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

Li, Ya; Heuser, Janet S.; Kosanke, Stanley D.; Hemric, Mark E.; Cunningham, Madeleine W.

doi:10.4049/jimmunol.172.5.3225

Cited by 62 publications

(57 citation statements)

References 47 publications

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“…It is probable that the cross-reactive peptides B2, B3A, S2-4, and LMM 35 share homology at the contact residues and trigger the TCR of clone 3E11-1.2. Cross-reactive clone 3E11-1.10 recognized the human cardiac myosin epitope S2-16, an epitope shown to produce severe myocarditis in the Lewis rat (28).…”

Section: Discussionmentioning

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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121

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: 99%

“…Peptides of the S2 fragment of the human cardiac myosin ␤-chain rod region were synthesized by Genemed Synthesis as 25-mers with 11-aa overlap (28) and were purified by HPLC.…”

Section: Synthetic Peptidesmentioning

confidence: 99%

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

Self Cite

121

109

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“…The amino acid sequence of S2-16 peptide is KRKLEG-DLKLTQESIMDLENDKQQL, and sequence of S2-1 peptide is SAEREKEMASMKEEFTRLKEALEKS. 20 …”

Section: Animals and Antigensmentioning

confidence: 99%

“…20 In this study, we investigate regulation of autoreactive T cells in the S2-16-induced EAM. Administration of autoantigen in IFA is well known to effectively induce antigen-specific unresponsiveness in animal models.…”

Section: Prevention Of Eam By S2-16 Peptide and Ifa Treatmentmentioning

confidence: 99%

Protection against Experimental Autoimmune Myocarditis Is Mediated by Interleukin-10-Producing T Cells that Are Controlled by Dendritic Cells

Heuser

Kosanke

et al. 2005

The American Journal of Pathology

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Experimental autoimmune myocarditis (EAM) can be induced in the LewisMyocarditis is an inflammatory heart disease that can be initiated by infectious pathogens. 1-3 Dilated cardiomyopathy, which may follow myocarditis and represent the chronic stage of disease, is a major cause of heart failure and heart transplantation. 4 -6 Evidence suggests that autoimmune responses to cardiac antigens exposed after heart damage may play an important role in prolonged damage of myocardium. 3,7-9 Nevertheless, little progress has been made in treating myocarditis by immunosuppression, because a complete understanding of key factors that regulate the pathogenic immune responses in autoimmune myocarditis are not well established.Experimental autoimmune myocarditis (EAM) generated in susceptible mouse and rat strains by immunization with purified cardiac myosin or a specific pathogenic cardiac myosin peptide in adjuvant has been used to investigate the pathogenesis of myocarditis induced by autoimmune mechanisms. 10 -20 Many studies have shown that cardiac antigen-induced myocarditis is a Tcell-mediated disease. 18,[21][22][23][24] However, the active induction of EAM relies on the use of bacterial adjuvants [complete Freund's adjuvant (CFA)] during immunization, suggesting that activation of the innate immune system is important in disease induction. [25][26][27] Inflammatory cytokines such as interleukin (IL)-1, tumor necrosis factor (TNF)-␣, and IL-12 promote myocarditis development in animals, 28 -31 whereas mice that lack TNF-Rp55 or are deficient in IL-12 signaling were protected from EAM. 32,33 In vivo inhibition of co-stimulatory molecule B7-1 and CD40 also markedly decreased myocardial inflammation. 34,35 A recent study directly demonstrated that cardiac antigen-loaded dendritic cells (DCs) induced autoimmune myocarditis when they were activated and transferred. 36 Taken together, these studies suggest that EAM induction is closely associated with not only the myocarditic epitopes of cardiac myosin and their reactive T cells, but also with the activation of antigen-presenting cells (APCs) such as DCs by inflammatory cytokines.

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“…Lewis rats are known to be susceptible to several experimental autoimmune diseases: adjuvant arthritis (30), experimental autoimmune encephalomyelitis (31), myocarditis (32), uveitis (20), and others (33). The immunized rats did not manifest clinical signs of muscle weakness or paralysis.…”

Section: Testing For Pathogenicity Of Immunizationmentioning

confidence: 99%

Identification of Aldolase as a Target Antigen in Alzheimer’s Disease

Mor

Izak

Cohen

2005

The Journal of Immunology

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Alzheimer’s disease (AD) is the most common human neurodegenerative disease, leading to progressive cognitive decline and eventually death. The prevailing paradigm on the pathogenesis of AD is that abnormally folded proteins accumulate in specific brain areas and lead to neuronal loss via apoptosis. In recent years it has become evident that an inflammatory and possibly autoimmune component exists in AD. Moreover, recent data demonstrate that immunization with amyloid-β peptide is therapeutically effective in AD. The nature of CNS Ags that are the target of immune attack in AD is unknown. To identify potential autoantigens in AD, we tested sera IgG Abs of AD patients in immunoblots against brain and other tissue lysates. We identified a 42-kDa band in brain lysates that was detected with >50% of 45 AD sera. The band was identified by mass spectrometry to be aldolase A. Western blotting with aldolase using patient sera demonstrated a band of identical size. The Ab reactivity was verified with ELISAs using aldolase. One of 25 elderly control patients and 3 of 30 multiple sclerosis patients showed similar reactivity (p < 0.002). In enzymatic assays, anti-aldolase positive sera were found to inhibit the enzyme’s activity, and the presence of the substrate (fructose 1,6-diphosphate) enhanced Ab binding. Immunization of rats and mice with aldolase in complete Freund’s adjuvant was not pathogenic. These findings reveal an autoimmune component in AD, point at aldolase as a common autoantigen in this disease, and suggest a new target for potential immune modulation.

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

Cited by 62 publications

References 47 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

Protection against Experimental Autoimmune Myocarditis Is Mediated by Interleukin-10-Producing T Cells that Are Controlled by Dendritic Cells

Identification of Aldolase as a Target Antigen in Alzheimer’s Disease

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