Myocarditis is a common cause of
dilated cardiomyopathy leading to
heart failure. Chronic stages of
myocarditis may be initiated by autoimmune responses to exposed cardiac Ags after myocyte damage.
Cardiac myosin, a heart
autoantigen, induced experimental autoimmune
myocarditis (EAM) in susceptible animals. Although
cardiac myosin-induced
myocarditis has been reported in Lewis rats, the main pathogenic
epitope has not been identified. Using overlapping synthetic
peptides of the S2 region of human
cardiac myosin, we identified an amino acid sequence, S2-16 (residues 1052-1076), that induced severe
myocarditis in Lewis rats. The myocarditic
epitope was localized to a truncated S2-16
peptide (residues 1052-1073), which contained a sequence identical in human and rat
cardiac myosin. The S2-16
peptide was not myocarditic for three other strains of rats, in which the lack of
myocarditis was accompanied by the absence of strong S2-16-specific lymphocyte responses in vitro. For Lewis rats, S2-16 was characterized as a cryptic
epitope of
cardiac myosin because it did not recall lymphocyte and Ab responses after immunization with
cardiac myosin. Lymphocytes from S2-16 immunized rats recognized not only S2-16, but also
peptides in the S2-28 region. Furthermore,
peptide S2-28 was the dominant
epitope recognized by T cells from
cardiac myosin immunized rats. S2-16 was presented by Lewis rat
MHC class II molecules, and
myocarditis induction was associated with an up-regulation of inflammatory
cytokine production. S2-16-induced EAM provides a defined animal model to investigate mechanisms of EAM and modulation of immune responses to prevent autoimmune
myocarditis.