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

Abstract

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...

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

“…The recognition of M5 peptides B2 and B3A by T cells from rheumatic heart disease is consistent with previous reports (25,46), although it remains to be determined which of the class II HLA molecules in this patient are presenting streptococcal peptides B2 and B3A to T cell clones cross-reactive for human myosin. A review of the literature fails to identify a strong association between class II HLA and rheumatic heart disease, but previous studies do indicate that a number of class II HLA alleles found in this patient are not associated with rheumatic heart disease.…”

“…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).…”

“…These data are supported by induction of IFN-␥ by the cross-reactive peptide epitopes responsible for the mimicry in both M protein and human cardiac myosin. Previous studies have demonstrated IFN-␥ in valve tissues in rheumatic carditis (72) as well as by peripheral T cell clones isolated from rheumatic patients and stimulated with heart and streptococcal Ags (25,46,72). Effector T cells which mediate disease in experimental models of autoimmune disease typically have, with a few exceptions, a Th1 proinflammatory phenotype.…”

“…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). The T cells in the valve infiltrate are believed to be the effectors of tissue damage (45) and would originate from T cells in peripheral blood after their contact with the infectious pathogen (46). It is our hypothesis that the T a Cross-reactive T cell clones were plated at 300 cells/well.…”

"Determinação de alvos antigênicos na doença reumática cardíaca utilizando phage display"

“…A coréia pode ocorrer na forma "pura" ou em associação com a cardite (DÉCOURT, 1972). Recentemente, observou-se que pacientes portadores de cardite leve (65%) apresentavam concomitantemente coréia enquanto que esta raramente estava associada com a presença de cardite grave (5%) (GUILHERME, et al 2001a). A proteína M é a mais abundante na superfície e é considerada como o principal componente antigênico da bactéria.…”