Repeat exposure to group A streptococcal M protein exacerbates cardiac damage in a rat model of rheumatic heart disease

Abstract

Rheumatic fever and rheumatic heart disease (RF/RHD) develop following repeated infection with group A streptococci (GAS). We used the Rat Autoimmune Valvulitis (RAV) model of RF/RHD to demonstrate that repetitive booster immunization with GAS-derived recombinant M protein (rM5) resulted in an enhanced anti-cardiac myosin antibody response that may contribute to the breaking of immune tolerance leading to RF/RHD and increased infiltration of heart valves by mononuclear cells. With each boost, more inflammatory cells were observed infiltrating heart tissue which could lead to severe cardiac damage. We also found evidence that both complement and anti-M protein antibodies in serum from rM5-immunized rats have the potential to contribute to inflammation in heart valves by activating cardiac endothelium. More importantly we have demonstrated by electrocardiography for the first time in the RAV model that elongation of P-R interval follows repetitive boost with rM5. Our observations provide experimental evidence for cardiac alterations following repeat exposure to GAS M protein with immunological and electrophysiological features resembling that seen in humans following recurrent GAS infection.

Scolopendra subspinipes mutilans L. Koch Ameliorates Rheumatic Heart Disease by Affecting Relative Percentages of CD4+CD25+FoxP3 Treg and CD4+IL17 T Cells

“…It has been reported that CD4 + T cells are the major effector cells in the heart valve of RHD patients, and the number of these cells is increased in the peripheral blood of RHD patients [16]. There are approximately 5% to 10% of CD4 + T cells in peripheral blood and spleen tissues of healthy persons.…”

Molecular Mimicry, Autoimmunity, and Infection: The Cross-Reactive Antigens of Group A Streptococci and their Sequelae

“…T cell lines from the model proliferated to both the rM6 protein and cardiac myosin. The model appeared to be very similar in appearance to the VCAM-1 activation (Figure 11D) and infiltration of CD4+ T cells into the VCAM-1 + endothelium/endocardium (not shown) (156) of the valve in rheumatic heart disease (48) (Figure 12). More recent studies identified A and B region peptide epitopes of M5 protein that induced valvulitis in the Lewis rat (8).…”

Rheumatic heart disease in the modern era: recent developments and current challenges

“…Typically the first streptococcal throat infection does not trigger an episode of rheumatic fever. One hypothesis is that recurrent infections are able to maintain the germinal center reaction and affinity for antibody maturation, thereby potentiating cross-reactivity 39,40 . As such, preexisting immune complexes would capture more antibodies leading to amplification of the immune response, which further favors the recognition of several host epitopes and propagates tissue damage feeding the disease onset 41 .…”