The microbiome and rheumatic heart disease: current knowledge and future perspectives.

Rheumatic heart disease (RHD) is a cardiovascular disease caused by an autoimmune response to group A Streptococcus (GAS) infection resulting in the damage of heart valves. RHD is the most commonly acquired heart disease among children and young adults with a global burden of over 40 million cases accounting for 306,000 deaths annually. Inflammation in the heart valves caused due to molecular mimicry between the GAS antigens and host cardiac proteins is facilitated by cytokines, cross-reactive antibodies and CD4+ T cells. The complex interaction between genetic and environmental factors linked with erratic events leads to the loss of immunological tolerance and autoimmunity in RHD. Despite extensive research on the etiopathogenesis of RHD, the precise mechanism underpinning the initiation of acute rheumatic fever (ARF) to the progression of RHD still remains elusive. Mounting evidences support the contribution of the human microbiome in the development of several immune-mediated diseases including rheumatoid arthritis, juvenile idiopathic arthritis, Kawasaki disease, inflammatory bowel disease and type 1 diabetes. The microbiome and their metabolites could play a crucial role in the integrity of the epithelial barrier, development of the immune system, inflammation and differentiation of T cell subsets. Consequently, microbiome dysbiosis might result in autoimmunity by molecular mimicry, epitope spreading and bystander activation. This review discusses various aspects of the interaction between the microbiome and the immune system in order to reveal causative links relating dysbiosis and autoimmune diseases with special emphasis on RHD.

Lack of Association Between TNF-α, IFN-γ, IL-10 Gene Polymorphisms and Rheumatic Heart Disease in South Indian Population.

BACKGROUND: Proinflammatory and anti-inflammatory cytokines play a crucial role in the development and maintenance of immune mediated inflammatory diseases including rheumatic heart disease (RHD). Polymorphisms in tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-10 genes influence the differential cytokine expression as well as the pathogenesis of various inflammatory and autoimmune diseases. OBJECTIVE: The aim of the study is to investigate the association between TNF-α, IFN-γ, and IL-10 gene polymorphisms and RHD in South Indian population. MATERIALS AND METHODS: TNF-α (-308, -238), IFN-γ (+874), and IL-10 (-1082, -819, -592) gene polymorphisms were determined in 100 patients with RHD and 127 healthy siblings by PCR. RESULTS: There was no significant difference in the genotype, allele, and haplotype frequencies of TNF-α, IFN-γ, and IL-10 polymorphisms between RHD patients and healthy siblings. CONCLUSION: The present study suggests that TNF-α, IFN-γ, and IL-10 gene variants may not be associated with the development of RHD in South Indian population.

Association of IL17 and IL23R gene polymorphisms with rheumatic heart disease in South Indian population.

BACKGROUND: IL-23/Th17 signaling pathway plays a crucial role in the cell-mediated immune response against bacterial infections and also in the pathogenesis of inflammatory and autoimmune diseases. Recent studies indicate that Th17 cell-associated cytokines are involved in the progression and maintenance of valvular lesions in rheumatic heart disease (RHD). Variants in the genes of cytokines that are potentially involved in Th17 response may influence interindividual differences in their expression levels, thereby contributing to the pathogenesis of immune-mediated diseases such as RHD. OBJECTIVE: The aim of the study is to investigate the association of IL17A, IL17F, and IL23R gene variants with the risk perception of RHD. METHODS: A total of 225 individuals (99 RHD patients and 126 healthy siblings) were recruited for the study. The IL17A (rs2275913), IL17F (rs763780), and IL23R (rs10889677) polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphisms and amplification-refractory mutation system-polymerase chain reaction methods, respectively. RESULTS: The frequency of IL17A (rs2275913) A/A genotype was significantly high in pooled RHD patients (odds ratio [OR] = 2.76; pc = 0.021), rheumatic fever (RF) patients (OR = 14.5; pc = 0.0001), and mitral valvular lesions patients (OR = 2.74; pc = 0.039) when compared to healthy siblings. However, the IL17F (rs763780) and IL23R (rs10889677) polymorphisms did not show any association with RHD. CONCLUSIONS: The results suggest that IL17A (rs2275913) polymorphism is associated with the development of RF/RHD in South Indian population. Further studies are required to substantiate the association of these genes with the disease risk.

"HLA-G 3'UTR gene polymorphisms and rheumatic heart disease: a familial study among South Indian population".

BACKGROUND: Rheumatic heart disease (RHD) is an autoimmune disease where cross reactive CD4+ T cells are involved in the pathogenesis of valvular damage. Human Leukocyte Antigen-G (HLA-G), an immunosuppressive molecule playing a crucial role in the inhibition of T cell response is associated with the pathogenesis of various autoimmune and inflammatory diseases. Genetic polymorphisms within the 3'untranslated region (UTR) of HLA-G influences its expression and thus disease pathogenesis. Hence, the present study aims to unravel the association of 14 bp Ins/Del (rs66554220) and +3142 C/G (rs1063320) polymorphisms in 3' UTR of HLA-G with RHD. METHODS: This familial study consists of 99 RHD families (99 RHD patients, 140 parents and 126 healthy siblings). The 14 bp Ins/Del and +3142 C/G polymorphisms were evaluated by PCR using sequence specific primers and its transmission disequilibrium (TD) was tested by TD test in 70 trio families. RESULTS: The frequency of +3142 C/C genotype was high in patients with combined valvular lesions (CVL) (OR = 5.88; pc = 0.012) and pooled RHD patients (P: OR = 2.76; p = 0.043; pc = 0.076) when compared to healthy siblings. Under the additive (OR = 5.50; pc = 0.026) and recessive genetic model (OR = 5.88; pc = 0.012), the +3142 C/C genotype was significantly associated with CVL in patients. CONCLUSION: The results suggest that the +3142 C/C genotype may be associated with minor risk for the development of RHD and is more likely to influence the severity of the disease.