Preferential recognition of human myocardial antigens by T lymphocytes from rheumatic heart disease patients

Abstract

Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are autoimmune sequelae of upper respiratory infections with group A streptococci (GAS). To gain a better understanding of the pathogenesis of these diseases, we examined the in vitro proliferative responses of peripheral blood mononuclear cells (PBMC) from RHD patients to human myocardial proteins in a T-cell Western assay. A number of myocardial proteins fractionated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis were recognized by PBMC from both patients and controls. However, PBMC from a significant percentage of RHD patients (40%) responded to a discrete band of myocardial proteins migrating with an apparent molecular mass of 50 to 54 kDa while none of the control subject PBMC responded to this protein band (P < 0.0001). To further investigate the link between infections with GAS and autoimmune carditis, we studied the proliferative responses of PBMC from patients and controls to myocardial proteins before and after in vitro stimulation of the cells with opsonized GAS isolated from ARF patients. Priming of PBMC with rheumatogenic GAS caused the percentage of RHD patients responding to the 50-to 54-kDa myocardial proteins to increase from 43 to 90% (P < 0.0284). By contrast, PBMC from control subjects failed to recognize the 50-to 54-kDa myocardial proteins even after stimulation with the opsonized streptococci (P < 0.0001). The assay sensitivity was increased from 40 to 90% after priming of a patient's cells with opsonized GAS, but the positive predictive value was 100% in both unprimed and primed cultures. Antibodies generated to partially purified 50-to 54-kDa myocardial proteins did not cross-react with either streptococcal homogenates, purified M protein, myosin, laminin, or vimentin, suggesting a lack of cross-reactivity at the humoral level. This study suggests that the 50-to 54-kDa myocardial proteins contain a putative antigen that is preferentially recognized by T cells from RHD patients and demonstrates that exposure to streptococcal antigens enhances the ability of patients to recognize these proteins.

Distinct Mitral Valve Proteomic Profiles in Rheumatic Heart Disease and Myxomatous Degeneration

“…However, patients with MXD did not display altered vimentin expression, suggesting that the mechanisms leading to valvar disease are distinct from those observed in MXD. 18 Collagen-VI expression, on the other side, was remarkably decreased in the RHD groups. It is a structural component of the ECM whose alpha chain has 108 kDa.…”

“…However, patients with MXD did not display altered vimentin expression, suggesting that the mechanisms leading to valvar disease are distinct from those observed in MXD. 18…”

Prognostic significance of soluble interleukin‐2 receptor levels in patients with dilated cardiomyopathy

“…There is a quantitative increase in lymphocytic infiltration of the cardiomyopathic heart, which includes interleukin‐2 receptor‐positive cells [5,6]. In analogy with other examples of organ‐specific autoimmune diseases [12], T‐cell activation is thought to play a role in the initiation and maintenance of myocardial damage (chiefly through the elaboration of cytotoxic cytokines). The interleukin‐2 receptor exists in a soluble form in sera and the release rate of the soluble form reflects T‐cell activation in vivo [13].…”

Pathogenesis of Group A Streptococcal Infections

“…T-cell epitopes have been reported for M5 protein, and a summary of our current knowledge of T-cell epitopes has been reported (123). T-cell responses to M protein have been investigated in a number of studies (123,138,154,167,216,250,435,436,455,456,521,522) involved in M protein-specific protective immune responses (436,455,456). Robinson and colleagues have mapped multiple T-cell epitopes of streptococcal M proteins.…”