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To better understand the relationship between infection
and autoimmune disease, we established a mouse model of
myocarditis, or inflammation of the heart, induced by CB3
infection . CB3 is believed to account for most cases of
myocarditis in North t disease in BALB/c mice .
Knowing that cardiac myosin/adjuvant immunization induces myocarditis similar to CB3 infection, we examined the myosin sequences responsible for disease induction. We found that none of the cardiac myosin sequences were cross-reactive with viral sequences . Furthermore, cross-reactivity between antibodies induced by myosin immunization or CB3 infection was not observed, which suggests that molecular mimicry is not a predominant mechanism in the development of CB3-induced myocarditis . Viral infections can induce damage to host tissues by direct (e.g., viral replication) or indirect (e.g., nitric oxide) mechanisms. In our model of CB3 myocarditis, however, we did not observe damage to the heart cells during the acute phase of disease . We found that CB3 replicates at a relatively low level in the heart and that necrosis and fibrosis did not appear until the chronic phase of disease, after virus had been cleared from the heart . Thus, a low level of viral replication is sufficient to provide cardiac myosin to the immune system. Overall, our studies of CB3-induced myocarditis favor the hypothesis that autoimmune disease is induced after viral infection of susceptible mice because the pathogen facilitates the release of cardiac myosin and nonspecifically stimulates the innate immune response in a manner similar to the effect of adjuvants . Is Virus Associated with Myocarditis?Many different microorganisms (e.g., streptococci, Trypanosoma, cytomegalovirus [CMV], and CB3) have been associated with the same autoimmune disease (e.g., myocarditis) . We have shown that two completely different viruses (CB3, a small nonenveloped RNA virus, and murine CMV, a large enveloped DNA virus) induce a similar biphasic myocarditis in susceptible BALB/c mice . Although infectious CB3 or murine CMV (MCMV) can be detected during the acute phase of myocarditis, viral levels do not correlate with the severity of inflammation . Because viral genome can be detected after infectious virus has been cleared from the heart, latent virus may attract inflammation during the chronic stage of disease. However, when we examined the heart for the presence of latent MCMV, we found that viral genome and transcript were present in mice both susceptible to and resistant to the development of chronic disease. These results indicate that persistence of virus alone is not the determining factor in the development of chronic myocarditis. Yet the best evidence that active viral infection is not required for myocarditis to develop comes from the demonstration that injecting susceptible mice with cardiac myosin emulsified in adjuvant induces experimental autoimmune myocarditis . In fact, the pathogenesis of experimental autoimmune myocarditis closely resembles the biphasic myocarditis associated with CB3 or MCMV infection. This finding indicates that the adjuvant effect produced by infections or adjuvants during the innate immune response can lead to the development of autoimmune disease when self-antigen is present. We have found in preliminary studies that the same pattern of TLR expression is induced by CB3 and the Mycobacterium in complete Freund's adjuvant, which suggests a common mechanism of activation . Innate Immune Response Initiates Myocarditis Since the innate immune response determines whether the chronic phase of myocarditis and dilated cardiomyopathy develop in mice , early activation of mast cells may result in a delayed-type hypersensitivity reaction later, during the chronic phase of the disease . Mast cells are found in the human heart in increased numbers during cardiovascular disease and congestive heart failure . We have also observed increased numbers of degranulating mast cells during chronic CB3 myocarditis in susceptible mice with severe disease . So the evidence presented by the CB3-induced model of myocarditis demonstrates that virus can trigger autoimmune disease in susceptible mice by immune-mediated mechanisms. But the question still remains: Why are autoimmune diseases so prevalent in women? Why Are Autoimmune Diseases So Prevalent in Women? Even though women's greater susceptibility to autoimmune diseases has been recognized for more than 100 years, only recently has attention focused on this topic . For some time, the basic immune response between men and women has been known to differ, with women producing a more vigorous immune response and increased antibody production . However, autoimmune diseases that develop in men often are more severe . Most of our understanding of sex differences in the immune response comes from work done in animal models. With the increase in the number of autoimmune cases in recent years, the possible role of infections in exacerbating disease, particularly in women, is of rising concern. |