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Rheumatic heart disease follows Group A Streptococcus (GAS) infection in Aboriginal Australians. A genome-wide study identified HLA as the strongest genetic risk factor. Risk and protective HLA_DQA1_DQB1 haplotypes bound with different affinities to core epitopes of pathogenic GAS M proteins. Abstract Background Rheumatic heart disease (RHD) after group A streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers proinflammatory cardiac valve-reactive T cells. Methods Genome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single-nucleotide polymorphisms were genotyped using Illumina HumanCoreExome BeadChips. Direct typing and imputation was used to fine-map the human leukocyte antigen (HLA) region. Epitope binding affinities were mapped for human cross-reactive GAS proteins, including M5 and M6. Results The strongest genetic association was intronic to HLA-DQA1 (rs9272622; P = 1.86 × 10−7). Conditional analyses showed rs9272622 and/or DQA1*AA16 account for the HLA signal. HLA-DQA1*0101_DQB1*0503 (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.09–1.90; P = 9.56 × 10−3) and HLA-DQA1*0103_DQB1*0601 (OR, 1.27; 95% CI, 1.07–1.52; P = 7.15 × 10−3) were risk haplotypes; HLA_DQA1*0301-DQB1*0402 (OR 0.30, 95%CI 0.14–0.65, P = 2.36 × 10−3) was protective. Human myosin cross-reactive N-terminal and B repeat epitopes of GAS M5/M6 bind with higher affinity to DQA1/DQB1 alpha/beta dimers for the 2-risk haplotypes than the protective haplotype. Conclusions Variation at HLA_DQA1-DQB1 is the major genetic risk factor for RHD in Aboriginal Australians studied here. Cross-reactive epitopes bind with higher affinity to alpha/beta dimers formed by risk haplotypes, supporting molecular mimicry as the key mechanism of RHD pathogenesis.

Acute Rheumatic Fever and Rheumatic Heart Disease (ARF/RHD) affect over 45 million people globally. ARF/RHD are autoimmune complications following group A streptococcal infections. Current diagnosis of ARF requires thorough medical examination, echocardiography and laboratory tests that are unavailable in most primary care settings where patients with ARF typically first present. This pilot study was conducted to determine whether machine learning-based predictive models could be used to stratify host tissue protein reactive antibodies associated with ARF, that could be incorporated into a lateral flow point-of-care (POC) platform for ARF screening. We investigated serum antibody levels against four host tissue proteins (cardiac myosin, laminin, keratin, and tropomyosin) known to increase in ARF. Serum samples were obtained from: (i) a rat autoimmune valvulitis model (RAV) of RHD (30 streptococcal M protein-injected rats versus 30 controls); and (ii) human samples (25 newly diagnosed ARF patients versus 50 healthy controls). Four machine learning algorithms (logistic regression, decision tree, random forest, and AdaBoost) predicted ARF status using antibody levels detected by enzyme-linked immunosorbent assay (ELISA). Rats injected with streptococcal M protein developed cardiac pathology and demonstrated three-fold higher optical density values for all four host tissue protein reactive antibodies compared to controls. ARF patients showed significantly elevated antibody levels against all host tissue proteins tested ( p  < 0.01). Random forest achieved optimal performance for rat data (sensitivity 100%, specificity 92.5%, AUROC = 0.97), while AdaBoost excelled for human samples using binary biomarkers (sensitivity 85.0%, specificity 82.8%, AUROC = 0.87). We demonstrate the screening potential of known host tissue protein reactive antibodies and propose lateral flow assay POC technology as a possible advancement toward improved early screening for ARF in resource-constrained environments.

Rheumatic heart disease (RHD) is a complication of group A streptococcal infection that results from a complex interaction between the genetic make-up of the host, the infection itself and several other environmental factors, largely reflecting poverty. RHD is estimated to affect 33.4 million people and results in 10.5 million disability-adjusted life-years lost globally. The disease has long been considered heritable but still little is known about the host genetic factors that increase or reduce the risk of developing RHD. In the 1980s and 1990s, several reports linked the disease to the human leukocyte antigen (HLA) locus on chromosome 6, followed in the 2000s by reports implicating additional candidate regions elsewhere in the genome. Subsequently, the search for susceptibility loci has been reinvigorated by the use of genome-wide association studies (GWAS) through which millions of variants can be tested for association in thousands of individuals. Early findings implicate not only HLA, particularly the HLA-DQA1 to HLA-DQB1 region, but also the immunoglobulin heavy chain locus, including the IGHV4-61 gene segment, on chromosome 14. In this Review, we assess the emerging role of GWAS in assessing RHD, outlining both the advantages and disadvantages of this approach. We also highlight the potential use of large-scale, publicly available data and the value of international collaboration to facilitate comprehensive studies that produce findings that have implications for clinical practice.Rheumatic heart disease is a complication of group A streptococcal infection and rheumatic fever. In this Review, Muhamed and colleagues assess the emerging role of genome-wide association studies in detecting loci associated with genetic susceptibility to rheumatic heart disease.

The indigenous populations of the South Pacific experience a high burden of rheumatic heart disease (RHD). Here we report a genome-wide association study (GWAS) of RHD susceptibility in 2,852 individuals recruited in eight Oceanian countries. Stratifying by ancestry, we analysed genotyped and imputed variants in Melanesians (607 cases and 1,229 controls) before follow-up of suggestive loci in three further ancestral groups: Polynesians, South Asians and Mixed or other populations (totalling 399 cases and 617 controls). We identify a novel susceptibility signal in the immunoglobulin heavy chain (IGH) locus centring on a haplotype of nonsynonymous variants in the IGHV4-61 gene segment corresponding to the IGHV4-61 *02 allele. We show each copy of IGHV4-61 *02 is associated with a 1.4-fold increase in the risk of RHD (odds ratio 1.43, 95% confidence intervals 1.27–1.61, P =4.1 × 10 −9 ). These findings provide new insight into the role of germline variation in the IGH locus in disease susceptibility. Rheumatic heart disease (RHD) is a chronic auto-inflammatory reaction to group A streptococcal infection, and frequently occurs in individuals from the South Pacific. This study finds a novel association between an immunoglobulin heavy chain allele and risk of RHD in Pacific Islanders and South Asians.

Acute rheumatic fever (ARF) is an autoimmune disease caused by group A streptococcal infection. Recurrent episodes of ARF can lead to rheumatic heart disease (RHD), which is the leading cause of cardiovascular mortality in children worldwide, especially in low- and middle-income countries. Investigations into the etiology of ARF and RHD constitute a crucial milestone in the advancement of both preventive measures and therapeutic interventions. The purpose of this mini review is to delineate the etiology and pathophysiological mechanisms underlying ARF and RHD. Selective searches were conducted in PubMed to retrieve literature published between 1968 and 2024, employing key terms such as “acute rheumatic fever”, “rheumatic heart disease”, “group A Streptococcus ”, “streptococcal pharyngitis”, “pathogenesis”, and “pathophysiology”. The pathogenesis of infections caused by group A streptococci, and their effects on ARF and RHD, have been thoroughly examined. A central hypothesis is that autoimmune responses are triggered by molecular mimicry, but alternate pathogenic mechanisms are continuously being explored. There is an urgent need for high-quality research that can inform efforts aimed at decreasing the occurrence of ARF and halting the advancement of RHD, which requires researchers to understand its causes and to develop appropriate preventive and therapeutic programs.

Cardio-rheumatology is an evolving and interdisciplinary field lying at the intersection of rheumatology and cardiovascular medicine that recognizes that individuals with autoimmune and inflammatory rheumatic complications have a much higher likelihood of developing cardiovascular diseases (CVDs). Inflammasomes are multiprotein complexes stimulated by the immune system after the detection of pathogens or cellular injury. Inflammasomes undergo a two-stage activation process initiated by nuclear factor (NF)-κB, subsequently playing a crucial role in innate immunity through activation of caspase 1 and the consequent release of proinflammatory cytokines such as IL-18 and IL-1β. However, a loss of control of inflammasome activation can cause inflammatory diseases in humans. Recent studies have focused on the role of inflammasomes in inflammatory cascades implicated in the pathogenesis of several diseases. Here, we review inflammasome activation, its mechanism of action, and its role in CVD. In particular, we describe the role of inflammasomes in rheumatic heart disease, Kawasaki disease, familial Mediterranean fever, ankylosing spondylitis, and rheumatoid arthritis as exemplars to illustrate pathobiological mechanisms and the potential for targeting inflammasomes for therapeutic benefit.

Post-streptococcal autoimmune syndromes, including acute rheumatic fever, rheumatic heart disease, and Sydenham’s chorea, represent a significant yet often under-recognized health and economic burden. This is especially true in low-income countries and among Indigenous populations in high-income nations, where the disease burden is most severe. These conditions arise from an autoimmune response to group A Streptococcus infections, leading to long-term health complications, disability, and premature death. Despite their widespread impact, no vaccine is currently available to prevent reinfections, and no specific therapy exists to treat the resulting autoimmune process. This study uses a rat model of rheumatic heart disease to evaluate the potential of low-dose interleukin 2 therapy in improving clinical outcomes and reducing the incidence of autoimmune diseases triggered by streptococcal infections.

Rheumatic Heart Disease (RHD) remains a significant health burden, particularly in regions with scarce healthcare resources, research on its immunological aspects remains insufficient. This study employed a two-sample Mendelian Randomization approach, utilizing GWAS data from the largest available datasets for gut microbiota and immune cells as exposures, with outcome data for Rheumatic Valve Diseases (RVD) and Rheumatic Heart Disease affecting other parts of the heart (RHD-other) obtained from the FinnGen study. The primary analytical method was the Inverse Variance Weighted (IVW) approach, complemented by heterogeneity analyses and MR-Egger regression to assess horizontal pleiotropy. Furthermore, a two-step mediation analysis was conducted to investigate the potential mediating role of immune cells in the association between gut microbiota and RHD. This study revealed significant inverse associations between gut microbiota abundance and Rheumatic Heart Disease (RHD) risk. Specifically, the gut abundance of genus Blautia was negatively correlated with RHD-other risk (P_IVW: 0.00932, OR [95%CI]: 0.000734[3.22e-06, 0.16937]), and genus Ruminococcaceae UCG005 showed a similar negative association (P_IVW: 0.038, OR [95%CI]: 0.165[0.02994, 0.90811]). Additionally, the proportions of CD4-CD8- T cell %leukocyte and CD4-CD8- T cell %T cell were inversely related to RHD-other risk (P_IVW: 0.02222, OR [95%CI]: 5.08027 [1.26133, 20.46191] and P: 0.01601, OR[95%CI]: 6.55576 [1.4196, 30.27582], respectively). Moreover, IgD on IgD + CD24 + B cells was found to be negatively correlated with RHD-other risk (P_IVW: 0.01867, OR [95%CI]: 2.17171 [1.1380, 4.14443]). The study also highlighted the protective effects of gut microbiota through mediation analyses: Blautia’s impact via IgD on IgD + CD24 + B cells showed a mediation proportion of 8.62514%; Ruminococcaceae UCG005’s influence via CD4-CD8- T cell %T cell and CD4-CD8- T cell %leukocyte resulted in mediation proportions of 35.25817% and 30.86827%, respectively. Significant inverse associations were observed between gut microbiota abundance and risk of Rheumatic Heart Disease (RHD), with specific findings for Rheumatic Valve Disease (RVD) and RHD affecting other parts of the heart (RHD-other). For RHD-other, higher abundance of Blautia (OR: 0.0007, 95% CI: 3.22e-06 to 0.169, p  = 0.009) and Ruminococcaceae UCG005 (OR: 0.165, 95% CI: 0.030 to 0.908, p  = 0.038) were associated with lower risk. Additionally, lower proportions of CD4-CD8- T cells (%leukocyte and %T cell) and IgD on IgD + CD24 + B cells were inversely related to RHD-other risk (ORs: 5.08 and 6.56, p  = 0.022 and p  = 0.016, respectively). For RVD, higher abundance of Candidatus Soleaferrea was protective (OR: 0.670, 95% CI: 0.460 to 0.976, p  = 0.037), while higher levels of CD11c on granulocytes were associated with increased risk (OR: 1.310, 95% CI: 1.023 to 1.679, p  = 0.032). Mediation analyses indicated that gut microbiota influence RHD risk through distinct immune pathways, with Blautia affecting RHD-other via IgD on B cells (8.62% mediation), Ruminococcaceae UCG005 via CD4-CD8- T cells (%T cell: 35.26%, %leukocyte: 30.87%). Genus Candidatus Soleaferrea affecting RVD through CD11c on granulocyte (15.01% mediation). The study concludes that higher gut abundance of Candidatus Soleaferrea protects against RVD through the mechanism involving CD11c on granulocytes. Additionally, Blautia exerts a protective effect against RHD-other through its influence on IgD on IgD + CD24 + B cells. Similarly, the abundance of genus Ruminococcaceae UCG005 provides protection against RHD-other by influencing CD4-CD8- T cell %T cell and CD4-CD8- T cell %leukocyte.

BackgroundRheumatic mitral stenosis (RMS) is the most common manifestation of rheumatic heart disease, with high morbidity and mortality. Interleukin-35 (IL-35) is a novel anti-inflammatory cytokine associated with many autoimmune diseases. However, the relation between IL-35 expression and RMS remains unknown. We aimed to study IL-35 expression in RMS and its association with disease progression.MethodsIL-35 concentration was analyzed in blood samples from 40 patients, including 20 moderate, 20 severe RMS, and 20 healthy controls by ELISA. Mitral valve (MV) IL-35 expression was determined by western blot and immunohistochemistry in patients with RMS (22 and 29 cases, respectively) in comparison to control specimens with mitral valve prolapsed (5 cases, respectively).ResultsIL-35 levels were significantly elevated in the blood of the RMS patients compared to those from healthy subjects(p<0.05) and positively correlated with the severity of RMS (r=0.317, p<0.05). The expression of IL-35 and its subunits (p35 and EBI3) was also detected in MV tissues of patients with moderate or severe RMS. The expression of IL-35 and its subunits (p35 and EBI3) had a positive association with the severity of RMS in MV tissues (r=0.528, p<0.01; r=0.561, p<0.001; r=0.456, p<0.01). Co-localization of p35 and EBI3 was seen in MV tissues of RMS patients in a predominantly perivascular pattern.ConclusionWe show for the first time an increase of IL-35 level in the blood and MV tissues of RMS patients, which is strongly correlated with the severity of RMS. These results suggest that IL-35 plays an important regulatory role in the progression of RMS.

Rheumatic heart disease (RHD) is an important and preventable cause of cardiovascular death and disability, but the lack of clarity about its exact mechanisms makes it more difficult to find alternative methods or prevention and treatment. We previously demonstrated that increased IL-17 expression plays a crucial role in the development of RHD-related valvular inflammatory injury. Macrophage autophagy/polarization may be a pro-survival strategy in the initiation and resolution of the inflammatory process. This study investigated the mechanism by which IL-17 regulates autophagy/polarization activation in macrophages. A RHD rat model was generated, and the effects of anti-IL-17 and 3-methyladenine (3-MA) were analyzed. The molecular mechanisms underlying IL-17-induced macrophage autophagy/polarization were investigated via in vitro experiments. In our established RHD rat model, the activation of the macrophage PINK1/Parkin autophagic pathway in valve tissue was accompanied by M1 macrophage infiltration, and anti-IL-17 treatment inhibited autophagy and reversed macrophage inflammatory infiltration, thereby attenuating endothelial–mesenchymal transition (EndMT) in the valve tissue. The efficacy of 3-MA treatment was similar to that of anti-IL-17 treatment. Furthermore, in THP-1 cells, the pharmacological promotion of autophagy by IL-17 induced M1-type polarization, whereas the inhibition of autophagy by 3-MA reversed this process. Mechanistically, silencing PINK1 in THP-1 blocked autophagic flux. Moreover, IL-17-induced M1-polarized macrophages promoted EndMT in HUVECs. This study revealed that IL-17 plays an important role in EndMT in RHD via the PINK1/Parkin autophagic pathway and macrophage polarization, providing a potential therapeutic target.