Antibody-mediated myocarditis: Genetic and induced susceptibility and the pathogenic potential of anti-myosin antibodies
Kuan, Anita Peilan
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Autoimmune disease occurs when (1) there is a breakdown in self-tolerance and (2) the target organ is susceptible to damage by the immune system. Our studies focus on the susceptibility of the target organ to damage. Our model is an antibody-induced murine autoimmune myocarditis. DBA/2 and BALB/c mice are both susceptible to Coxsackie B virus-induced autoimmune myocarditis as well as to cardiac myosin (CM)-induced myocarditis. Though both mouse strains develop serum anti-CM antibody titers, displaying similar isotype profiles, and though the alpha-CM heavy chain of these two strains differ by only one amino acid, the anti-CM antibodies in BALB/c mice do not appear to contribute to pathogenesis. Studies in our laboratory have found that administration of purified monoclonal anti-CM antibodies isolated from myosin immunized nice induces disease in DBA/2 nice but not in BALB/c mice. We have found that susceptibility to antibody-mediated cardiac damage correlates with the presence of myosin in the extracellular matrix (ECM) of the heart and maps to a 15-centimorgan susceptibility locus on chromosome 12. We have furthermore found that antibody isotype determines pathogenicity. While IgM anti-CM antibodies do not induce disease in DBA/2 mice, these same antibodies become pathogenic when converted to the IgG isotype. We have demonstrated that the IgM antibodies do penetrate the myocardium during cardiac ischemia. Their lack of pathogenicity reflects their inability to leave the vascular compartment and penetrate cardiac tissue. In addition, we have found that under conditions of cardiac inflammation resistant BALB/c mice become susceptible to antibody-induced myocarditis, presumably through alterations in the ECM. To understand induction of anti-myosin antibodies we have studied the antigenic crossreactivity between myosin and N-acetylglucosamine (GlcNAc). GlcNAc is the immunodominant epitope of the group A streptococcal carbohydrate. Anti-myosin antibodies from myosin-immunized nice crossreact with GlcNAc, similar to a subset of anti-myosin/anti-streptococcal antibodies found in patients with rheumatic carditis. Immunization with GlcNAc conjugated to a T-dependent carrier induces anti-CM antibody titers in BALB/c nice while immunization with GlcNAc conjugated to a T-independent carrier induces crossreactivity antibodies in both BALB/c and DBA/2 mice. Furthermore, in the absence of the inhibitory FcgammaRIIB the autoreactivity present in the T-independent response is accentuated in BALB/c mice.