CARDIAC ALPHA-MYOSIN HEAVY-CHAINS DIFFER IN THEIR INDUCTION OF MYOCARDITIS - IDENTIFICATION OF PATHOGENIC EPITOPES

BALB/c mice develop autoimmune myocarditis after immunization with mou se cardiac myosin, whereas C57B/6 mice do not. To define the immunogen icity and pathogenicity of cardiac myosin in BALB/c mice, we immunized mice with different forms of cardiac myosin. These studies demonstrat e the discordance of immunogenicity and pathogenicity of myosin heavy chains. The cardiac alpha-myosin heavy chains of BALB/c and C57B/6 mic e differ by two residues that are near the junction of the head and ro d in the S2 fragment of myosin. Myosin preparations from both strains are immunogenic in susceptible BALB/c as well as in nonsusceptible C57 B/6 mice; however, BALB/c myosin induces a greater incidence of diseas e. To further delineate epitopes of myosin heavy chain responsible for immunogenicity and disease, mice were immunized with fragments of gen etically engineered rat alpha cardiac myosin. Epitopes in the region o f difference between BALB/c and C57B/6 (residues 735-1032) induce dise ase in both susceptible and nonsusceptible mice. The data presented he re demonstrate that pathogenic epitopes of both mouse and rat myosin r eside in the polymorphic region of the S2 subunit. In addition, these studies suggest that polymorphisms in the autoantigen may be part of t he genetic basis for autoimmune myocarditis.