MOLECULAR ANALYSIS OF HUMAN CARDIAC MYOSIN-CROSS-REACTIVE B-CELL AND T-CELL EPITOPES OF THE GROUP-A STREPTOCOCCAL M5 PROTEIN

The group A streptococcal M protein is an important virulence determin ant eliciting protective and autoimmune responses against the streptoc occus and cardiac myosin, respectively. In this report, the major huma n cardiac myosin-cross-reactive T-cell epitopes of M5 protein are iden tified and localized to myosin-like repeats within the M5 molecule, BA LB/c mice were immunized with human cardiac myosin, and the dominant m yosin-cross-reactive T-cell epitopes of M5 protein were identified wit h a panel of 23 overlapping peptides spanning the A, B, and C repeat r egions of M5 protein. Human cardiac myosin-cross-reactive T-cell epito pes of M5 protein were localized to several sequences in the M5 peptid es NT4 (GLKTENEGLKTENEGLKTE), NT5 (KKEHEAENDKLKQQRDTL), B1B2 (VKDKIAKE QENKETIGTL), B2 (TIGTLKKJLDETVKDKZA), B3A (IGTLKKILDETVKDKAK), and C3 (KGLRRDLDASREAKKQ), The NT4 repeated sequence LKTEN was highly homolog ous with a site conserved in cardiac myosins, the B repeat region pept ides were 47% homologous to human cardiac myosin amino acid sequence, and the C3 sequence RRDL was identical to a highly conserved site in s keletal and cardiac myosins, Immunization of BALB/c mice with each of the overlapping M5 peptides revealed myosin-cross-reactive B-cell epit opes throughout the A and C repeat regions and one major epitope in th e B repeat region containing the previously reported Gin-Lys-Ser-Lys-G ln (QKSKQ) epitope, The data suggest that the M5 peptides elicited hig her antibody titers to cardiac myosin than to skeletal myosin and that several sites in the A and B repeat regions of M5 protein induced myo cardial inflammatory infiltrates.