Autoimmune determinants of rheumatic carditis: localization of epitopes in human cardiac myosin.

Abstract

Rheumatic carditis is a sequela of group A streptococcal throat infection. Although the pathogenic mechanisms which lead to heart damage in acute rheumatic fever (ARF) are not well understood, autoimmune processes have been implicated, involving molecular mimicry between streptococci and the human heart. We have studied the immunological cross-reactions between the group A Streptococcus and human heart to understand their molecular and immunological basis. Human and mouse monoclonal antibodies (mAb) and affinity-purified anti-myosin antibodies from acute rheumatic fever sera were characterized and shown to cross-react with group A streptococcal M protein and myosin. Studies of proteolytic fragments of human cardiac myosin identified sites of cross-reactivity in the rod region of the myosin heavy chain. Murine monoclonal antibodies cross-reactive with streptococcal M protein and myosin recognized epitopes located in the S2 and light meromyosin (LMM) subfragments of the heavy chain. None of the cross-reactive monoclonal antibodies recognized the S1 subfragment. One broadly cross-reactive monoclonal antibody was highly cytotoxic for heart cells in vitro and reactive with the LMM fragment. The data suggest that the cross-reactive epitopes recognized by these antibodies are conformational, dependent upon their alpha-helical structures, and potentially damaging to host tissues.