Induction of Autoimmune Valvular Heart Disease by Recombinant Streptococcal M Protein

Abstract

Rheumatic heart disease is an autoimmune sequela of group A streptococcal infection. Previous studies have established that streptococcal M protein is structurally and immunologically similar to cardiac myosin, a well-known mediator of inflammatory heart disease. In this study, we investigated the hypothesis that streptococcal M protein could produce inflammatory valvular heart lesions similar to those seen in rheumatic fever (RF). Fifty percent (3 of 6) of Lewis rats immunized with recombinant type 6 streptococcal M protein (rM6) developed valvulitis as well as focal lesions of myocarditis. Valvular lesions initiated at the valve surface endothelium spread into the valve. Anitschkow cells and verruca-like lesions were present. T cells from rM6-immunized rats proliferated in the presence of purified cardiac myosin, but not skeletal myosin. A T-cell line produced from rM6-treated rats proliferated in the presence of cardiac myosin and rM6 protein. The study demonstrates that the Lewis rat is a model of valvular heart disease and that streptococcal M protein can induce an autoimmune cell-mediated immune attack on the heart valve in an animal model. The data support the hypothesis that a bacterial antigen can break immune tolerance in vivo, an important concept in autoimmunity.

Fluoride Exposure Attenuates Expression of Streptococcus pyogenes Virulence Factors

“…M protein has been implicated in the pathogenesis of both rheumatic fever and ASPGN. One putative mechanism for M protein's role in these disorders is presumably the crossreaction of anti-M protein antibodies with host myosin proteins (43,44). Several factors may have contributed to the decreased incidence of rheumatic fever and APSGN in industrialized countries, including the introduction of antibiotics, aggressive treatment of streptococcal pharyngitis, and improved public health measures.…”

Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

“…Streptococcal M protein mimics cardiac myosin sequences or epitopes and immunization with the M protein or peptides leads to myocardial and valvular inflammatory heart lesions in BALB/c mice and Lewis rats. 22,31 Therefore, it would seem that the ␣-helical structure is not the critical factor in breaking self tolerance, but that unique and/or cryptic epitopes present in cardiac myosin are the decisive factor. In fact, unique epitopes within cardiac myosin have been described to produce myocarditis.…”

A Lipid Core Peptide Construct Containing a Conserved Region Determinant of the Group A Streptococcal M Protein Elicits Heterologous Opsonic Antibodies

“…Protective immunity to GAS infection has been associated with typespecific opsonic antibodies against M protein (10,21), although the presence of opsonic antibodies specific to the Cregion has been demonstrated in humans (17) and in mice immunized with C-region peptides (18) and is also important in the elicitation of protective immunity to GAS (4). The variability in M proteins and the potential for the induction of autoimmunity due to antigenic molecular mimicry between the GAS M protein and heart antigens (6,11,13,19) represent significant hurdles in the development of a vaccine covering a wide range of strains. Multivalent M protein constructs containing epitopes from several type-specific regions of different M proteins (4,7,8) and those based on the conserved C-region (2-5) have shown promising results in animal trials.…”