Genome-wide analyses have shown that the MHC class II region is the principal locus that confers susceptibility to a number of human
autoimmune diseases. Due to the high degree of linkage disequilibrium across the MHC, it has been difficult to dissect the contribution of individual genes to
disease susceptibility. As a result, intensive efforts have been made to generate mice transgenic for human class II molecules as models of
autoimmune disease. However, in every case, additional manipulations-such as immunization with Ag in adjuvant, expression of
immunostimulants on target tissues, or coexpression of TCR transgenes-have been required to induce disease. In this study, we show that expression of the human
HLA-DQ8 (DQA1*0301/DQB1*0302) molecule alone in three lines of transgenic nonobese diabetic murine class II-deficient (mII(-/-)) mice results in the spontaneous development of autoimmune
myocarditis. The disease shares key features of human
myocarditis and was characterized by lymphocytic infiltrates in the myocardium and cardiac myocyte destruction, circulating
IgG autoantibodies against
cardiac myosin heavy chain, and premature death due to
heart failure. We demonstrate that
myocarditis could be transferred into healthy
HLA-DQ8(+)RAG-1(-/-)mII(-/-) nonobese diabetic recipients with lymphocytes, but not sera. It has been widely thought that autoimmune
myocarditis is of infectious etiology, with the immune responses arising secondary to cardiac damage from pathogens. These studies provide direct experimental evidence that spontaneous autoimmune
myocarditis can occur in the absence of
infection and that expression of
HLA-DQ8 confers susceptibility to this organ-specific
autoimmune disease.