Cellular infiltrate, major histocompatibility antigen expression and immunopathogenic mechanisms in cardiac myosin-induced myocarditis.

Immunization with cardiac myosin induces severe myocarditis in genetically predisposed mice. The disease closely parallels that seen after infection with Coxsackievirus B3 and is characterized by a diffuse interstitial cellular infiltrate. To analyze the immunopathologic events in the heart tissue of cardiac myosin-immunized A/J and A.SW mice, the phenotype of inflammatory cells and the expression of class I and class II major histocompatibility (MHC) antigens (Ag) was examined at different time points using the immunoperoxidase method. On day 14 after the initial immunization, very few inflammatory cells were seen, whereas on day 21 the lesions were severe and extended over the whole ventricular wall. At both time points tested, the inflammatory infiltrate was composed of Mac-1+ cells, representing 70 to 80% of the infiltrate, and Thy-1.2+ cells, representing 20 to 25%. These Thy-1.2+ cells consisted of CD4+ cells and to a lesser extent of CD8+ cells. Essentially, no B cells were found on day 14, and on day 21 their frequency was only 1 to 2%. Furthermore, massive Ig deposits were observed along the infiltrated myofibers. Both on day 14 and 21, MHC class II Ag expression was associated with cells of the inflammatory infiltrate, but no aberrant I-A Ag expression was found on endothelial cells of coronary vessels or on myofibers. Similarly, no increased MHC class I Ag expression was seen on myofibers on day 14. However, on day 21 the infiltrated myofibers did show an increase in surface MHC class I Ag expression, thereby suggesting that this phenomenon is a consequence of the inflammatory process. Furthermore, in vivo administration of monoclonal antibodies to either CD4 or CD8 protected cardiac myosin-immunized mice from myocarditis, and a similar effect was achieved by monoclonal antibody to I-A Ag. Thus, cardiac myosin-induced myocarditis is mediated by a cooperation between CD8+ cells and MHC class II restricted, i.e., CD4+ cells.