Repeat exposure to group A streptococcal M protein exacerbates cardiac damage in a rat model of rheumatic heart disease

Rheumatic fever and rheumatic heart disease (RF/RHD) develop following repeated infection with group A streptococci (GAS). We used the Rat Autoimmune Valvulitis (RAV) model of RF/RHD to demonstrate that repetitive booster immunization with GAS-derived recombinant M protein (rM5) resulted in an enhanced anti-cardiac myosin antibody response that may contribute to the breaking of immune tolerance leading to RF/RHD and increased infiltration of heart valves by mononuclear cells. With each boost, more inflammatory cells were observed infiltrating heart tissue which could lead to severe cardiac damage. We also found evidence that both complement and anti-M protein antibodies in serum from rM5-immunized rats have the potential to contribute to inflammation in heart valves by activating cardiac endothelium. More importantly, we have demonstrated by electrocardiography for the first time in the RAV model that elongation of P–R interval follows repetitive boost with rM5. Our observations provide experimental evidence for cardiac alterations following repeated exposure to GAS M protein with immunological and electrophysiological features resembling that seen in humans following recurrent GAS infection.     

Superantigen-induced T cell responses in acute rheumatic fever and chronic rheumatic heart disease patients

CD4+ and CD8+ T cells from healthy donors, acute rheumatic fever (ARF) and chronic rheumatic heart disease (CRHD) patients responded variably to a superantigen from Streptococcus pyogenes--Streptococcal pyrogenic erythrogenic toxin A (SPE-A). In vitro culture of CD4+ T cells from ARF patients (CD4-ARF) with SPE-A exhibited a Th1 type of response as they produced high levels of IL-2, while CD4+ T cells from CRHD patients (CD4-RHD) secreted IL-4 and IL-10 in large amounts, i.e. Th2 type of cytokine profile. The skewing of human CD4+ T cells (in response to SPE-A stimulation) to Th1 or Th2 type reflects the role of the two subsets in a disorder with differing intensities at the two extremes of the spectrum. Moreover, the anergy induction experiments revealed that CD8-ARF and CD8-RHD undergo anergy (to different extents), whereas CD4+ T cells do not, in response to re-stimulation by SPE-A. These results initially demonstrate that both CD4+ and CD8+ T cells respond differentially to SPE-A, and hence it is an important observation with respect to the pathogenesis of ARF/CRHD. Anergy in CD8+ T cells in the presence of SPE-A in vitro goes a step further to show the clinical relevance of these cells and their possible role in suppression of the disease.     

Genetic variants in rheumatic fever and rheumatic heart disease

Genetic association studies in rheumatic heart disease (RHD) have the potential to contribute toward our understanding of the pathogenetic mechanism, and may shed light on controversies about RHD etiology. Furthermore, genetic association studies may uncover biomarkers that can be used to identify susceptible individuals, and contribute toward developing vaccine and novel therapeutic targets. Genetic predisposition to rheumatic fever and RHD has been hypothesized by findings from familial studies and observed associations between genes located in the human leukocyte antigens on chromosome 6p21.3 and elsewhere in the genome. We sought to summarize, from published Genetic association studies in RHD, evidence on genetic variants implicated in RHD susceptibility. Using HuGENet? systematic review methods, we evaluated 66 studies reporting on 42 genes. Existing meta‐analyses of candidate gene studies suggest that TGF‐β1 [rs1800469], and IL‐1β [rs2853550] single nucleotide polymorphisms (SNPs) contribute to susceptibility to RHD, whereas the TNF‐α [rs1800629 and rs361525], TGF‐β1 [rs1800470 and rs4803457], IL‐6 [rs1800795], IL‐10 [rs1800896] were not associated with RHD. However, candidate gene studies in RF/RHD are relatively small, thus lacking statistical power to identify reliable and reproducible findings, emphasizing the need for large‐scale multicenter studies with different populations.     

Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease

Molecular mimicry is a hallmark of the pathogenesis of rheumatic fever where the streptococcal group A carbohydrate epitope, N-acetyl glucosamine, and the α-helical coiled-coil streptococcal M protein structurally mimic cardiac myosin in the human disease, rheumatic carditis, and in animal models immunized with streptococcal M protein and cardiac myosin. Recent studies have unraveled the potential pathogenic mechanisms by which the immune response against the group A streptococcus attacks the rheumatic valve leading to chronic rheumatic heart disease. Both B- and T-cell responses are involved in the process, and evidence for the hypotheses of molecular mimicry and epitope spreading are reviewed.     

Anti-endothelial cell antibodies in rheumatic heart disease

To evaluate the anti‐endothelial cell antibodies (AECA), anti‐cardiolipin antibodies (aCL) and serum mannose‐binding lectin (MBL) profiles of a large cohort of Yemeni patients with rheumatic heart disease (RHD) and to correlate these findings with clinical features of the disease. Patients (n = 140) were recruited from Al‐Thawra Hospital in Sana'a, Yemen. All had RHD diagnosed according to modified Jones' criteria. We also studied 140 sex‐ and age‐matched healthy blood donors from the same area. Echocardiography was performed according to the recommendations of the American Society of Echocardiography. Solid phase enzyme‐linked immunosorbent assays (ELISAs) were used to measure AECA and aCL titres and serum MBL levels. Forty per cent of the patients were AECA‐positive, but only 7·8% were positive for aCL antibodies. Serum MBL levels were significantly lower in the RHD group (median 4221 ng/ml versus 5166 ng/ml in healthy controls). AECA titres were correlated positively with patient age, duration of RHD and the severity of aortic stenosis, as determined by echocardiographic findings. In several autoimmune rheumatic diseases, such as systemic lupus erythematosus, vasculitis and scleroderma, AECA have been shown to play pathogenic roles by producing proinflammatory and procoagulant effects (increased expression of adhesion molecules and tissue factors, increased cytokine release) in endothelial cells. In RHD, these autoantibodies might represent a pathological link between activation of the valvular endothelium and valvular damage.     

风湿性心脏病粘附斑激酶表达与心肌间质纤维化关系的研究

目的研究粘附斑激酶在风湿性心脏病心肌组织中的表达及其与风湿性心脏病的心肌间质纤维化之间的关系。方法采用免疫组化法和原位杂交法检测粘附斑激酶在20例风湿性心脏病患者心肌组织和5例正常心肌组织中的表达,心肌行VG染色后,图像分析心肌胶原体积分数及心肌血管周围胶原面积比例,并测定心肌组织羟脯氨酸含量,将所得结果进行相关分析。结果风湿性心脏病患者心肌组织不同程度表达粘附斑激酶,且较正常对照组明显升高(P<0.05),粘附斑激酶蛋白和mRNA的表达量与心肌胶原体积分数、心肌血管周围胶原面积比例和羟脯氨酸含量呈显著正相关。结论粘附斑激酶可能在风湿性心脏病心肌间质纤维化进程中发挥重要作用,它可能是促进风湿性心脏病心肌胶原合成的重要信号分子。     

风湿性心脏病与成人先心病围手术期心肌酶变化的比较

目的通过对风湿性心脏病（RHD组）和成人先天胜心脏病（CHD组）患者围术期心肌酶的变化进行动态观察,探讨不同病种的手术对心肌损伤的影响。方法44例成人患者接受心内直视手术,其中RHD组24例患者接受二尖瓣置换术;CHD组20例患者为先天性房间隔缺损或室间隔缺损。手术前1d、术后1d,3d、5d和8d分别取静脉血,测定并比较两组患者血清门冬酸氨基转移酶（AST）、肌酸激酶（CK）及其同工酶MB（CK-MB）、乳酸脱氢酶（LDH）、α-羟丁酸脱氢酶（HBHD）的变化。结果两组患者术前5种心肌酶均在正常范围,术后1d分别升高到术前的2～11倍（P〈0．01）,术后3d均有不同程度的恢复,到术后8d,除两组的LDH和HBHD仍高于术前外,其它酶的释放量均已恢复到正常水平。术后心肌酶的释放量RHD组较CHD组为高（P〈0．05）。结论择期手术的RHD和CHD患者术前心肌酶的释放量在正常水平。术后两组心肌酶释放的高峰时间及心肌酶的恢复次序是一致的,术后RHD组患者心肌酶的释放量较CHD组患者高。     

Cytotoxic T lymphocyte-associated antigen-4 polymorphism in patients with rheumatic heart disease

Acute rheumatic fever (ARF) is a systemic inflammatory disease occurring as a consequence of an exaggerated immune response to group A, beta haemolytic streptococcal pharyngitis. The molecular mimicry between human target organs/tissues and specific components of the infectious organism leads to the development of autoimmune reactions and cardiac tissue damage in rheumatic heart disease (RHD). Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T cell activation and proliferation during the immune response. CTLA-4 gene polymorphism has been shown to affect the inhibitory function of CTLA-4. We aimed to analyze the association of CTLA-4 gene locus at position 49 of exon 1 with susceptibility to ARF/RHD. This study included a total of 98 patients with RHD as a sequela of ARF, who fulfilled the revised classification criteria of Jones and 154 healthy unrelated controls. CTLA-4 +49 A/G polymorphism was genotyped by using PCR-RLFP technique. Data was analyzed by binary logistic regression models. The frequencies of GG, GA and AA genotypes were found to be 14%, 47% and 39%, respectively, in patients and 6%, 45% and 49%, respectively, in controls. The GG genotype was found to be significantly different between patients and controls (OR: 3.11; P = 0.016). GA and AA genotypes did not statistically differ between patients and controls. Our data showed a significant association of +49G /G polymorphism in a small patient group with RHD.     

The association between mannose-binding lectin gene polymorphism and rheumatic heart disease

Mannan-binding lectin (MBL) is an innate pattern recognition molecule known to play a key role in pathogen clearance. As MBL2 gene polymorphism is associated to an increased susceptibility to infection, we aimed to determine genetic variations in the MBL2 gene in rheumatic heart disease (RHD). Genetic variations in the promoter and exon 1 region of the MBL2 gene were analyzed in 107 patients with RHD and 105 controls by real-time polymerase chain reaction. The frequency of MBL2* A/A genotype was significantly higher in RHD patients (71/107, 66.36% vs 52/105, 49.52%, p ≤ 0.02, OR = 1.99, 95% CI, 1.15–3.50). A/A genotypes were associated with higher levels of MBL in RHD compared with controls with the same genotype (p ≤ 0.004). The frequency of HYPA/HYPA, HYPA/LYQA, and LYQA/LYQA haplotypes was also increased in RHD (p ≤ 0.03, OR = 1.98, 95% CI, 1.05–3.73). However, the frequency of MBL2 variant alleles (termed “O”) was lower among patients (39/214, 18.2% vs 63/210, 30.0%, p ≤ 0.006, OR = 0.52, 95% CI, 0.33–0.82), which was also seen for O/O genotypes (3/107, 2.8% vs 10/105, 9.5%, p ≤ 0.05, OR = 0.27, 95% CI, 0.07–1.03). This data suggests a role for MBL genotypes in the susceptibility to RHD. However, it still remains unclear whether A/A homozygosity is a risk factor for RHD or rheumatic fever itself.     

Streptococcal–vimentin cross‐reactive antibodies induce microvascular cardiac endothelial proinflammatory phenotype in rheumatic heart disease

Rheumatic heart disease (RHD) is characterized by the presence of anti‐streptococcal group A antibodies and anti‐endothelial cell antibodies (AECA). Molecular mimicry between streptococcal antigens and self proteins is a hallmark of the pathogenesis of rheumatic fever. We aimed to identify, in RHD patients, autoantibodies specific to endothelial autoantigens cross‐reactive with streptococcal proteins and to evaluate their role in inducing endothelial damage. We used an immunoproteomic approach with endothelial cell‐surface membrane proteins in order to identify autoantigens recognized by AECA of 140 RHD patients. Cross‐reactivity of purified antibodies with streptococcal proteins was analysed. Homologous peptides recognized by serum cross‐reactive antibodies were found through comparing the amino acid sequence of streptococcal antigens with human antigens. To investigate interleukin (IL)‐1R‐associated kinase (IRAK1) and nuclear factor‐κB (NF‐κB) activation, we performed a Western blot analysis of whole extracts proteins from unstimulated or stimulated human microvascular cardiac endothelial cells (HMVEC‐C). Adhesion molecule expression and release of proinflammatory cytokines and growth factors were studied by multiplex bead based immunoassay kits. We observed anti‐vimentin antibodies in sera from 49% RHD AECA‐positive patients. Cross‐reactivity of purified anti‐vimentin antibodies with heat shock protein (HSP)70 and streptopain streptococcal proteins was shown. Comparing the amino acid sequence of streptococcal HSP70 and streptopain with human vimentin, we found two homologous peptides recognized by serum cross‐reactive antibodies. These antibodies were able to stimulate HMVEC‐C inducing IRAK and NF‐κB activation, adhesion molecule expression and release of proinflammatory cytokines and growth factors. In conclusion, streptococcal–vimentin cross‐reactive antibodies were able to activate microvascular cardiac endothelium by amplifying the inflammatory response in RHD.     

风湿性心脏病伴发脑栓塞患者脑血流动力学初探

目的：研究风湿性心脏病伴发血栓脱落致脑栓塞(stroke caused by thrombosis of rheumatic heart disease,RHD)患者的血流动力学特征。方法：用经颅多普勒超声(transcranial Doppler,TCD)连续观查30例确诊的风湿性心脏病伴发血栓脱落致脑栓塞患者,另选同期在我院体检中心体检的正常患者60例进行对照。结果：RHD患者主要表现为椎基底动脉收缩期血流缓慢、脉动指数降低、Vp和Vm间的差距变小、波峰圆钝、多数患者出现频窗充填。除Vd值以外,两组病人左右椎动脉和基底动脉的Vp、Vm、PI值间均存在显著性差异(P<0.05)。结论：RHD患者的血流动力学表现具有相对的特异性,TCD可作为其临床初步筛查和辅助诊断手段之一。     

Significantly increased levels of mannose-binding lectin (MBL) in rheumatic heart disease: a beneficial role for MBL deficiency

Although mannose-binding lectin (MBL) is known to be involved in the primary defense against microorganisms, there are emerging lines of evidence for an active proinflammatory role for MBL in different chronic diseases. In this study we determined the circulating levels of MBL in patients with rheumatic heart disease (RHD). A total of 100 patients (77 women, 23 men; mean age 45.8 +/- 11 years, range 19-76 years) with chronic RHD, and a previous diagnosis of rheumatic fever, were studied. Transthoracic echocardiography was performed in all patients to evaluate valvular heart disease. Ninety-nine healthy individuals matched for age, sex and ethnic origin were included as controls. MBL concentration was measured by enzyme-linked immunosorbent assay and C3 and C4 levels by turbidimetry. MBL levels were significantly higher in patients with RHD than in healthy subjects (mean +/- SEM: 3036.2 +/- 298.9 ng/ml versus 1942.6 +/- 185.5 ng/ml, P <0.003). In addition, MBL deficiency was more prevalent in controls (17.1%) than in patients (9% P <0.09). Concentrations of C4 were within the normal range (22.7 +/- 0.8 mg/dl, normal: 10.0-40.0 mg/dl), while C3 concentrations were found to be elevated (109.2 +/- 3.6 mg/dl, normal: 50.0-90.0 mg/dl). No correlation was observed between serum MBL levels and valve area or the type of surgical procedure. The significantly elevated circulating MBL levels in patients with RHD together with the greater prevalence of MBL deficiency in controls suggest that MBL may cause undesirable complement activation contributing to the pathogenesis of RHD.     

Genetic susceptibility to rheumatic heart disease and streptococcal pharyngitis: association with HLA-DR alleles

Acute rheumatic fever (ARF) is a systemic inflammatory disease that develops as a consequence of an exaggerated immune response to group A beta-haemolytic streptococci, which causes pharyngitis. Major manifestations of ARF include carditis, arthritis and chorea. Several investigators have attempted to establish a relation between ARF and human leucocyte antigens (HLA). Heterogeneity in various studies has been found, although associations with certain antigens were reported. The aim of this study was to analyse whether HLA-DR alleles play a role in the resistance or susceptibility to streptococci-related disorders including rheumatic heart disease (RHD) as a sequela of ARF and recurrent streptococcal pharyngitis in Turkish patients. The study included 102 patients with RHD, 71 persons with recurrent streptococcal pharyngitis and 130 healthy controls. HLA-DR alleles were typed by using polymerase chain reaction (PCR)-sequence-specific primers. Positive association with HLA-DRB1*07 allele was found for RHD when compared with healthy controls [29.4% vs 13.1%; P < 0.01, P-corrected: P < 0.01, odds ratio (OR) 2.78, 95% confidence interval (CI) 1.43-5.26] and also for recurrent streptococcal pharyngitis (26.8% vs 13.1%; P < 0.05, P-corrected: P < 0.05, OR 2.44, 95% CI 1.17-3.56). The frequency of HLA-DRB1*11 allele was decreased in patients with RHD (23.5% vs 42.3%; P < 0.01, P-corrected: P < 0.01, OR 0.42, 95% CI 0.24-0.75). Data suggest that HLA-DRB1*07 allele may be a genetic factor in increasing the susceptibility to develop RHD and recurrent streptococcal pharyngitis. HLA-DRB1*11 allele seems to be a protective factor against RHD.     

Proteomic analysis of mitral valve in Lewis rat with acute rheumatic heart disease

Rheumatic heart disease (RHD) makes a heavy burden in human lives and economy. The proteomic analysis of acute rheumatic heart disease (ARHD) can provide precious data to study RHD at the early stages, but no one has looked into. So based on our early research we applied the method of continuous GAS stimulation on Lewis rats to duplicate the animal model of ARHD. And the mitral valves of rats in control group (n=10) and ARHD group (n=10) were selected for proteomic analysis of ARHD with the iTRAQ labeling based 2D LC-ESI-MS/MS quantitative technology. We identified 3931 proteins in valve tissue out of which we obtained 395 differentially expressed proteins containing 176 up-regulated proteins and 119 down-regulated proteins. Changes in levels of GAPDH (6.793 times higher than the control group) and CD9 (2.63 times higher than the control group) were confirmed by Western blot or immunohistochemistry. The differentially expressed proteins such as GAPDH, CD9, myosin, collagen and RAC1 may be potential biomarkers for ARHD. Moreover, the mitral valve protein profile shed light on further understanding and investigating ARHD.     

Fibroblast growth factor-21 is positively associated with atrial fibrosis in atrial fibrillation patients with rheumatic heart disease

Objective: Fibroblast growth factor-21 (FGF-21) has been discovered as a strong hormone, plays an important role in lipid metabolism, glucose metabolism, associated with several diseases such as obesity, metabolic syndrome, diabetes mellitus, and cardiovascular events; however, no evidence is available concerning the relationship of FGF-21 and atrial fibrosis in patients with atrial fibrillation (AF) and rheumatic heart disease (RHD). Methods: Twenty-four rheumatic heart disease patients were divided into two groups, 12 cases with AF and 12 cases with sinus rhythm (SR). Clinical characteristics and blood samples were collected before surgery; right atrial appendage samples were taken in the surgery of valve replacement. HE staining was performed to determine cross-sectional area of atrial myocytes; Masson stained sections and mRNA levels of cardiac fibrosis biomarkers were used to evaluate the degree of cardiac fibrosis; the level of FGF-21 was evaluated via enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and real-time polymerase chain reaction (PCR). Results: Compared with SR group, cross-sectional area of atrial myocytes and collagen volume fraction were significantly increased in the atrial tissue of AF group. The distribution of FGF-21 in the AF group was remarkably higher than SR group. In addition, plasma and mRNA levels of FGF-21 in atrial tissue of AF showed the same trend as the result of immunohistochemistry. Using linear correlation analysis, the expression level of FGF-21 was found to be positively related to the degree of atrial fibrosis. Conclusion: FGF-21 might involve in the development and maintenance of atrial fibrosis in atrial fibrillation with rheumatic heart disease, and FGF-21 could be used as a novel biomarker to evaluate myocardial fibrosis in the future.     

Microscopical atrial amyloidosis in chronic heart disease

Nineteen out of 121 consecutive cardiac biopsies from 107 patients were found to contain amyloid deposits on routine Congo red screening. Seventeen were left atrial appendages removed during mitral valvotomy for chronic rheumatic mitral valve disease while the remaining two were right atrial appendages excised during surgical repair of atrial septal defects. The distribution of amyloid deposits within the atria and their tinctorial characteristics are described. The high prevalence of atrial amyloidosis observed could not be attributed to generalized or senile amyloidosis. The possibility that this is a distinctive localized form of amyloidosis secondary to chronic heart disease is discussed.     

Comprehensive analysis of antibody responses to streptococcal and tissue antigens in patients with acute rheumatic fever

Acute rheumatic fever (ARF) is an autoimmune disease occurringin individuals following untreated group A streptococcal infectionbelieved to be triggered by antibodies to bacterial componentsthat cross-react with human tissues. We developed a multiplexedimmunoassay for the simultaneous quantitation of antibodiesto nine streptococcal-related antigens including streptolysinO (SLO), DNase B, collagen I and IV, fibronectin, myosin, groupA carbohydrate, M6 protein and streptococcal C5a peptidase.Utilizing this method, we examined serum from 49 ARF, 58 pharyngitispatients and age- and sex-matched controls in samples collectedat initial disease onset, and at 4 weeks, 6 months and 1 yearafter diagnosis. Antibody responses were significantly higherfor SLO, DNase B, M6 protein, group A carbohydrate and the cross-reactiveantigens collagen I and myosin in ARF compared with pharyngitispatients (P 0.05). Moreover, we found significantly elevatedantibody responses in the ARF patients with rheumatic heartdisease to fibronectin and collagen I compared with ARF patientswithout heart disease. The major differences between the ARFpatients with and without carditis appear to be in the immuneresponse to the putative heart valve components, collagen Iand fibronectin.     

The immune responses to human and microbial heat shock proteins in periodontal disease with and without coronary heart disease

The human 60 kDa and microbial 65 kDa heat shock proteins (HSP) have been implicated in the pathogenesis of chronic periodontitis (P) and coronary heart disease (CHD). We have studied four male non-smoking cohorts of 81 subjects, matched for age. Group (a) consisted of a healthy group with minimal gingivitis (n = 18), group (b) were patients with P (n = 23), group (c) patients with CHD and minimal gingivitis (n = 20) and group (d) patients with CHD and P (n = 20). T cells separated from peripheral blood were found to be primed to both microbial HSP65 and human HSP60 but significant CD4, human leucocyte antigen (HLA) class II-restricted proliferative responses were found only with the human HSP60 in patients with P (P < 0.001) and CHD without (P < 0.001) or with (P < 0.00001) periodontitis. Dose-dependent inhibition of T cell proliferative responses was carried out to determine the receptors involved in recognition of HSP60 and HSP65. Monoclonal antibodies to CD14 showed inhibition of T cell proliferation stimulated by both HSP60 and HSP65, consistent with the role of CD14 as a receptor for these HSPs in P and CHD. The toll-like receptor 2 (TLR-) and TLR-4 were then studied and these showed that TLR-4 was recognized by microbial HSP65, whereas TLR-2 was recognised by human HSP60 in both P and CHD. However, a dissociation was found in the HSP60 and TLR4 interaction, as TLR4 appeared to have been recognized by HSP60 in P but not in CHD. The results suggest an autoimmune or cross-reactive CD4(+) class II-restricted T cell response to the human HSP60 in P and CHD. Further studies are required to determine if there is a common epitope within HSP60 that stimulates T cell proliferation in P and CHD.     

Antibodies to heterogeneous nuclear ribonucleoproteins in sera from patients with rheumatic autoimmune diseases

Ribonucleoprotein (RNP) particles sedimenting at 40 S in sucrose gradients were prepared from calf thymus nuclei. They were identified as heterogeneous nuclear RNP (hnRNP) on the basis of size, electron microscopic examination, buoyant density, and protein electrophoretic patterns. Sera from patients with systemic lupus erythematosus, rheumatoid arthritis, and mixed connective tissue disease were found to interact with hnRNP by counter-immunoelectrophoresis and enzyme-linked immunosorbent assay (ELISA). Small nuclear RNP (snRNP) were purified by immunoaffinity using a monoclonal anti-snRNP antibody immobilized on Sepharose beads. Inhibition of the ELISA assay for snRNP with anti-hnRNP Fab fragments and cross-over experiments revealed that the autoantibodies detected in human sera recognize common epitopes present on snRNP and hnRNP.     

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

ABSTRACT

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; p_c = 0.021), rheumatic fever (RF) patients (OR = 14.5; p_c = 0.0001), and mitral valvular lesions patients (OR = 2.74; p_c = 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.