川崎病基因多态性的研究进展

川崎病是儿童获得性心脏病的首要原因,其病因和发病机制仍不十分清楚.基因与环境因素间的相互作用可能扮演了重要角色.近十年来,多个与川崎病发病相关的基因区域的遗传学研究取得了重大突破.新近研究发现,肌醇1,4,5-三磷酸肌醇3-激酶C是一个与川崎病易患性相关的新信号路径.该文通过对近年来川崎病基因多态性的相关论文进行检索和分析,对川崎病细胞因子基因多态性、人类白细胞抗原多态性、半胱氨酰天冬氨酸蛋白酶-3基因多态性及与静脉输注丙种球蛋白治疗川崎病疗效相关的基因多态性等作一综述.     

川崎病冠状动脉损害中相关基因的研究进展

川崎病足儿童获得性心脏病的主要病因之一,易并发冠状动脉扩张和冠状动脉瘤.目前已发现基因异常在川崎病冠状动脉损害的发病机制中有重要作用,其中MMP基因、MICA基因、IL-10(-627A/C)启动基因、肾上腺髓质素基因等都与冠状动脉损害相关.该文通过对川崎病遗传因素的研究,为冠状动脉损害的临床诊断、早期干预和治疗提供了依据,提示川崎病遗传学的进一步探索具有良好的前景.     

川崎病冠状动脉病变相关细胞因子基因多态性

川崎病是好发于5岁以下儿童的急性全身性中小血管炎性综合征,以全身中小动脉急性炎症反应为主要病理改变,可导致冠状动脉扩张、心肌梗死及猝死.细胞因子是主要由免疫细胞分泌的、能调节细胞功能的小分子多肽.在免疫应答过程中,细胞因子对于炎症细胞间相互作用、细胞的生长和分化有重要调节作用.川崎病急性期超抗原激活自身免疫反应,大量细胞因子及炎症介质释放入血,参与川崎病的发生发展及血管病变.许多炎症反应细胞因子与川崎病并发冠状动脉损害有关.该文就多种细胞因子在川崎病合并冠状动脉病变中的作用机制进行综述.     

与川崎病有关的细胞因子基因多态性

川崎病(KD)是一种以全身血管炎为主要病理变化的疾病,好发于5岁以下的婴幼儿,其发病机制至今尚未完全阐明。细胞因子是由多种细胞特别是免疫细胞产生的具有免疫调节和效应功能的蛋白质或小分子多肽。研究表明,KD患儿免疫系统处于激活状态,多种细胞因子水平存在明显异常,并参与KD发生发展的过程,某些细胞因子基因多态性与KD易感性、并发冠状动脉损害及难治性KD有关。现就多种细胞因子水平在KD中的变化及其在KD中的作用进行综述,并重点探讨与KD相关的细胞因子基因多态性。     

甘露糖结合凝集素基因多态性与川崎病

川崎病是一种儿童常见的自身免疫性疾病,以全身中小动脉炎症病变为主要特征,但其发病机制仍不完全清楚.近几年的研究显示川崎病与多种遗传基因片段的多态性有关,甘露糖结合凝集素基因与川崎病的关系也逐渐引起关注.该文就甘露糖结合凝集素结构和功能做一简述,并着重介绍甘露糖结合凝集索基因多态性与川崎病易患性和心血管损伤之间的关系.     

川崎病冠状动脉损害易患基因研究进展

川崎病是一种好发于5岁以下儿童的急性全身性中、小血管炎性综合征,该病的病因和发病机制至今尚未明确.流行病学资料显示川崎病的发病存在明显的种族差异,在亚裔人群中的发病率明显高于非亚裔人群.冠状动脉损害是川崎病最为严重的并发症,可导致缺血性心肌病、心肌梗死甚至猝死,未经治疗的患儿约25％会发生冠状动脉损害,而经过治疗的患儿冠状动脉损害发生率仍为5％.近年来该病已取代风湿热成为发达国家儿童获得性心脏病最常见的病因.目前关于冠状动脉损害的研究是川崎病的研究热点,而遗传因素在川崎病及冠状动脉损害的发生过程中起重要作用.研究显示ITPCK、CASP3、TNF-α、CD40、IL-10、PELI1、GRIN3A、CTLA-4、SNX24、LRP1B等多种基因易患性与川崎病冠状动脉损害密切相关,该文就川崎病患儿冠状动脉损害易患基因研究进展作一综述.     

BLK基因多态性与川崎病及其临床特点的相关性

目的探讨汉族人群中BLK基因2个SNP位点rs2736340和rs2618476的多态性与川崎病(KD)以及动脉损伤的相关性。方法采取病例对照研究方法,分别选取179例KD患儿和同期182例体检正常儿童作为研究对象。利用PCRRFLP的方法测定BLK基因两个SNP位点多态性分布,并进行统计分析。结果 SNP位点(rs2736340)3种基因型(TT、CT和CC)在KD组与对照组之间分布的差异无统计学意义(P=0.093);但KD患儿T等位基因频率高于对照组,差异有统计意义(P=0.021)。SNP位点(rs2618476)3种基因型(CC、CT、TT)分布,在KD患儿与对照组之间的差异有统计学意义(P=0.021),KD组患儿CC基因型比例较高;且KD患儿C等位基因频率高于对照组,差异有统计意义(P=0.006)。KD患儿中2个SNP位点多态性均与皮疹、手足水肿以及动脉损伤无相关性,SNP(rs2618476)的多态性和口腔黏膜病变相关(P=0.018)。结论 BLK基因SNP位点(rs2736340)的T等位基因与KD相关。另一SNP位点(rs2618476)多态性与KD易感性相关;且KD患儿中该位点的多态性与口腔黏膜病变相关。     

甘露糖结合蛋白基因多态性与川崎病相关性的研究

目的　探讨甘露糖结合蛋白 (MBP)基因第 5 4号密码子GGC→GAC变异与川崎病 (KD)的关系。方法　采用PCR RFLP法对中国汉族 16 0例健康儿童及 95例川崎病患儿的MBP基因多态性进行检测。结果　中国汉族健康儿童MBP基因多态性分布与文献报道的中国香港地区华人及丹麦高加索人群无统计学差异。川崎病患儿MBP基因GGC/GAC基因型频率明显高于健康对照组 (45 2 %vs 2 5 0 % ,P <0 0 5 ) ,而GGC/GGC基因型频率显著低于健康对照组 (5 1 6 %vs 73 8% ,P <0 0 5 )。川崎病患儿GAC等位基因频率明显高于健康对照组(2 5 8%vs 13 8% ,P <0 0 5 ) ,而GGC等位基因频率明显低于健康对照组 (74 2 %vs 86 2 % ,P <0 0 5 )。结论　川崎病发病受遗传背景影响 ,与MBP第 5 4号密码子基因多态性密切相关。     

MPO基因多态性与川崎病及其临床表型的相关性分析

目的探讨我国中部汉族人群中MPO基因的单核苷酸多态性(SNP)位点(rs2333227,—643G/A)多态性与川崎病(KD)及其临床特点的相关性。方法采用病例对照研究方法,选取237例典型KD患儿和249例正常儿童作为研究对象。利用PCR-RFLP的方法测定SNP位点多态性分布;并收集KD患儿临床资料。结果 KD患儿SNP位点(rs2333227)的基因型(GG、GA、AA)频率与正常儿童相比差异有统计学意义(P=0.039),且等位基因频率差异亦存在统计学意义(P=0.012),G等位基因为风险因子。该SNP位点GG基因型的患儿手足水肿的比例高于其他基因型的患儿,差异具有统计学意义(P=0.029)并与腹腔积液的特点相关(P=0.028);该SNP位点多态性与结膜充血、皮疹、冠状动脉损伤肝脏肿大、脾脏肿大、小叶性肺炎等影像学特点无关(P0.05)。结论 MPO基因SNP位点(rs2333227)与KD的易感性相关,G等位基因为风险因子;且该SNP位点多态性可能与部分临床特点相关。     

Toll样受体4和CD14基因多态性与川崎病易感性的相关研究

目的探讨Toll样受体4(TLR4)及脂多糖受体CD14基因多态性与川崎病(KD)易感性的关系。方法应用三色荧光标记流式细胞术检测76例KD患儿和118例健康儿童外周血白细胞TLR4表达水平,采用聚合酶链反应限制性片断长度多态性(PCR-RFLP)法检测2组儿童TLR4基因(-896A/G),(-1196C/T)位点和CD14基因(-260C/T)位点的基因型频率和等位基因频率及其与KD的关系。结果1.KD组和健康对照组外周血淋巴细胞、中性粒细胞、单核细胞TLR4平均免疫荧光强度(MFI)分别为2.87±0.96,10.55±4.87,23.36±8.28和3.26±0.65,7.55±1.21,25.41±6.97;2.在KD组和健康对照组均未发现TLR4基因(-896A/G)和(-1196C/T)的多态位点;3.KD组和健康对照组CD14基因(-260C/T)位点均有突变,其CC,CT,TT基因型分布分别为35.5%、30.3%、34.2%和38.1%、47.5%、14.4%,差异有统计学意义(χ2=11.62P<0.05);其C,T等位基因频率则分别为50.7%、49.3%和61.9%、38.1%,差异有统计学意义(χ2=4.76P<0.05);其等位基因频率的相对风险分析发现T等位基因携带者发生KD的风险是C等位基因的1.58倍。结论TLR4基因(-896A/G)和(-1196C/T)位点多态性与KD发病无关,CD14基因(-260C/T)多态性T等位基因与KD发病密切相关,其可能是KD发病的遗传学易感因素。     

Polymorphism of Angiotensin-1 Converting Enzyme Gene and Kawasaki Disease

Kawasaki disease is an acute febrile illness typically elicited by vasculitis and occurring in young children. We investigated the polymorphism of the angiotensin-1 converting enzyme (ACE) gene in children with Kawasaki disease and also in age-matched controls. A total of 107 children, with a mean age at diagnosis of 1.71 ± 1.48 years, who suffered from Kawasaki disease and who were treated with aspirin as well as intravenous immunoglobulin were enrolled in this study. Control subjects consisted of 107 children, with a mean age of 1.84 ± 1.20 years. The polymorphisms of the ACE gene, including I/D, A-240T, and G2350A, were examined using a polymerase chain reaction method for Kawasaki disease patients and also for control subjects. We noted a significant difference in the distribution of the ACE gene I/D genotype between Kawasaki disease and control groups. The ACE gene G2350A polymorphism and associated allelic frequencies demonstrated an association with Kawasaki disease. Our results revealed no evidence of any association between the ACE gene polymorphism and the frequency of coronary artery aneurysm associated with Kawasaki disease, although our results do support a role for the I/D and G2350A polymorphism of the ACE gene in determining the risk of Kawasaki disease in the population of Taiwan.     

川崎病诊治进展

川崎病的病因及发病机制至今未明.其病因可能与感染、遗传易感及超免疫反应有关,发病机制与免疫反应、细胞因子及炎性介质、血管内皮功能紊乱、血小板活化、易感基因多态性等有关.联合应用丙种球蛋白和阿司匹林是川崎病的首选治疗方案.对于糖皮质激素的使用临床尚有争议,严重冠状动脉病变可采用外科及介入治疗.     

Clinical Characteristics of Hemophagocytic Lymphohistiocytosis Related to Kawasaki Disease

It is difficult to predict the prognosis or clinical course of secondary hemophagocytic lymphohistiocytosis (HLH) due to the various underlying causes. The authors analyzed the clinical and laboratory findings and outcomes in patients with HLH who had initially been diagnosed with Kawasaki disease (KD), and evaluated the clinical significance of each factor. Among the 21 patients with HLH, 5 had initially been diagnosed with KD and 16 had other etiologies. A comparative analysis was performed for fever duration, presence of cytopenia, serum ferritin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride, fibrinogen, hyponatremia, reactivation, and survival rate in those HLH patients associated with KD (group I) and other causes (group II). In patients in group I, a higher level of reactivation (20%), a lower survival rate (P = .001), higher AST (P = .031) and ferritin (P = .005), and frequent hyponatremia (P = .000) were found compared to patients in group II. Interestingly, patients in group I was older than the average of age of most KD patients. A high index of suspicion on the progression from KD to HLH would be mandatory when the KD patients show elevated AST and ferritin and the presence of hyponatremia, and especially so if the patient is of older age.     

血管紧张素转换酶基因多态性与川崎病的相关性

目的　探讨血管紧张素转换酶 (ACE)基因多态性与川崎病 (KD)及KD并冠状动脉损伤 (CAL)之间的关系。方法　以ACE基因第 1 6内含子的一个 2 87bp的Alu片段插入 /缺失 (I/D)型为多态性标志 ,运用聚合酶链反应 (PCR)技术分别检测KD患儿 2 8例 (其中并发冠状动脉扩张 1 0例 )和正常对照儿童 35例ACE基因I/D多态性频率 ;并同时采用紫外分光光度计法测定血清ACE浓度。结果　 1 .KD患儿血清中ACE浓度明显高于正常对照儿童血清中ACE浓度 (P <0 .0 5) ;两组内DD基因型ACE浓度最高 ,DI基因型次之 ,Ⅱ基因型最低 ;DD基因型与Ⅱ基因型ACE浓度存在显著性差异 (P <0 .0 5)。 2 .KD组与正常对照组比较基因频率DD型间有显著性差异 (P <0 .0 5)。 3 .KD组中 ,发生冠状动脉扩张患儿血清ACE明显高于冠状动脉正常患儿血清ACE浓度 (P <0 .0 5)。结论　ACE基因DD型与KD的发生有关 ,并可能通过影响血清中ACE浓度导致CAL。     

Kawasaki Disease and Epstein-Barr Virus

We report the results of virological (serological and molecular biological) studies of Epstein-Barr virus (EBV) in patients with Kawasaki disease (KD). Forty-nine (86%) of 57 Kawasaki disease patients and 15 (68%) of 22 patients with recurrent Kawasaki disease had serological evidence of primary Epstein-Barr virus infection during the first month after the onset of their disease based on the results of a sensitive method of detecting antibody to viral capsid antigen (VCA). The serological response to EBV was significantly low and transient. EBV sequences were identified directly in peripheral blood mononuclear cell (PBMC) DNA samples from 23 (56%) of 41 KD patients within 2 weeks after onset by means of the polymerase chain reaction (PCR). EBV sequences were also detected in 10 (83%) of 12 repeatedly tested KD patients within 3 months after onset. In contrast, only 7 (18%) of 40 control DNA samples were PCR-positive. These virological studies indicate that an unusual EBV-cell interaction may occur in KD.     

Conjunctival Biopsy in Patients with Kawasaki Disease

Kawasaki disease (KD) is an acute vasculitis of infants and young children that is associated with bilateral nonexudative conjunctivitis during the acute illness. Epidemiologic evidence has suggested an infectious cause but the etiology of KD remains unknown. We examined conjunctival biopsy specimens from seven patients with typical KD to characterize the pathologic changes during the acute disease. Light microscopic examination revealed nonspecific, mild inflammatory changes that included vascular dilatation, infiltration with scattered lymphocytes, increased numbers of plasma cells in the conjunctival stroma, and increased prominence of goblet cells in the epithelium. No pathogens were identified by special stains for bacteria and rickettsiae, nor were viral particles seen by electron microscopy. We conclude that the conjunctivitis of acute KD is characterized by vascular dilatation with a mild mononuclear cell response with no pathognomonic features. The conjunctiva can be readily sampled in these patients and biopsy may prove useful in selected patients to exclude other clinical entities in the differential diagnosis.     

Serum Sodium Levels in Patients with Kawasaki Disease

The purpose of this study was to assess the hypothesis that lower serum sodium levels are associated with cardiovascular sequelae in patients with Kawasaki disease (KD). We used the database of the 16th nationwide survey of KD in Japan. We investigated the distribution of serum sodium levels and the relationship between serum sodium levels and cardiovascular sequelae. Of the reported cases, serum sodium levels were reported in 13,569 patients (89%). The proportion of patients with serum sodium levels 130 mEq/L or less, was greater in complete cases than in incomplete cases. The proportion of patients with serum sodium levels 130 mEq/L or less was increased with age. The largest proportion of patients with serum sodium levels 130 mEq/L or less was found in the category of 3–5 days since onset of illness. A serum sodium of level 135 mEq/L or less was an independent risk factor for cardiovascular sequelae (odds ratio, 1.79, 95% confidence interval, 1.42–2.26). Among patients with KD, there are significant differences in serum sodium levels between diagnostic categories, age, and days since the onset of illness. The sodium level may be a simple predictor of cardiovascular sequelae.     

川崎病患儿抗心磷脂抗体检测的意义

目的：检测川崎病(KD)患儿血清中抗心磷脂抗体(ACA),探讨ACA与KD血管损害的关系。方法：55例急性期KD患儿,采用ELISA方法检测血中ACA-IgG,IgM和IgA三种亚型。结果：55例急性期KD患儿血清ACA-IgG阳性31例,ACA-IgM阳性13例。急性期KD组ACA-IgG,IgM阳性率比对照组显著增高(P<0.01);治疗后ACA-IgG阳性率仍高于对照组(P<0.05),而ACA-IgG阳性或阴性两组的临床表现比较差异均无显著性(P>0.05),但6例伴有血栓形成者有5例ACA-IgG阳性。结论：ACA-IgG是KD常见的抗体,ACA-IgG阳性与KD血栓性血管损害关系密切,但对病情判断无作用。     

Para-aortic Lymphadenopathy Associated with Kawasaki Disease

Background

Kawasaki disease is an acute vasculitis that occurs mainly in children. Cervical lymphadenopathy is one of the major presenting manifestations of Kawasaki disease. We report a case of Kawasaki disease with para aortic lymphadenopathy, as an unusual feature in this disease.

Case Presentation

This 2.5 year old girl presented with persistent high grade fever, erythematous rash, bilateral non purulent conjunctivitis, red lips, and edema of extremities. Laboratory results included an elevated erythrocyte sedimentation rate, leukocytosis, anemia, and positive C-reactive protein. On second day after admission she developed abdominal pain. Ultrasonography of abdomen revealed multiple lymph nodes around para aortic area, the largest measuring 12mm×6mm. Treatment consisted of aspirin and high dose intravenous γ-globulin. Ultrasonography and CT scan of abdomen performed one week later showed disappearance of the lymph nodes.

Conclusion

There are few previous reports of lymphadenopathy in unusual sites such as mediastinum in Kawasaki disease. Para aortic lymph nodes enlargement might be an associated finding with acute phase of Kawasaki disease. In these patients a close observation and ultrasonographic follow up will prevent unnecessary further investigation.     

Anticardiolipin Response in Kawasaki Disease

ABSTRACT. Antibodies against cardiolipin are formed in many different infectious diseases, and high levels are associated with susceptibility to thrombosis, especially in patients with systemic lupus erythematosus. In view of the postulated infectious etiology of Kawasaki disease and its association with thrombosis, we have studied the occurrence of anticardiolipin antibodies in this disease. Serial serum specimens from 36 patients were tested, using a solid-phase enzyme immunoassay. A change of at least 0.3 optical density units between two consecutive specimens for at least one immunoglobulin class was observed in 47% of cases. Peak levels occurred one to two weeks after the onset of symptoms. Four patients developed coronary artery aneurysms, and they all showed a clear anticardiolipin response. Anticardiolipin antibodies might be one factor contributing to coagulation abnormalities in patients with Kawasaki disease.