Neurobehavioral and carditis abnormalities in Lewis Rat Autoimmune Valvulitis Model following exposure to streptococcal M proteins

Abstract

<p><b>Background:</b> An autoimmune response triggered by Group A streptococcal (GAS) infection leads to Acute Rheumatic Fever/Rheumatic Heart Disease (ARF/RHD) and neurobehavioral changes. This cross-reactive immune response leads to Sydenham’s Chorea (SC) as the antibodies bind to basal ganglia and neuronal cells. It’s been demonstrated that injection of Lewis rats with M protein from Streptococcus dysgalactiae subspecies equisimilis (SDSE) also led to valvular lesions. Therefore, we hypothesised that M proteins of GAS and SDSE may also be associated with the development of neurobehavioral changes associated with post streptococcal sequalae.</p> <p><b>Methods:</b> Standard neurobehavioral assessments and electrocardiography were performed on Lewis rats before and after injecting recombinant GAS or SDSE M proteins. ELISA and Western blot analysis were performed to determine the cross reactivity of antibodies with purified host connective tissue, cardiac and neuronal proteins. Histological assessments were performed to confirm inflammatory changes in cardiac and neuronal tissue.</p> <p><b>Results:</b> In addition to cardiac complications, Lewis rats injected with either GAS or SDSE M proteins showed significant similar neurobehavioral changes compared to control rats injected with PBS. Antibodies against GAS and SDSE antigens cross-reacted with purified lysoganglioside, dopamine 1 and dopamine 2 receptors and tubulin and endogenous proteins of basal ganglia. In addition, antibodies from GAS and SDSE M proteins showed elevated binding to striatum and cortex in vitro. </p> <p><b>Conclusion:</b> Neurobehavioral changes observed in our experimental model exposed to GAS and SDSE antigens were comparable to human disease and demonstrated for the first time that M proteins of SDSE could also initiate and drive the autoimmune responses, simultaneously causing both cardiac and neurobehavioral changes.</p>