摘要
世界卫生组织(WHO)西太平洋区(WPR)已经将2012年确定为本区各成员国消除麻疹的期限,但是,近几年我国部分省市仍然发生着麻疹疫情的暴发流行。
与往年相比,2005年上海市麻疹病例数明显上升。流行病学调查显示,超过70%的麻疹患者是成人,大部分成人患者临床症状比较严重,但原因不明,也不清楚其致病机制。为探讨导致成人麻疹患者临床症状严重的原因,本研究拟从麻疹病毒的分子流行病学及麻疹患者免疫功能两个侧面开展研究工作。
本研究首先对来自上海三个不同医院的成人麻疹患者进行流行病学调查。病例调查结果显示,3.3%(2/61)及9.8%(6/61)病人分别有及无明确的麻疹疫苗免疫史,而86.9%(53/61)的病例不知道既往是否接种过麻疹疫苗。同时从三个不同医院收集成人麻疹疑似病例的咽拭子、尿液。用Vero/SLAM细胞系从咽拭子、尿液标本中分离病毒,采用免疫荧光(抗麻疹病毒H蛋白单克隆抗体)及电子显微镜观察等方法对临床分离物进行鉴定证实,用RT-PCR法扩增所分离病毒N基因C末端450核甘酸片断,并将获得的PCR产物经纯化后测定序列;Phylogenetic分析数据提示2006-2007年在上海流行并引起成人感染的21株麻疹病毒基因型别均属H1a型。
为研究麻疹病毒感染成人对机体免疫功能的影响,收集了三个医院患者的血液标本,分离血浆及PBMC,并保存于低温冰箱及液氮。同时收集正常成人血标本,分离PBMC后用2006年本室分离的麻疹病毒攻击健康成人PBMC,收集细胞上清及细胞。用CBA的方法检测对照及患者血浆及体外刺激的PBMC培养上清液中Il-2、IL-4、IL-5、IL-10、TNFα、IFNγ及IFNα蛋白表达;用RT-PCR检测对照和患者及体外病毒攻击的PBMC中相应细胞因子的基因表达;用流式细胞仪检测对照及患者PBMC中CD14~+、CD4~+、CD4~+CD25~+及表达TLR2/4淋巴细胞等各种细胞百分比。实验结果显示,麻疹感染早期,成人患者先天性免疫功能受到广泛抑制,包括外周血中表达TLR2/4的淋巴细胞缺失、Ⅰ型干扰素缺乏等;同时患者细胞免疫功能也出现异常,表现为患者细胞因子IL-2、IFNγ及IL-10在转录、翻译水平均显著上调,CD14~+细胞、CD4~+ T细胞数目显著减少伴随着CD4~+CD25~+调节性T细胞数目明显增加。统计学分析发现,患者外周血中CD4~+CD25~+T细胞数目与其血浆中IL-10的量呈正相关关系。
综上所述,本研究揭示了2006-2007年在上海造成成人麻疹感染的病毒基因型别;并证实病毒变异不是造成成人麻疹患者临床症状严重的主要原因。本研究还证实,在成人感染麻疹病毒的早期,其外周血中表达TLR2/4的淋巴细胞缺失、Ⅰ型干扰素缺乏等先天性免疫功能受到广泛抑制,表现出Th1/Th2免疫反应共同存在的现象,患者CD14~+细胞、CD4~+T细胞数目显著减少,而CD4~+CD25~+调节性T细胞的数目却明显上调;另外,与其他文献报道的儿童麻疹病例相比,本课题研究对象血浆IFNγ及IL-10的量上升的幅度相对很高,从而提示高水平分泌的IFNγ、IL-10及上调的CD4~+CD25~+调节性T细胞可能是造成成人麻疹患者临床症状严重的主要原因;而CD4~+CD25~+T细胞可能是成人麻疹患者体内高水平的IL-10主要细胞来源。上述研究为提出控制近年出现的麻疹疫情暴发流行的策略及措施提供了流行病学线索和实验依据。
In 2005,the Regional Committee for Western Pacific,of which China is a member state,endorsed the plan to eliminate measles by 2012.However,measles outbreak and epidemic still took place in several provinces of China.
In 2005,there was a significant increase in measles patients in Shanghai compared with that of the previous years.The case survey data suggested that more than 70%of patients were adults,and the majority of patients displayed severe disease symptoms.To elucidate the causes of such phenomenon,we planed to identify the genetic characterization of measles virus circulated in Shanghai,as well as to study the immuno-pathogenesis of adult measles cases.
The current research conducted an epidemiologic survey on the adult measles patients admitted into 3 different hospitals in Shanghai first.The case investigation data suggested that 3.3%(2/61)or 9.8%(6/61)patients had or had not vaccinated with measles vaccine before,the rest 86.9%(53/61) of cases did not know their previous measles vaccination history.At the same time,we collected the blood,urine,and throat swab samples from patients.Then we isolated MV from clinical samples and titrated them with Vero-SLAM cell line.Cultures were confirmed with Immuno-fluorescent Assay by using a monoclonal antibody to measles virus H protein or by viewing the electronic microscope.The sequences of the 450 nucleotides coding for the COOH-terminus of the nucleoprotein from all clinical isolates were detected.Sequences were analyzed,and phylogenetic trees were constructed.The phylogenetic analysis based on both nucleotide and amino acid homology showed that all 21 isolates formed three small clusters within Hla.
To illucidate the immuno-pathology caused by measles virus in adult measles patients,we collected blood samples from healthy adults admitted to the blood bank and adult measles patients from 3 hospitals in Shanghai,and isolated the plasma and PBMC;moreover,we using a wild type measles virus we isolated in 2006 to stimulate the normal PBMC,collected the culture supernatant and cells post infection.Then we detected the IL-2,IL-4,IL-5,IL-10,TNFα,IFNγand IFNαgene expression in patients' PBMC as well as in-vitro cultured cells by RT-PCR,as well as checked the protein level in patients' plasma and in-vitro culture supernatant by CBA technique; We also quantified the CD14~+,CD4~+,CD4~+ CD25~+ cell population and the number of cells expression TLR2/4 in PBMC.Our results showed that in acute measles phase, the innate immune system of the adult patients was marked suppressed with significant reduction of TLR2/4 expressing cells and blocked typeⅠinterferon secretion;For adaptive immune,there was a mixed Th1 and Th2 immune response with down-regulated CD 14~+,CD4~+ cell population but up-regulated CD4~+ CD25~+ percentile in adult patients.Statistic analysis showed that,in adult measles patients,CD4~+ CD25~+ cell population positively correlated to plasma IL-10 production.
Taken together,our data identified all 21 clinical isolates gotten from 2006 to 2007 as H1a genotype viruses,which suggested that virus mutation may not be the main cause of severe disease symptoms observed in adult measles patients in Shanghai.Our data also confirmed that in acute measles infection,the innate immune system of the adult patients was marked suppressed with significant reduction of TLR2/4 expressing cells and blocked typeⅠinterferon secretion;There was a mixed Thl(characterized by the elevated IL-2/IFNγproduction) and Th2 immune response (characterized by an elevated IL-10),but the number of CD 14~+,CD4~+ T cell population were down-regulated with the up-regulated CD4~+ CD25~+ T percentile.Our results suggested that the robust IFNγand IL-10 production,and the marked elevated CD4~+ CD25~+ T cell population may related to the severe disease symptoms observed in adult measles patients in Shanghai;and CD4~+ CD25~+ T cell might be the cellular source of the robust IL-10 production in adult measles patients.The above study provides laboratory evidences and epidemiologic clue for the police makers to construct appropriate measles control strategies,which may help to better handle the measles outbreaks and epicemic in our country.
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