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【摘要】 目的 观察手足口病（HFMD）患儿IL-18与Th1型细胞因子IL-1、IL-8及Th2型细胞因子IL-4、IL-10的水平变化，并探讨手足口病发病的分子机制。
方法 选取2011年10月～2014年3月收治住院并诊断为HFMD患儿46例作为病例组，其中普通病例40例（普通病例组），重症病例6例（重症病例组）， 选取同期经过健康体检中心体检的健康幼儿40例作为对照组，采用形态观察、ELISA法检测各细胞因子水平、淋巴细胞凝胶电泳观察手段进行研究。
结果 与对照组比较，病例组表皮层增厚，血管增生、扩张，伴有炎症细胞浸润、表皮细胞碎片。与对照组比较，普通病例组和重症病例组的IL-18、IL-1、IL-8、IL-4、IL-10水平均显著升高（P<0.01）。通过淋巴细胞凝胶电泳观察到，病例组彗星细胞比对照组多。
结论 IL-18可能通过影响Th1型、Th2型细胞因子水平对Th1/Th2平衡进行调控而参与手足口病发病机制，IL-18有可能作为临床干预手足口病的潜在靶点。
【关键词】 白细胞介素18；手足口病；细胞因子
【Abstract】 Objective To observe the changes of levels of IL-18，Th1 cytokines （IL-1 and IL-8） and Th2 cytokines（IL-4 and IL-10） of children with hand-foot-mouth disease（HFMD），and to investigate the molecular mechanism of HFMD.
Methods 46 children who were admitted to hospital and diagnosed with HFMD were collected as case group，among which 40 normal cases were selected as normal case group，and 6 severe cases were selected as severe case group.And 40 healthy children proved by physical examination in physical examination center in the same period were selected as control group.Then，morphologic changes of skin lesion was observed，levels of cytokines was tested by ELISA，damage of lymphocyte was observed by gel electrophoresis.
Results Compared with the control group，epidermis of the cases group thickened，blood vessels proliferated and expanded，associating with inflammatory cell infiltration and epidermal cells fragments.Levels of IL-18， IL-1， IL-8，IL-4 and IL-10 of both normal case group and severe case group significantly increased comparing with those of the control group（P<0.01）.Observation of lymphocytes gel electrophoresis showed that the case group had more comet cells than the control group.
Conclusion IL-18 might regulate Th1/Th2 balance by affecting the levels of cytokine of type Th1 and Th2，which might be the part of the molecular mechanism of HFMD，and IL-18 is expected to become the potential molecule in the targeted therapy of HFMD.
【Key words】 interleukin-18；hand-foot-mouth disease；cytokines
手足口病（hand-foot-mouth disease，HFMD）是一种儿科常见的传染病，由多种肠道病毒引起，以 5 岁以下儿童发病为主[1]，其感染所致疾病多以发热和手、足、口腔等部位的皮疹或疱疹为主要特征。柯萨奇病毒A16型（coxsackievirusA16，CoxAl6）和肠道病毒7l型（enterovirus71，EV71）是引起HFMD的最常见病原[2]，HFMD确切的发病机制仍不清楚，病毒感染后可致机体细胞免疫功能紊乱，体液免疫功能受损等诸多病理改变[3]。白细胞介素18（Interleukin-18，IL-18）主要由活化的单核-巨噬细胞产生，能促进多种免疫细胞的增殖和分化，從而明显提高机体的免疫功能，增强机体抗肿瘤、抗病毒、抗炎症能力[4]，被认为是靶向调节Th1/Th2平衡的重要因子。本研究通过检测HFMD患儿IL-18表达、Th1型细胞因子IL-1、IL-8以及Th2型细胞因子IL-4、IL-10的水平变化，从IL-18调控细胞免疫、体液免疫和炎症反应角度探讨HFMD的可能病理机制。 参 考 文 献
[1] 陈 鹏，陶泽新，王海岩，等. 新型人类肠道病毒的研究进展[J].病毒学报，2013，29（2）：211-217.
[2] Li W，Yi L，Su J，et al.Seroepidemiology of human enterovirus71 and coxsackievirusA16 among children in Guangdong province，China[J].BMC Infect Dis，2013，13：322.
[3] 王跃飞，郑 瑞，陈葆国，等.手足口病相关免疫学指标检测的病例对照研究[J].浙江预防医学，2010，22（10）：15-17，21.
[4] Lin X，Huang R，Zhang S，et al.Methyl helicterate protects against CCl4-induced liver injury in rats by inhibiting oxidative stress，NF-κB activation，Fas/FasL pathway and cytochrome P4502E1 level[J].Food Chem Toxicol，2012，50（10）：3413-3420.
[5] Ushio S，Namba M，Okura T，et al.Cloning of the cDNA for human IFN-gamma-inducing factor，expression in Escherichia coli，and studies on the biologic activities of the protein[J].J Immunol，1996，156（11）：4274-4279.
[6] Verardi PH，Legrand FA，Chan KS，et al.IL-18 expression results in a recombinant vaccinia virus that is highly attenuated and immunogenic[J].J Interferon Cytokine Res，2014，34（3）：169-178.
[7] Tang HP，Sun LX，Han W.Endothelial cells on the proliferation and expression of intercellular adhesion molecule 1 and interleukin 8 of vascular smooth muscle cells[J].Genet Mol Res，2013，12（4）：4363-4370.
[8] 潘興寿，蓝景生，李天资，等.大蒜素治疗病毒性心肌炎疗效分析[J].右江医学，2010，38（2）：120-122.
[9] Szymanowski K，Niepsuj-Binias J，Dera-Szymanowska A，et al.An influence of immunomodulation on Th1 and Th2 immune response in endometriosis in an animal model[J]. Biomed Res Int，2013，2013：849492.
[10] Novick D，Kim S，Kaplanski G，et al.Interleukin-18，more than a Th1 cytokine[J].Semin Immunol，2013，25（6）：439-448.
（收稿日期：2015-02-10 修回日期：2015-04-14）
（编辑：梁明佩）
方法 选取2011年10月～2014年3月收治住院并诊断为HFMD患儿46例作为病例组，其中普通病例40例（普通病例组），重症病例6例（重症病例组）， 选取同期经过健康体检中心体检的健康幼儿40例作为对照组，采用形态观察、ELISA法检测各细胞因子水平、淋巴细胞凝胶电泳观察手段进行研究。
结果 与对照组比较，病例组表皮层增厚，血管增生、扩张，伴有炎症细胞浸润、表皮细胞碎片。与对照组比较，普通病例组和重症病例组的IL-18、IL-1、IL-8、IL-4、IL-10水平均显著升高（P<0.01）。通过淋巴细胞凝胶电泳观察到，病例组彗星细胞比对照组多。
结论 IL-18可能通过影响Th1型、Th2型细胞因子水平对Th1/Th2平衡进行调控而参与手足口病发病机制，IL-18有可能作为临床干预手足口病的潜在靶点。
【关键词】 白细胞介素18；手足口病；细胞因子
【Abstract】 Objective To observe the changes of levels of IL-18，Th1 cytokines （IL-1 and IL-8） and Th2 cytokines（IL-4 and IL-10） of children with hand-foot-mouth disease（HFMD），and to investigate the molecular mechanism of HFMD.
Methods 46 children who were admitted to hospital and diagnosed with HFMD were collected as case group，among which 40 normal cases were selected as normal case group，and 6 severe cases were selected as severe case group.And 40 healthy children proved by physical examination in physical examination center in the same period were selected as control group.Then，morphologic changes of skin lesion was observed，levels of cytokines was tested by ELISA，damage of lymphocyte was observed by gel electrophoresis.
Results Compared with the control group，epidermis of the cases group thickened，blood vessels proliferated and expanded，associating with inflammatory cell infiltration and epidermal cells fragments.Levels of IL-18， IL-1， IL-8，IL-4 and IL-10 of both normal case group and severe case group significantly increased comparing with those of the control group（P<0.01）.Observation of lymphocytes gel electrophoresis showed that the case group had more comet cells than the control group.
Conclusion IL-18 might regulate Th1/Th2 balance by affecting the levels of cytokine of type Th1 and Th2，which might be the part of the molecular mechanism of HFMD，and IL-18 is expected to become the potential molecule in the targeted therapy of HFMD.
【Key words】 interleukin-18；hand-foot-mouth disease；cytokines
手足口病（hand-foot-mouth disease，HFMD）是一种儿科常见的传染病，由多种肠道病毒引起，以 5 岁以下儿童发病为主[1]，其感染所致疾病多以发热和手、足、口腔等部位的皮疹或疱疹为主要特征。柯萨奇病毒A16型（coxsackievirusA16，CoxAl6）和肠道病毒7l型（enterovirus71，EV71）是引起HFMD的最常见病原[2]，HFMD确切的发病机制仍不清楚，病毒感染后可致机体细胞免疫功能紊乱，体液免疫功能受损等诸多病理改变[3]。白细胞介素18（Interleukin-18，IL-18）主要由活化的单核-巨噬细胞产生，能促进多种免疫细胞的增殖和分化，從而明显提高机体的免疫功能，增强机体抗肿瘤、抗病毒、抗炎症能力[4]，被认为是靶向调节Th1/Th2平衡的重要因子。本研究通过检测HFMD患儿IL-18表达、Th1型细胞因子IL-1、IL-8以及Th2型细胞因子IL-4、IL-10的水平变化，从IL-18调控细胞免疫、体液免疫和炎症反应角度探讨HFMD的可能病理机制。 参 考 文 献
[1] 陈 鹏，陶泽新，王海岩，等. 新型人类肠道病毒的研究进展[J].病毒学报，2013，29（2）：211-217.
[2] Li W，Yi L，Su J，et al.Seroepidemiology of human enterovirus71 and coxsackievirusA16 among children in Guangdong province，China[J].BMC Infect Dis，2013，13：322.
[3] 王跃飞，郑 瑞，陈葆国，等.手足口病相关免疫学指标检测的病例对照研究[J].浙江预防医学，2010，22（10）：15-17，21.
[4] Lin X，Huang R，Zhang S，et al.Methyl helicterate protects against CCl4-induced liver injury in rats by inhibiting oxidative stress，NF-κB activation，Fas/FasL pathway and cytochrome P4502E1 level[J].Food Chem Toxicol，2012，50（10）：3413-3420.
[5] Ushio S，Namba M，Okura T，et al.Cloning of the cDNA for human IFN-gamma-inducing factor，expression in Escherichia coli，and studies on the biologic activities of the protein[J].J Immunol，1996，156（11）：4274-4279.
[6] Verardi PH，Legrand FA，Chan KS，et al.IL-18 expression results in a recombinant vaccinia virus that is highly attenuated and immunogenic[J].J Interferon Cytokine Res，2014，34（3）：169-178.
[7] Tang HP，Sun LX，Han W.Endothelial cells on the proliferation and expression of intercellular adhesion molecule 1 and interleukin 8 of vascular smooth muscle cells[J].Genet Mol Res，2013，12（4）：4363-4370.
[8] 潘興寿，蓝景生，李天资，等.大蒜素治疗病毒性心肌炎疗效分析[J].右江医学，2010，38（2）：120-122.
[9] Szymanowski K，Niepsuj-Binias J，Dera-Szymanowska A，et al.An influence of immunomodulation on Th1 and Th2 immune response in endometriosis in an animal model[J]. Biomed Res Int，2013，2013：849492.
[10] Novick D，Kim S，Kaplanski G，et al.Interleukin-18，more than a Th1 cytokine[J].Semin Immunol，2013，25（6）：439-448.
（收稿日期：2015-02-10 修回日期：2015-04-14）
（编辑：梁明佩）