Tissue distribution of lymphocytes in rheumatic heart valves as defined by monoclonal anti-T cell Antibodies

Raizada, Veena; Williams, Ralph C.; Chopra, Prem; Gopinath, N; Prakash, K; Sharma, Kumudini; Cherian, Keziah; Panday, Sharad; Arora, Ramesh; Nigam, M; Zabriskie, John B.; Husby, Gunnar

doi:10.1016/0002-9343(83)91124-5

Cited by 110 publications

(49 citation statements)

References 17 publications

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“…The presence of CD4 ϩ T cells at the heart lesion sites of RHD patients has been shown (13)(14)(15). The functional role of these infiltrating T cells was described by our group.…”

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confidence: 69%

Mimicry in Recognition of Cardiac Myosin Peptides by Heart-Intralesional T Cell Clones from Rheumatic Heart Disease

Faé

Silva

Oshiro

et al. 2006

The Journal of Immunology

136

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Molecular mimicry between Streptococcus pyogenes Ags and human proteins has been considered as a mechanism leading to autoimmune reactions in rheumatic fever and rheumatic heart disease (RHD). Cardiac myosin has been shown as a putative autoantigen recognized by autoantibodies of rheumatic fever patients. We assessed the human heart-intralesional T cell response against human light meromyosin (LMM) and streptococcal M5 peptides and mitral-valve-derived proteins by proliferation assay. Cytokines induced by LMM peptides were also evaluated. The frequency of intralesional T cell clones that recognized LMM peptides was 63.2%. Thirty-four percent of T cell clones presented cross-reactivity with different patterns: 1) myosin and valve-derived proteins; 2) myosin and streptococcal M5 peptides; and 3) myosin, valve-derived proteins and M5 peptides. In addition, several LMM peptides were recognized simultaneously showing a multiple reactivity pattern of heart-infiltrating T cells. Inflammatory cytokines (IFN-γ and TNF-α) were predominantly produced by heart-infiltrating T cells upon stimulation with LMM peptides. The alignment of LMM and streptococcal M5 peptides showed frequent homology among conserved amino acid substitutions. This is the first study showing the cellular response by human heart-infiltrating T cells against cardiac myosin epitopes in RHD patients. The high percentage of reactivity against cardiac myosin strengthens its role as one of the major autoantigens involved in rheumatic heart lesions. T cell reactivity toward myosin epitopes in RHD patients may also trigger the broad recognition of valvular proteins with structural or functional similarities.

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“…The presence of CD4 ϩ T cells at the heart lesion sites of RHD patients has been shown (13)(14)(15). The functional role of these infiltrating T cells was described by our group.…”

mentioning

confidence: 69%

Mimicry in Recognition of Cardiac Myosin Peptides by Heart-Intralesional T Cell Clones from Rheumatic Heart Disease

Faé

Silva

Oshiro

et al. 2006

The Journal of Immunology

136

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“…These T-cell clones predominantly recognized M5 peptides encompassing residues 81 to 103 (15 of 32 [46.9%]). Peptides M5(1-20), M5 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), and M5(163-177) were recognized by 3 of 32 (9.4%), 3 of 32 (9.4%), and 6 of 36 (16.7%) peptide-reactive heart-infiltrating T-cell clones, respectively (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

“…Peptide M5(1-20) was recognized by PBMC from 35.1% of patients with severe RHD and those from 8.6% of controls, (P ϭ 0.01) ( Table 1). Peptides M5 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and M5(125-139) were predominantly recognized by PBMC from patients with mild RHD compared with controls (P ϭ 0.008 and P ϭ 0.01, respectively) ( Table 1). Although 54.5% of patients with mild RHD and 5.4% of patients with severe RHD presented Sydenham chorea (P Ͻ 0.001) we could not identify any specific antipeptide reactivity among these patients.…”

Section: Resultsmentioning

confidence: 99%

T-Cell Reactivity against Streptococcal Antigens in the Periphery Mirrors Reactivity of Heart-Infiltrating T Lymphocytes in Rheumatic Heart Disease Patients

et al. 2001

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T-cell molecular mimicry between streptococcal and heart proteins has been proposed as the triggering factor leading to autoimmunity in rheumatic heart disease (RHD). We searched for immunodominant T-cell M5 epitopes among RHD patients with defined clinical outcomes and compared the T-cell reactivities of peripheral blood and intralesional T cells from patients with severe RHD. The role of HLA class II molecules in the presentation of M5 peptides was also evaluated. We studied the T-cell reactivity against M5 peptides and heart proteins on peripheral blood mononuclear cells (PBMC) from 74 RHD patients grouped according to the severity of disease, along with intralesional and peripheral T-cell clones from RHD patients. Peptides encompassing residues 1 to 25, 81 to 103, 125 to 139, and 163 to 177 were more frequently recognized by PBMC from RHD patients than by those from controls. The M5 peptide encompassing residues 81 to 96 [M5(81-96) peptide] was most frequently recognized by PBMC from HLA-DR7 ؉ DR53 ؉ patients with severe RHD, and 46.9% (15 of 32) and 43% (3 of 7) of heart-infiltrating and PBMC-derived peptide-reactive T-cell clones, respectively, recognized the M5(81-103) region. Heart proteins were recognized more frequently by PBMC from patients with severe RHD than by those from patients with mild RHD. The similar pattern of T-cell reactivity found with both peripheral blood and heart-infiltrating T cells is consistent with the migration of M-protein-sensitized T cells to the heart tissue. Conversely, the presence of heart-reactive T cells in the PBMC of patients with severe RHD also suggests a spillover of sensitized T cells from the heart lesion.Rheumatic fever (RF) is a sequel of group A streptococcal throat infection and remains an important health problem in developing countries. About 30% of RF patients develop rheumatic heart disease (RHD), with high morbidity and cost to the public health system. Molecular mimicry between streptococcal antigens, mainly the M protein, and heart tissue proteins is proposed as an important factor leading to the heart lesions found in RHD patients. Several studies have been performed with human peripheral blood mononuclear cells (PBMC) showing reactivity against the streptococcal cell wall and tissue antigens (20,25). CD4 ϩ T cells are the predominant population at the site of heart lesions (23, 16).Yoshinaga et al. (30) reported that T-cell lines derived from heart valve specimens and PBMC from RF patients react with cell wall and membrane streptococcal antigens. These lymphocytes did not cross-react with M protein or mammalian cytoskeletal proteins. Autoreactivity to heart antigens caused by streptococcal infections was also suggested by results of immunization in which peripheral T lymphocytes from RHD patients stimulated in vitro with streptococci were able to recognize a 50-to 54-kDa myocardial protein fraction (7). Our group previously reported intralesional T-cell clones, from surgical fragments of patients with severe RHD, capable of recognizing immunodominant...

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“…In rheumatic heart disease, it is well established that T cells infiltrate heart valves (25,(43)(44)(45)(46), and valve damage appears to be T lymphocyte dependent. In support of cross-reactive T cells in valve lesions, T cells from valves of rheumatic fever patients have been shown to proliferate in response to peptides of streptococcal M5 protein and heart tissue Ags (25).…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that the cross-reactive T cells isolated from rheumatic valves expand upon recognition of cross-reactive Ag in the valve of which laminin is only one example. Fae et al (56) (43,44,60). Receptor tuning (61), a process by which the activation threshold of a T cell can be altered, may be another way of generating a cross-reactive TCR with higher affinity for the self Ag cardiac myosin.…”

Section: Discussionmentioning

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

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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Tissue distribution of lymphocytes in rheumatic heart valves as defined by monoclonal anti-T cell Antibodies

Cited by 110 publications

References 17 publications

Mimicry in Recognition of Cardiac Myosin Peptides by Heart-Intralesional T Cell Clones from Rheumatic Heart Disease

Mimicry in Recognition of Cardiac Myosin Peptides by Heart-Intralesional T Cell Clones from Rheumatic Heart Disease

T-Cell Reactivity against Streptococcal Antigens in the Periphery Mirrors Reactivity of Heart-Infiltrating T Lymphocytes in Rheumatic Heart Disease Patients

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

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