Autoantibodies to cardiac myosin in mouse cytomegalovirus myocarditis

Abstract

Myocarditis accompanies sublethal mouse cytomegalovirus (MCMV) infection in susceptible BALB/c mice and persists beyond the acute phase of infection, in the absence of demonstrable virus antigen but in the continuing presence of autoantibodies to cardiac muscle. Heart tissue autoantibodies of the IgG class were first detected by ELISA in sera at Days 3-5 post-infection (PI) and persisted to Day 100, in two strains of MCMV-infected mice which are susceptible (BALB/c) and resistant (C57BL/10) to MCMV-induced myocarditis. Analysis by immunoblot showed that autoantibodies in early immune sera (Day 10) from both mouse strains reacted with the contractile proteins troponin, tropomyosin and myosin, as well as with other unidentified polypeptides within normal mouse organ homogenates. However, the dominant reactivity of late immune sera (Day 100) was to a 200,000 molecular weight (MW) polypeptide in muscle homogenates identified as the heavy chain of myosin. Autoantibodies reacting with the cardiac or striated muscle isoforms of myosin were assessed by ELISA in BALB/c and C57BL/10 mice. At Days 28, 56 and 100 PI only the susceptible BALB/c strain had high titres of autoantibodies reacting with the cardiac isoform of myosin. Increasing the virus dose given to C57BL/10 mice resulted in slight increases in titres of anti-myosin antibody; however, the peak antibody titres did not approach those of BALB/c mice and persisting myocarditis did not develop. Absorption experiments showed that cardiac myosin-specific antibodies were present in immune sera from susceptible BALB/c mice at Day 100 but not in resistant C57BL/10 mice by ELISA and immunoblot. These results demonstrate that autoimmunity to myosin is a prominent feature of the humoral autoimmune response following MCMV infection, and that there are differences both in fine isoform specificity and titre of anti-myosin antibodies between strains of mice that develop persisting myocarditis and strains that do not. Cardiac myosin-specific autoantibodies may play an immunopathogenic role in CMV-induced myocarditis.