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.     

The polymorphisms of interleukin 17A (IL17A) gene and its association with pediatric asthma in Taiwanese population

Background:  The interleukin 17A ( IL17A ) gene, located on chromosome 6p and linked to asthma phenotype, is a highly potential candidate gene conferring asthma susceptibility. The purpose of this study was to investigate the genetic association between single nucleotide polymorphisms (SNPs) of IL17A and asthma in Taiwanese children.
Methods:  We selected and performed genotyping on nine SNPs that encompass the genomic region of IL17A in Taiwanese children with or without asthma. A total of 1939 subjects containing 1027 subjects in testing group and 931 subjects in validation group were recruited in this study.
Results:  After Bonferroni correction, SNP rs8193036 was found to have a weak association ( P  = 0.0074 × 9 = 0.066) in genotype frequency test. This association was confirmed by validation group. Logistic regression adjusted allergy comorbidity and gender showed a slightly weaker association.
Conclusions:  The results indicated an independent role of IL17A promoter polymorphism rs8193036 in the association with pediatric asthma in Taiwanese population.     

Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma

Background:  A genome-wide association study identified ORM1-like 3 (orosomucoid 1-like 3, ORMDL3 ) as an asthma candidate gene. Single nucleotide polymorphisms (SNPs) in the region including ORMDL3 on chromosome 17q21 were related to childhood asthma risk and ORMDL3 expression levels in Europeans.
Objective:  We examined whether polymorphisms in ORMDL3 and the adjacent gasdermin-like ( GSDML ) gene associated with asthma in the genome-wide association study are related to childhood asthma and atopy in a Mexico City population.
Methods:  We genotyped rs4378650 in ORMDL3 and rs7216389 in GSDML in 615 nuclear families consisting of asthmatic children aged 4–17 years and their parents. Atopy was determined by skin prick tests to 25 aeroallergens.
Results:  Individuals carrying the C allele of rs4378650 or the T allele of rs7216389 had increased risk of asthma [relative risk (RR) = 1.73, 95% confidence interval (CI) 1.19–2.53, P  = 0.003 for one or two copies of rs4378650 C, and RR = 1.64, 95% CI 1.12–2.38, P  = 0.009 for one or two copies of rs7216389 T). Linkage disequilibrium between the two SNPs was high ( r ² = 0.92). Neither of the SNPs was associated with the degree of atopy. A meta-analysis of five published studies on rs7216389 in nine populations gave an odds ratio for asthma of 1.44 (95% CI, 1.35–1.54, P  < 0.00001).
Conclusions:  Our results and the meta-analysis provide evidence to confirm the finding from a recent genome-wide association study that polymorphisms in ORMDL3 and the adjacent GSDML may contribute to childhood asthma.     

Toll样受体9基因启动子单核苷酸多态性与儿童变应性哮喘的相关性

目的 研究Toll样受体9(toll-like receptor 9,TLR9)基因启动子区单核苷酸多态性在浙江汉族儿童中的分布,探讨其与哮喘易感性及其表型之间的相关性.方法 对312例变应性哮喘患儿(哮喘组)和339名健康儿童(对照组)采用DNA直接测序法检测TLR9基因-1486(rs187084)和-1237(rs5743836)单核苷酸多态性;采用ELISA法检测两组不同基因型血清干扰素γ(interferon-γ,IFN-γ)、白细胞介素12(interleukin-12,IL-12)和白细胞介素4(interleukin-4,IL-4)水平;采用化学发光法检测血清总免疫球蛋白E(immunoglobulin E,IgE)水平;采用酶免疫荧光法检测血清变应原特异IgE.结果 (1)哮喘组和对照组均存在-1486位点T→C突变,哮喘组TT、TC和CC 3种基因型的频率分别是3 8.8%、48.4%和12.8%,对照组分别是41.0%、44.3%和14.7%;未发现-1237位点存在多态性.(2)哮喘组和对照组-1486位点各基因型的频率分布差异无统计学意义(P＞0.05),年龄分层后比较差异也无统计学意义(P＞0.05).(3)哮喘组-1486位点3种基因型的血清IFN-γ和IL-4水平差异有统计学意义(P＜0.01),CC基因型的IFN-γ水平较低而IL-4水平较高;对照组2种细胞因子的差异无统计学意义(P＞0.05).哮喘组和对照组血清IL-12水平在3种基因型间差异均无统计学意义(P＞0.05).(4)哮喘组-1486位点不同基因型血清总IgE水平差异无统计学意义(P＞0.05).结论 浙江汉族儿童不存在TLR9基因-1237位点多态性.TLR9基因-1486 C/T位点单核苷酸多态性与浙江汉族儿童哮喘易感性、血清IL-12及总IgE水平无关;-1486 C/T位点多态性与哮喘患儿血清IFN-γ和IL-4水平有关联,CC基因型的IFN-γ水平较低而IL-4水平较高.

Abstract：

Objective To investigate the distribution characteristics of the single nucleotide polymorphisms (SNPs) in the promoter region of the toll-like receptor 9 gene (TLR9)in Chinese Han children from Zhejiang province, and their associations with asthma susceptibility and phenotypes. Methods A case-control study was conducted. A total of 312 asthmatic children aged between 1.9 and 11.6 and 339 age matched healthy controls were enrolled in this study from April 2007 to November 2008. The -1486 C/T in rs187084 and -1237 C/T in rs5743836 loci of the TLR9 gene were genotyped by direct DNA sequencing of the PCR products. Serum levels of IFN-γ, IL-12 and IL-4 were detected by enzyme linked immunosorbent assay. Serum levels of total IgE were detected by chemiluminescence, and serum levels of ildren (P＜0.01). The CC genotype had the lowest levels of serum IFN-γand the highest levels of serum IL-4 among the three genotypes. There were no significant differences in these cytokines among the healthy controls (P＞0.05). No statistical differences of serum IL-12 were found among the three genotypes in the two groups (P＞0.05). (4) There were no significant differences of total IgE (log-transformed) among the three genotypes in the asthmatic children (P＞0. 05). Conclusion The -1237 C/T polymorphism of TLR9 gene was not detected in Chinese Han children in this study. The - 1486 C/T polymorphism was associated with the levels of serum IFN-γ and IL-4 in children with asthma.However, there were no correlations between the -1486C/T polymorphism and serum IL-12 levels, total IgE levels or asthmatic susceptibility.     

Association between HSD17B1 rs605059 polymorphisms and the risk of uterine diseases: a systemic review and meta-analysis

The aim of this study was to evaluate the HSD17B1 gene polymorphisms in the risks of endometrial cancer, endometriosis and uterine leiomyoma by meta-analysis. A comprehensive electronic search was conducted in PubMed, Medline (Ovid), Embase, Weipu, Wanfang and CNKI. The pooled ORs were performed using the Revman 5.2 softerware. 8 case-control studies were included: 3 were about endometrial cancer, 4 were about endometriosis and 1 was about uterine leiomyoma. The result showed no significant association between HSD17B1 rs605059 gene polymorphisms and risks of endometrial cancer (AA vs. AG+GG: OR = 1.11, 95% CI = 0.94-1.32; AA+AG vs. GG: OR = 1.79, 95% CI = 0.42-7.52; AG vs. AA+ GG: OR = 0.87, 95% CI = 0.76-1.00; AA vs. GG: OR = 1.43, 95% CI = 0.62-3.30; A vs. G: OR = 1.00, 95% CI = 0.91-1.11) or endometriosis (AA vs. AG+GG: OR = 0.99, 95% CI = 0.75-1.32; AA+AG vs. GG: OR = 1.73, 95% CI = 0.92-3.25; AG vs. AA+ GG: OR = 1.24, 95% CI = 1.00-1.53; AA vs. GG: OR = 1.54, 95% CI = 0.79-2.97; A vs. G: OR = 1.23, 95% CI = 0.90-1.68). No association was found in a subgroup analysis based on Asian ethnicity for endometriosis. This meta-analysis suggested that HSD17B1 rs605059 polymorphisms were not associated with the risks of endometrial cancer and endometriosis. Further studies are needed to validate the conclusion and clarify the relationship between HSD17B1 rs605059 polymorphisms and the risk of uterine leiomyoma.     

Th17与自身免疫性疾病

Th17细胞是新近发现的一类新型的能够分泌白细胞介素17(interleukin 17,IL-17)的CD4+T细胞.在IL-6和TGF-β作用下,初始CD4+T细胞分化为Th17细胞.分化成熟的Th17细胞可以分泌IL-17,IL-17F和IL-22等多种细胞因子,其中IL-17和IL-17F是其主要效应分子.临床前和临床数据均表明:Th17细胞与一些自身免疫性疾病(如系统性红斑狼疮、类风湿性关节炎、多发性硬化、银屑病、炎症性肠病、自身免疫性甲状腺疾病)有关.     

Cytokines and Chemokines in Neuromyelitis Optica: Pathogenetic and Therapeutic Implications

Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extensive transverse myelitis. The discovery of an NMO‐specific autoantibody to the aquaporin‐4 (AQP4) water channel has improved knowledge of NMO pathogenesis. Many studies have focused on inflammatory and pathological biomarkers of NMO, including cytokines and chemokines. Increased concentrations of T helper (Th)17‐ and Th2‐related cytokines and chemokines may be essential factors for developing NMO inflammatory lesions. For example, interleukin‐6 could play important roles in NMO pathogenesis, as it is involved in the survival of plasmablasts that produce anti‐AQP4 antibody in peripheral circulation and in the enhancement of inflammation in the central nervous system. Therefore, assessment of these useful biomarkers may become a supportive criterion for diagnosing NMO. Significant advances in the understanding of NMO pathogenesis will lead to the development of novel treatment strategies. This review focuses on the current advances in NMO immunological research, particularly that of cytokines and chemokines.     

Distinct sustained structural and functional effects of interleukin‐33 and interleukin‐25 on the airways in a murine asthma surrogate

Interleukin‐25 (IL‐25) and IL‐33, which belong to distinct cytokine families, induce and promote T helper type 2 airway inflammation. Both cytokines probably play a role in asthma, but there is a lack of direct evidence to clarify distinctions between their functions and how they might contribute to distinct ‘endotypes’ of disease. To address this, we made a direct comparison of the effects of IL‐25 and IL‐33 on airway inflammation and physiology in our established murine asthma surrogate, which involves per‐nasal, direct airway challenge. Intranasal challenge with IL‐33 or IL‐25 induced inflammatory cellular infiltration, collagen deposition, airway smooth muscle hypertrophy, angiogenesis and airway hyper‐responsiveness, but neither increased systemic production of IgE or IgG1. Compared with that of IL‐25, the IL‐33‐induced response was characterized by more sustained laying down of extracellular matrix protein, neoangiogenesis, T helper type 2 cytokine expression and elevation of tissue damping. Hence, both IL‐25 and IL‐33 may contribute significantly and independently to asthma ‘endotypes’ when considering molecular targets for the treatment of human disease.     

A meta-analysis of the association between Caesarean section and childhood asthma

Background Children born by Caesarean section have modified intestinal bacterial colonization and consequently may have an increased risk of developing asthma under the hygiene hypothesis. The results of previous studies that have investigated the association between Caesarean section and asthma have been conflicting. Objective To review published literature and perform a meta‐analysis summarizing the evidence in support of an association between children born by Caesarean section and asthma. Methods MEDLINE, Web Science, Google Scholar and PubMed were searched to identify relevant studies. Odds ratio (OR) and 95% confidence interval (CI) were calculated for each study from the reported prevalence of asthma in children born by Caesarean section and in control children. Meta‐analysis was then used to derive a combined OR and test for heterogeneity in the findings between studies. Results Twenty‐three studies were identified. The overall meta‐analysis revealed an increase in the risk of asthma in children delivered by Caesarean section (OR=1.22, 95% CI 1.14, 1.29). However, in this analysis, there was evidence of heterogeneity (I²=46%) that was statistically significant (P<0.001). Restricting the analysis to childhood studies, this heterogeneity was markedly decreased (I²=32%) and no longer attained statistical significance (P=0.08). In these studies, there was also evidence of an increase (P<0.001) in the risk of asthma after Caesarean section (OR=1.20, 95% CI 1.14, 12.6). Conclusion In this meta‐analysis, we found a 20% increase in the subsequent risk of asthma in children who had been delivered by Caesarean section.     

Interleukin 17 contributes to the chronicity of inflammatory diseases such as rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and bone resorption. The proinflammatory cytokine interleukin 17 (IL‐17), primarily produced by Th17 cells, has been shown to be involved in all stages of the disease and to be an important contributor of RA chronicity. Three major processes drive the IL‐17‐mediated chronicity. Several epigenetic events, enhanced in RA patients, lead to the increased production of IL‐17 by Th17 cells. IL‐17 then induces the production of several inflammatory mediators in the diseased synovium, which are further synergistically enhanced via combinations of IL‐17 with other cytokines. IL‐17 also promotes the survival of both the synoviocytes and inflammatory cells and promotes the maturation of these immune cells. This leads to an increased number of synoviocytes and inflammatory cells in the synovial fluid and in the synovium leading to the hyperplasia and exacerbated inflammation observed in joints of RA patients. Furthermore, these IL‐17‐driven events initiate several feedback‐loop mechanisms leading to increased expansion of Th17 cells and thereby increased production of IL‐17. In this review, we aim to depict a complete picture of the IL‐17‐driven vicious circle leading to RA chronicity and to pinpoint the key aspects that require further exploration.     

Endogenous interleukin‐6 amplifies interleukin‐17 production and corticoid‐resistance in peripheral T cells from patients with multiple sclerosis

Interleukin‐6 (IL‐6) has been implicated in the induction of pathogenic IL‐17‐producing T cells in autoimmune diseases, and studies evaluating the role of this cytokine in T‐cell function in patients with multiple sclerosis (MS) are lacking. Our objective was to evaluate the role of IL‐6 receptor (IL‐6R) signalling on in vitro functional status of T cells from patients with relapsing–remitting MS during clinical remission. Our results demonstrated that, even during the remission phase, activated T cells from patients produce higher levels of IL‐17, and this cytokine was positively correlated with disease severity, as determined by Expanded Disability Status Scale score. In the MS group, the blockade of IL‐6R signalling by anti‐IL‐6R monoclonal antibody reduced IL‐17 production and elevated IL‐10 release by activated CD4⁺ T cells, but it did not alter the production of these cytokines by activated CD8⁺ T cells. Blockade of IL‐6R signalling also reduced the ability of monocytes to up‐regulate T helper type 17 phenotype in patients with MS. Finally, both cell proliferation and IL‐17 release by CD4⁺ and, mainly, CD8⁺ T cells from patients with MS were less sensitive to hydrocortisone inhibition than control group. Interestingly, IL‐6R signalling blockade restored the ability of hydrocortisone to inhibit both T‐cell proliferation and IL‐17 production. Collectively, these results suggest that IL‐6 might be involved in MS pathogenesis by enhancing IL‐17 production and reducing corticoid inhibitory effects on activated T cells.     

气道内应用IL-12抑制抗原诱导的过敏性气道反应

目的探讨气道内应用白细胞介素 12 (IL- 12 )对抗原诱导的过敏性反应的影响。方法 C5 7BL/ 6小鼠经 OVA免疫建立哮喘模型 ,在主动免疫及抗原激发阶段气道内应用 IL- 12 ,观察肺泡灌洗液细胞成份、肺部淋巴细胞产生细胞因子、外周血 Ig E水平变化。结果 1致敏阶段应用 IL- 12可明显抑制嗜酸性粒细胞浸润、肺淋巴细胞对 IL- 5的分泌以及血浆总 Ig E和抗原特异性 Ig E的水平 ;2激发阶段应用 IL- 12可明显抑制嗜酸性粒细胞的浸润 ,抑制肺淋巴细胞产生 IL- 4、IL- 5 ,增加其产生 IFN- γ,但对抗原特异性 Ig E无明显影响 ;3如致敏和激发阶段均应用 IL- 12 ,则明显抑制肺淋巴细胞产生 IL- 4、IL- 5 ,增强 IFN- γ产生 ,抑制气道内嗜酸性粒细胞的浸润及血浆 Ig E的升高。结论气道应用 IL- 12对抗原诱导的气道过敏性炎症有明显调节作用 ,且与应用时机有关 ,为 IL- 12治疗哮喘提供依据     

Th17细胞在小鼠变应性鼻炎鼻黏膜中的表达及意义

目的：探讨T辅助细胞17(Th17)在小鼠变应性鼻炎鼻黏膜中的表达及意义。方法：以卵清蛋白致敏的Balb/c小鼠变应性鼻炎模型作为实验组,同期以生理盐水替代作为对照组。取两组小鼠鼻黏膜,制成单细胞悬液,使用流式细胞仪检测两组小鼠鼻黏膜中Th17细胞比例。结果：两组小鼠鼻黏膜中均存在Th17细胞,并且实验组中Th17比例[(1.27±0.138)%与(0.771±0.088)%]高于对照组,差异具有统计学意义(P<0.05)。结论：明确变应性鼻炎鼻黏膜中Th17细胞比例,为变应性鼻炎的治疗提供理论依据以及新思路。     

Mice genetically inactivated in interleukin‐17A receptor are defective in long‐term control of Mycobacterium tuberculosis infection

Interleukin-17A (IL-17A), a pro-inflammatory cytokine acting on neutrophil recruitment, is known to play an important role during Mycobacterium tuberculosis infection, but the role of IL-17A receptor signalling in immune defence against this intracellular pathogen remains poorly documented. Here we have analysed this signalling using C57BL/6 mice genetically inactivated in the IL-17 receptor A subunit (IL-17RA^−/−). Although early after infection bacterial growth was controlled to the same extent as in wild-type mice, IL-17RA^−/− mice were defective in exerting long-term control of M. tuberculosis infection, as demonstrated by a progressively increasing pulmonary bacterial burden and shortened survival time. Compared with infected wild-type mice, IL-17RA^−/− mice showed impaired recruitment of neutrophils to the lungs at the early but not the late stage of infection. Pulmonary tumour necrosis factor-α, IL-6 and particularly IL-10 levels were decreased in the absence of IL-17RA signalling, whereas IL-1β was increased. CD4⁺-mediated and γδ-mediated IL-17A production was dramatically increased in IL-17RA^−/− mice (confirming part of their phenotype), whereas production of interferon-γ and expression of the bactericidal enzyme inducible nitric oxide synthase were not affected. Collectively, our data suggest that early but not late neutrophil recruitment is essential for IL-17A-mediated long-term control of M. tuberculosis infection and that a functional interferon-γ response is not sufficient to control M. tuberculosis growth when the IL-17RA pathway is deficient. As treatment of auto-immune diseases with anti-IL-17A antibodies is actually being tested in clinical studies, our data suggest that caution should be taken with respect to possible reactivation of tuberculosis.