Rheumatic Heart Disease: Pathogenesis and Vaccine.

Rheumatic fever (RF) and rheumatic heart disease (RHD) follow untreated S. pyogenes throat infections in children who present susceptible genes that favor the development of autoimmune reactions. In this review, we focus on the genes that confer susceptibility and on the autoimmune reactions that occur due to molecular mimicry between human-tissue proteins and streptococcal M protein. Polyarthritis is the initial manifestation, which can evolve to carditis and severe valve damage; these culminate in rheumatic heart disease (RHD) or Sydenham's chorea, which affects the central nervous system. A perspective on vaccine development to prevent the disease is also discussed.

Rheumatic heart disease: mediation by complex immune events.

Rheumatic fever (RF) is an autoimmune disease caused by the Gram-positive bacteria Streptococcus pyogenes following an untreated throat infection in susceptible children. Rheumatic heart disease (RHD), the most serious complication, occurs in 30-45% of RF patients and leads to chronic valvular lesions. Here, we focus on the genes that confer susceptibility for developing this disease. Molecular mimicry mediates the cross-reactions between streptococcal antigens and human proteins. Several autoantigens have been identified, including cardiac myosin epitopes, vimentin, and other intracellular proteins. In heart tissue, antigen-driven oligoclonal T cell expansions probably cause the rheumatic heart lesions. These cells are CD4+ and produce inflammatory cytokines (TNF alpha and IFN gamma). IL-4+ cells are found in the myocardium; however, these cells are very scarce in the valve lesions of RHD patients. IL-4 is a Th2-type cytokine and plays a regulatory role in the inflammatory response mediated by Th1 cytokines. Our findings indicate that the Th1/Th2 cytokine balance has a role in healing myocarditis while the low numbers of IL-4-producing cells in the valves probably induced the progressive and permanent valve damage.

No evidence for association of the TP53 12139 and the BAX-248 polymorphisms with endemic pemphigus foliaceus (fogo selvagem).

Pemphigus foliaceus (PF) is an autoimmune bullous epidermal disease, characterized by autoantibodies specific to the desmosomal protein desmoglein 1 (dsg1) and by acantholysis, the rupture of the cellular junctions among keratinocytes. Known also as fogo selvagem (wild fire) in Brazil, the disease has distinct epidemiological characteristics, being endemic in certain regions of South America. It is a multifactorial (complex) disease, with oligo- or polygenic disease susceptibility. In view of the previously reported evidences of a role for apoptosis dysregulation in pemphigus pathogenesis, we hypothesized that genetic variants of molecules participating in apoptosis may contribute to interindividual variation of susceptibility to PF. The TP53 12139(G,C) and the BAX-248(G,A) single nucleotide polymorphisms (SNP) were analysed in a genetic association study. The allelic, genotypic and allele carrier frequencies for these SNPs did not differ statistically between the patient and the control groups, for both the Euro- and the Afro-Brazilian population strata. The results of this study lead us to conclude that, although the TP53 and BAX alleles analysed differ functionally, this variation does not alter the functionality of the molecules in a way that would interfere with the development of the disease.