA-DR1 or -DR4. Replacement of amino acids within the motif showed tha t the PEVKEK motif binds specifically to HLA-DR3. Moreover, both p2C a nd GAD(65) peptides bind in the same position within the peptide bindi ng groove of the DR3 molecule which is an essential requirement for T- cell cross-reactivity. The results support molecular mimicry between p 2C of coxsackie B-like enteroviruses and GAD(65). However, this molecu lar mimicry may be limited to the HLA-DR3 positive subpopulation of ID DM patients.