The autoimmune side of rheumatic fever. (2014)

A cute rheumatic fever (ARF) is a multisystemic disease caused by an abnormal immunological response after group A Streptococcus (GAS) pharyngitis in predisposed people. Among the major criteria for diagnosis of ARF (Jones criteria) are carditis, polyarthritis, Sydenham chorea, erythema marginatum and subcutaneous nodules [1]. The disease usually presents with one or more acute episodes, while in 30–50% of all recurrent cases ARF may lead to chronic rheumatic heart disease (RHD) with progressive and permanent damage of the cardiac valves. Despite a notable reduction in the disease prevalence in industrialized countries, RHD remains one of the major causes of morbidity and mortality in developing countries. Over 15 million cases of RHD are estimated worldwide, with 282,000 new cases and 233,000 deaths annually. The pathogenesis is not yet completely clarified; however, RHD may represent the most convincing model of an autoimmune disease triggered by infections, since the infectious agent is proven [Table 1]. The endocardial valve tissue is the main localization of cardiac damage. Peripheral T lymphocytes, interacting with adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1), infiltrate a non-vascularized tissue. Roberts et al. [2] demonstrated that VCAM-1 was expressed on the valvular endothelium in rheumatic valves, and that at the valve surface CD4+ and CD8+ T lymphocytes were adherent to valve endothelium and penetrated through the subendothelial layer. Thus, T cell extravasation into the valve through the surface valvular endothelium appeared to be an important event in the development of RHD [2]. Furthermore, the evidence that the disease has an autoimmune background derives from the presence of anti-GAS antibodies as one of the major features in patients with rheumatic valvular disease. Antibodies and complement deposits have been detected in the heart of RHD patients, suggesting an autoimmune process [3]. The pathogenesis of RHD results from an immune response consisting of humoral and cellular components after exposure to Streptococcus pyogenes. The classic triad of the disease comprises the presence of the rheumatogenic group A streptococcal strain, a genetically susceptible host, and aberrant host immune response. There is a closer association of human leukocyte antigen (HLA) class II molecules (which participate in antigen presentation to T cell receptors) with an increased risk of acute rheumatic fever or rheumatic heart disease than class I molecules. The autoimmune hypothesis was suggested in a 2001 study in which Lewis rats immunized with recombinant type 6 streptococcal M protein (rM6) developed valvulitis as well as focal lesions of myocarditis. Indeed, streptococcal M protein is structurally and immunologically similar to cardiac myosin working as antigenic mimicry. Interestingly, the valvular lesions initiated at the valve surface endothelium spread into the valve, and Anitschkow cells and verruca-like lesions were present. T lymphocytes from rM6immunized rats proliferated in the presence of purified cardiac myosin, but not skeletal myosin, while a T cell line produced from rM6-treated rats proliferated in the presence of cardiac myosin and rM6 protein. It was suggested that streptococcal M protein can induce an autoimmune cell-mediated immune attack on the heart valve in such an animal model [4]. Furthermore, antibodies against group A Streptococcus were demonstrated to react with human heart preparations. It is suspected that after binding to the antigenic peptide, the specific HLA complexes can initiate aberrant T cell activation. Molecular mimicry is another key step since it takes place between streptococcal M protein and several self cardiac proteins (tropomyosin, keratin, cardiac myosin, laminin, vimentin). The complement cascade seems to be activated through the lectin pathway. Indeed, mannose-binding lectin (MBL), by acting as a soluble rheumatic fever, rheumatic heart disease (RHD), autoantibodies, antiphospholipid syndrome, anti-endothelial cell antibodies