Induction of Myocarditis and Valvulitis in Lewis Rats by Different Epitopes of Cardiac Myosin and Its Implications in Rheumatic Carditis

Galvin, Jeffrey E.; Hemric, Mark E.; Kosanke, Stanley D.; Factor, Stephen M.; Quinn, Anthony; Cunningham, Madeleine W.

doi:10.1016/s0002-9440(10)64373-8

Cited by 92 publications

(95 citation statements)

References 43 publications

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“…These animal studies suggest that myosin reciprocally induces myosin-reactive T cells in the heart which may cross-react with M protein (21). Although pathogenic T cells may initially be cross-reactive, chronic inflammation in the target organ may lead to the eventual epitope spreading to proteins present in the valve (42).…”

Section: Discussionmentioning

confidence: 97%

“…Reaction of Ag with an Ab or T cell does not necessarily mean that it is the cause of disease. In the case of skeletal myosin, it does not cause disease in animals, whereas cardiac myosin produces fulminant myocarditis and valvulitis in rats and mice (21,22). Crossreactive T cells entering the valve in rheumatic carditis lead to chronic inflammation and potentially to epitope spreading and recognition of epitopes within the valve perpetuating heart disease.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we investigated human cross-reactive B cell responses against mimicking Ags in rheumatic carditis and found that sera and human mAbs from rheumatic carditis reacted with the major heart autoantigen cardiac myosin (17)(18)(19)(20). The importance of cardiac myosin is related to its ability to produce myocarditis and valvular heart disease in animal models (21)(22)(23). Group A streptococcal M protein, an ␣-helical coiled coil molecule with high homology to cardiac myosin, induced valvular rheumatic-like heart disease in Lewis rats (24).…”

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confidence: 99%

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T Cell Mimicry and Epitope Specificity of Cross-Reactive T Cell Clones from Rheumatic Heart Disease

Ellis

Hildebrand

et al. 2005

The Journal of Immunology

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120

109

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Mimicry between streptococcal M protein and cardiac myosin is important in the pathogenesis of rheumatic heart disease. M protein-specific human T cell clones derived from rheumatic carditis were cross-reactive with human cardiac myosin, and laminin, a valve protein. Among the 11 CD4+ and CD8+ cross-reactive T cell clones, at least 6 different reactivity patterns were distinguished, suggesting different degrees of cross-reactivity and a very diverse T cell repertoire. The latter was confirmed by a heterogeneous Vβ gene and CDR3 usage. HLA restriction and Th1 cytokine production in response to rM6 protein were preserved when the T cell clones were stimulated by human cardiac myosin or other α-helical proteins, such as tropomyosin and laminin. The cross-reactive human T cell clones proliferated to B2 and B3A, dominant peptide epitopes in the B repeat region of streptococcal M protein. In human cardiac myosin, epitopes were demonstrated in the S2 and light meromyosin regions. In our study, T cell mimicry was defined as recognition of structurally related Ags involved in disease and recognized by the same T cell. Mimicry in our study was related to α-helical coiled coil proteins which have a repetitive seven-aa residue periodicity that maintains α-helical structure and thus creates a high number of degenerate possibilities for recognition by T cells. The study of human T cell clones from rheumatic heart disease revealed potential sites of T cell mimicry between streptococcal M protein and human cardiac myosin and represents some of the most well-defined T cell mimicry in human autoimmune disease.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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T Cell Mimicry and Epitope Specificity of Cross-Reactive T Cell Clones from Rheumatic Heart Disease

Ellis

Hildebrand

et al. 2005

The Journal of Immunology

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120

109

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“…Previous studies have demonstrated that cardiac myosin is an immunodominant Ag in autoimmune myocarditis, and pathogenic regions of cardiac myosin have been identified using the EAM model in both rats and mice (10,22,(31)(32)(33)(34)(35)(36)(37)(38). Cardiac myosin is a large peptide, which is composed of two H chains and two pair of L chains.…”

mentioning

confidence: 99%

Cryptic Epitope Identified in Rat and Human Cardiac Myosin S2 Region Induces Myocarditis in the Lewis Rat

Heuser

Kosanke

et al. 2004

The Journal of Immunology

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Myocarditis is a common cause of dilated cardiomyopathy leading to heart failure. Chronic stages of myocarditis may be initiated by autoimmune responses to exposed cardiac Ags after myocyte damage. Cardiac myosin, a heart autoantigen, induced experimental autoimmune myocarditis (EAM) in susceptible animals. Although cardiac myosin-induced myocarditis has been reported in Lewis rats, the main pathogenic epitope has not been identified. Using overlapping synthetic peptides of the S2 region of human cardiac myosin, we identified an amino acid sequence, S2–16 (residues 1052–1076), that induced severe myocarditis in Lewis rats. The myocarditic epitope was localized to a truncated S2–16 peptide (residues 1052–1073), which contained a sequence identical in human and rat cardiac myosin. The S2–16 peptide was not myocarditic for three other strains of rats, in which the lack of myocarditis was accompanied by the absence of strong S2–16-specific lymphocyte responses in vitro. For Lewis rats, S2–16 was characterized as a cryptic epitope of cardiac myosin because it did not recall lymphocyte and Ab responses after immunization with cardiac myosin. Lymphocytes from S2–16 immunized rats recognized not only S2–16, but also peptides in the S2–28 region. Furthermore, peptide S2–28 was the dominant epitope recognized by T cells from cardiac myosin immunized rats. S2–16 was presented by Lewis rat MHC class II molecules, and myocarditis induction was associated with an up-regulation of inflammatory cytokine production. S2–16-induced EAM provides a defined animal model to investigate mechanisms of EAM and modulation of immune responses to prevent autoimmune myocarditis.

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“…The S2 segment (amino acids 596-1,295), corresponding to the rod region of the protein, has been found to contain the epitopes responsible for producing the inflammatory response in this model of myocarditis. 30 Adoptive transfer by antimyosin-specific sera was successful in DBA/2 mice, but not in BALB/c or A/J mice. 31 The susceptibility of the DBA/2 strain to antibody-induced myocarditis seems to be related to extracellular expression of myosin in the heart, supporting the notion that antimyosin antibodies are not able to induce disease in the undamaged heart.…”

Section: Autoantibodies Targeting Cardiac Myosinmentioning

confidence: 96%

Contribution of Acquired Factors to the Pathogenesis of Dilated Cardiomyopathy - The Cause of Dilated Cardiomyopathy: Genetic or Acquired? (Acquired-Side) -

Yoshikawa

2011

Circ J

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Induction of Myocarditis and Valvulitis in Lewis Rats by Different Epitopes of Cardiac Myosin and Its Implications in Rheumatic Carditis

Cited by 92 publications

References 43 publications

T Cell Mimicry and Epitope Specificity of Cross-Reactive T Cell Clones from Rheumatic Heart Disease

T Cell Mimicry and Epitope Specificity of Cross-Reactive T Cell Clones from Rheumatic Heart Disease

Cryptic Epitope Identified in Rat and Human Cardiac Myosin S2 Region Induces Myocarditis in the Lewis Rat

Contribution of Acquired Factors to the Pathogenesis of Dilated Cardiomyopathy - The Cause of Dilated Cardiomyopathy: Genetic or Acquired? (Acquired-Side) -

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