SummaryInjury to cardiac myocytes often leads to the production of anti-myosin antibodies. While these antibodies are a marker of myocardial injury, their contribution to pathogenesis in diseases such as autoimmune myocarditis or rheumatic fever is much less dear. We demonstrate in this report that monodonal anti-myosin antibodies can mediate myocarditis in a susceptible mouse strain. Additionally, we show disease susceptibility depends on the presence of myosin or a myosin-like molecule in cardiac extraceUular matrix. This study demonstrates that susceptibility to autoimmune heart disease depends not only on the activation of self-reactive lymphocytes but also on genetically determined target organ sensitivity to autoantibodies.
BALB/c mice develop autoimmune myocarditis after immunization with mouse cardiac myosin, whereas C57B/6 mice do not. To define the immunogenicity and pathogenicity of cardiac myosin in BALB/c mice, we immunized mice with different forms of cardiac myosin. These studies demonstrate the discordance of immunogenicity and pathogenicity of myosin heavy chains. The cardiac a-myosin heavy chains of BALB/c and C57B/6 mice differ by two residues that are near the junction of the head and rod in the S2 fragment of myosin. Myosin preparations from both strains are immunogenic in susceptible BALB/c as well as in nonsusceptible C57B/6 mice; however, BALB /c myosin induces a greater incidence of disease. To further delineate epitopes of myosin heavy chain responsible for immunogenicity and disease, mice were immunized with fragments of genetically engineered rat a cardiac myosin. Epitopes in the region of difference between BALB /c and C57B /6 (residues 735-1032) induce disease in both susceptible and nonsusceptible mice.The data presented here demonstrate that pathogenic epitopes of both mouse and rat myosin reside in the polymorphic region of the S2 subunit. In addition, these studies suggest that polymorphisms in the autoantigen may be part of the genetic basis for autoimmune myocarditis. (J. Clin. Invest. 1993.
Autoantibodies against myosin are associated with myocarditis and rheumatic heart disease. In this study, the antigenic cross-reactivity of myosin and N-acetyl-glucosamine (GlcNAc), the dominant epitope of Group A streptococcal polysaccharide, was examined. Six antimyosin monoclonal antibodies (MAbs) derived from mice with cardiac myosin-induced myocarditis were characterized. All MAbs cross-reacted with GlcNAc, mimicking a subset of MAbs derived from rheumatic carditis patients that bind both myosin and streptococcal polysaccharide. Variable (V) region gene usage was diverse, with five of six MAb heavy-chain V regions encoded by distinct members of the J558 family and the sixth encoded by a member of the VGAM3.8 family. Light-chain V-region segments were derived from the Vk1, Vk4/5, Vk10, and Vk21 families. These antimyosin, anti-GlcNac MAbs demonstrated several T-cell-dependent features: they were predominantly immunoglobulin G, were encoded by V-region genes expressed late in development, and displayed somatic mutation. A direct correlation between the extent of somatic mutation and the affinity for myosin was observed. Affinity for GlcNAc also increased with the frequency of mutation, demonstrating that affinity maturation can occur simultaneously for both self antigen and foreign antigen. Based on these observations, we immunized mice with GlcNAc coupled to bovine serum albumin and demonstrated that a T-cell-dependent response to GlcNAc leads to antimyosin reactivity. We speculate that the pathogenic antibody response in rheumatic carditis may reflect the conversion of a T-cell-independent response to GlcNAc to a T-cell-dependent cross-reactive response to GlcNAc and myosin.
Abstract-Antimyosin reactivity is associated with cardiac damage in autoimmune myocarditis, an inflammatory heart disease characterized by a cellular infiltrate in the myocardium and myocyte necrosis. We are interested in the pathogenicity of antimyosin antibodies and their ability to cause autoimmune myocarditis. We have shown that antimyosin antibodies of the IgG isotype will induce disease in the DBA/2 mouse. In the present study, we show that IgM antimyosin antibodies do not induce myocarditis; however, these same antibodies become pathogenic when converted to the IgG isotype. Although IgM antibodies can penetrate the myocardium during cardiac inflammation, they are usually less able to leave the vascular compartment and penetrate cardiac tissue, thus accounting for their lack of pathogenicity. Thus, antimyosin B cells may be potentially pathogenic only after antigen activation and heavy chain class switching or under conditions that alter vascular permeability in the heart. (Circ Res. 2000;86:281-285.)
We have obtained 10 mAb from two independent fusions that are anti-idiotypic to the combining site of an anti-I-Jk antibody. These mAb block Ts cell function isn a genetically restricted manner in vitro and in vivo and recognize a determinant on macrophage membranes. In addition, they do not affect the I-Ek-restricted activation of a Th cell line specific for pigeon heart cytochrome c. We conclude that these mAb may recognize a molecule other than conventional I-Ek on cells interacting with Ts cells that is involved in mediating Ts activity. The molecule recognized may be a modified I-Ek molecule or a molecule not encoded by the genes encoding I-Ek.
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