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.

Association of HLA-DRB1 Alleles with Rheumatic Fever and Rheumatic Heart Disease: A Meta-analysis.

BACKGROUND: Rheumatic fever (RF) and its sequel rheumatic heart disease (RHD) is an autoimmune disease caused by an abnormal host immune response to group A streptococcus (GAS) infection. The HLA class II molecules are entailed in immune-mediated infectious, inflammatory, and autoimmune diseases including RHD. However, HLA class II genes are reported to be associated with RF/RHD across different populations with a very little consistency. OBJECTIVE: The aim of the study is to investigate the association between HLA class II genes and RF/RHD by meta-analysis. METHODS: A comprehensive literature search was conducted to identify all relevant case-control studies published before December 31, 2019. The data were extracted using standardized form and pooled odds ratio (OR) with 95% confidence interval (CI) are calculated to assess the strength of the association between HLA class II genes and RF/RHD. RESULTS: Thirteen studies for HLA-DRB1 alleles (1065 patients and 1691 controls) and eight studies for HLA-DQB1 alleles (644 patients and 1088 controls) were finally included. The meta-analysis showed a significantly higher frequency of HLA-DRB1*07 allele (OR = 1.68, P < .0001) in RF/RHD patients when compared to controls, while the frequency of HLA-DRB1*15 allele (OR = 0.60, P = .03) was significantly lower in RF/RHD patients than in controls. However, there were no significant differences in the frequency of HLA-DQB1 alleles between RF/RHD patients and controls. CONCLUSIONS: The results of the meta-analysis suggest that the differential presentation of autoimmune peptides by HLA-DRB1*07 (susceptible) and HLA-DRB1*15 (protective) alleles with different affinities may play a crucial role in the pathogenesis of RF/RHD.

Association of HLA-G 3'UTR 14-bp Ins/Del polymorphism with breast cancer among South Indian women.

AIM: Human leucocyte antigen-G (HLA-G) and tumour necrosis factor-alpha (TNF-α) are potent immune mediators implicated in the pathogenesis of breast cancer. The polymorphisms in the 3' untranslated region (3'UTR) of HLA-G and promoter region of TNF-α are well known to influence their expression levels and may consequently contribute to varied disease predisposition. Therefore, in the present study, we explored the effect of HLA-G 3'UTR (14-bp Ins/Del and +3142 C/G) and TNF-α promoter (-238 G/A and -308 G/A) polymorphisms on breast cancer risk among South Indian women. METHODS: A total of 342 women (100 patients with breast cancer, 142 patients with benign breast disorder and 100 healthy women volunteers) were enrolled for this study. Genotyping of HLA-G and TNF-α polymorphisms were performed by direct PCR DNA amplification and amplification refractory mutation system PCR methods, respectively. RESULTS: Significantly higher frequencies of HLA-G 14-bp Ins allele and Ins/+3142G haplotype were observed in patients with breast cancer than healthy controls (OR=1.56, Pc=0.036) and patients with benign breast disorder (OR=1.47, Pc=0.046). Similarly, subgroup analysis based on age at diagnosis (age≤50 years and >50 years) of breast cancer revealed higher frequencies of 14-bp Ins allele and Ins/+3142G haplotype in the patients of age >50 years than healthy controls (OR=1.77, Pc=0.03). Additionally, the extended haplotypes and multifactor dimensionality reduction analysis of the studied polymorphisms revealed significant contribution of HLA-G 14-bp Ins/Del polymorphism towards breast cancer risk. CONCLUSION: The findings of the present study suggest that the HLA-G 14-bp Ins/Del polymorphism could influence breast cancer pathogenesis among South Indian women.