王嘉瑜，俞雪蓮，張曦

上海市疾病預(yù)防控制中心，上海 200336

流行性感冒(簡稱流感)是流感病毒(influenza virus) 引起的一種急性上呼吸道傳染病，傳染性強(qiáng)、傳播快、潛伏期短、發(fā)病率高。其中，甲型流感病毒由于抗原變異率高，極易造成大范圍流行。在1918～1919年流感大流行中，世界20億人口約一半被感染，死亡人數(shù)達(dá)2 000萬，高于第一次世界大戰(zhàn)中死亡人數(shù)的總和。1957年7月，H2N2亞洲流感(Asian influenza)在中國暴發(fā)，隨即在全球流行；該病毒在美國造成約70 000人死亡。1968年，由亞洲流感病毒抗原轉(zhuǎn)變進(jìn)化的H3N2甲型流感病毒(香港流感)在美國造成約34 000人死亡。1997年，中國香港地區(qū)發(fā)生H5N1禽流感疫情，造成6人死亡。禽流感病毒感染人后，病死率近50%，引起廣泛關(guān)注。2009年4月，由四源基因重配[1]變異形成的新型甲型H1N1(pdm09)流感病毒(即2009甲型H1N1流感病毒)由于在人群中引起較高的發(fā)病率，對世界公共衛(wèi)生構(gòu)成了嚴(yán)重威脅。相較于季節(jié)性流感，新型甲型H1N1流感的易感人群為18歲以下，且青少年群體在重癥患者中占極大比例[2-7]。有研究指出[8]，青少年患者的重癥感染可能與過度免疫應(yīng)答相關(guān)。因此，開展對流感及其相關(guān)細(xì)胞因子的研究，有助于分析外周血細(xì)胞因子表達(dá)水平與病毒致病能力的關(guān)系，了解流感病毒的致病機(jī)制，從而促進(jìn)對疾病的研究和防治。

1 細(xì)胞因子在抗流感病毒感染中的免疫調(diào)節(jié)作用

天然免疫(innate immunity)是機(jī)體對抗病原體侵襲的第1道屏障。研究顯示[9]，流感病毒進(jìn)入機(jī)體后首先入侵呼吸道上皮細(xì)胞，細(xì)胞經(jīng)歷凋亡/壞死后啟動機(jī)體天然免疫應(yīng)答，并產(chǎn)生趨化因子(chemokine)，如單核細(xì)胞趨化蛋白1(monocyte chemoattractant protein 1，MCP-1)、調(diào)節(jié)激活正常T細(xì)胞表達(dá)和分泌因子(regulated upon activation，normal T cell expressed and secreted，RANTES)、白細(xì)胞介素8(interleukin 8，IL-8)等[10]，介導(dǎo)中性粒細(xì)胞及巨噬細(xì)胞浸潤。Mogensen等[11]研究指出，外周血IL-1、IL-6、腫瘤壞死因子α(tumor necrosis factor α，TNF-α)和IL-8等炎性細(xì)胞因子的高表達(dá)已成為病毒感染的標(biāo)志。研究顯示，IL、TNF-α及趨化因子對介導(dǎo)炎癥反應(yīng)發(fā)生、調(diào)節(jié)免疫應(yīng)答強(qiáng)度起重要作用[12]。TNF-α可通過激活T細(xì)胞，促進(jìn)IL-1、IL-2、IL-6的產(chǎn)生及分泌[13]。IL-1是機(jī)體抗病毒感染早期產(chǎn)生的效應(yīng)分子，可合成急性反應(yīng)蛋白，并促進(jìn)IL-8的分泌[11,14]。IL-8是主要的炎性細(xì)胞因子，對中性粒細(xì)胞及T細(xì)胞有趨化作用。IL-6調(diào)節(jié)機(jī)體免疫應(yīng)答，參與機(jī)體抗感染防御[15]。IL-1、IL-6、IL-12、IL-23等在外周血含量上升將導(dǎo)致機(jī)體發(fā)熱、血管通透性增加及巨噬細(xì)胞招募等一系列炎性反應(yīng)產(chǎn)生。

單核-巨噬細(xì)胞招募至肺實質(zhì)及肺泡部位是適應(yīng)性免疫初始激活的關(guān)鍵。實際上，流感病毒感染引起的細(xì)胞或體液免疫是由T輔助細(xì)胞(T helper cell，Th細(xì)胞)通過分泌不同細(xì)胞因子所誘導(dǎo)的[16]。Th細(xì)胞根據(jù)其分泌細(xì)胞因子的不同可分為Th1細(xì)胞﹝γ干擾素(interferon γ，IFN-γ)、IL-1、IL-2、IL-6、IL-12、TNF-α﹞和Th2細(xì)胞(IL-4、IL-5、IL-10)2個亞群。外周血IL-2、IL-12等Th1類細(xì)胞因子表達(dá)上調(diào)可促使細(xì)胞毒性T淋巴細(xì)胞(cytotoxic T lymphocyte，CTL)分化，活化自然殺傷(nature killer，NK)細(xì)胞，清除流感病毒。IL-2 是T細(xì)胞生長因子(T cell growth factor，TCGF)，可促使已活化的T細(xì)胞增殖、分化，成熟為效應(yīng)CTL，并刺激其他細(xì)胞因子(如TNF、IFN-γ)分泌。IL-12可引起Thl細(xì)胞分化，并抑制由IL-4介導(dǎo)的Th2細(xì)胞分化；此外，IL-12可刺激外周血T細(xì)胞、NK細(xì)胞分泌IFN-γ，抑制流感病毒復(fù)制。在體液免疫方面，IL-5等Th2類細(xì)胞因子有助于刺激B細(xì)胞生長和免疫球蛋白產(chǎn)生，阻斷病毒與細(xì)胞表面受體結(jié)合，激活補(bǔ)體或NK細(xì)胞，并最終清除病毒及受感染細(xì)胞。Th17細(xì)胞是一類新近被定義的Th細(xì)胞，其分泌的細(xì)胞因子(IL-6、IL-17、IL-21、IL-22)中，IL-17是主要效應(yīng)分子，可迅速啟動由中性粒細(xì)胞介導(dǎo)的炎癥反應(yīng)，并促進(jìn)IL-1、TNF-α大量分泌[17]；另一方面，IL-17的大量產(chǎn)生亦可導(dǎo)致患者嚴(yán)重的病理損傷[18-20]。

2 細(xì)胞因子參與和介導(dǎo)免疫病理損傷

2009年11月，Bermejo-Martin等[21]報道了新型甲型H1N1流感重癥患者體內(nèi)Th1、Th17類細(xì)胞因子上升的現(xiàn)象，這是較早對新型甲型H1N1流感患者體內(nèi)細(xì)胞因子表達(dá)失調(diào)的研究。事實上，流感病毒感染機(jī)體后，一方面，呼吸道上皮細(xì)胞釋放趨化因子，誘導(dǎo)巨噬細(xì)胞等炎性細(xì)胞浸潤，并招募外周血T細(xì)胞滲透至感染的肺組織，抵抗病毒感染；另一方面，炎性細(xì)胞浸潤也會造成機(jī)體早期炎癥性病理損傷，加重疾病的嚴(yán)重程度。近期一項對輕、重癥新型甲型H1N1流感患者血清細(xì)胞因子表達(dá)水平的研究結(jié)果顯示[22]，當(dāng)患者處于疾病早期，體內(nèi)IL-1、IL-12、IFN-γ、IL-6、TNF-α、IL-5、IL-10、IL-17、IL-23等細(xì)胞因子血清濃度均有所上升，這與此前的一些研究結(jié)果相符[21,23-25]。這一現(xiàn)象說明，在感染初期，病毒誘導(dǎo)天然免疫系統(tǒng)產(chǎn)生大量促炎細(xì)胞因子參與機(jī)體免疫應(yīng)答，高表達(dá)的IL-1、IL-6、IL-12和IL-23與發(fā)熱等流感樣癥狀相關(guān)。該研究進(jìn)一步指出[22]，隨著病程進(jìn)展，患者體內(nèi)IL-6、IL-10表達(dá)水平顯著上升。IL-6作為重要的促炎細(xì)胞因子，介導(dǎo)組織炎癥反應(yīng)，調(diào)節(jié)免疫應(yīng)答。IL-10作為抗炎細(xì)胞因子，調(diào)節(jié)炎癥反應(yīng)強(qiáng)度，誘導(dǎo)T細(xì)胞分化。與普通季節(jié)性流感相比，新型甲型H1N1流感重癥患者的適應(yīng)性免疫應(yīng)答相對處于抑制狀態(tài)。Lee等[26]研究顯示，新型甲型流感重癥患者體內(nèi)IL-17、IL-23表達(dá)水平略有上升，可能是由其他原因造成的[24,27]。一些研究指出，在新型甲型H1N1流感重癥肺炎患者體內(nèi)，T細(xì)胞免疫應(yīng)答下調(diào)[ 28,29]，Th17等T細(xì)胞亞群功能受損[30-32]。在某些程度上，造成病毒在體內(nèi)持續(xù)復(fù)制，病毒清除時間增加，從而導(dǎo)致炎性反應(yīng)持續(xù)增強(qiáng)，使肺組織等損傷[22,28,33]，導(dǎo)致并發(fā)癥。

1997年，在中國香港地區(qū)暴發(fā)的H5N1禽流感疫情因其高病死率而受到廣泛關(guān)注。研究顯示，由H5N1禽流感病毒介導(dǎo)的細(xì)胞因子失調(diào)與病毒的高致病性相關(guān)[34-36]。體外研究證實，與H3N2和H1N1流感病毒相比，H5N1流感病毒能更有效地誘導(dǎo)人原代巨噬細(xì)胞分泌炎性細(xì)胞因子[10]，這可能與NS1蛋白結(jié)構(gòu)的不同相關(guān)。這一發(fā)現(xiàn)為甲型H5N1流感病例中出現(xiàn)的以炎性細(xì)胞因子過度表達(dá)及功能失調(diào)為特點的“細(xì)胞因子風(fēng)暴”(cytokine storm)現(xiàn)象提供了佐證。“細(xì)胞因子風(fēng)暴”是機(jī)體天然免疫系統(tǒng)由于某些原因致使多種炎性介質(zhì)(包括細(xì)胞因子、氧自由基、凝血因子等)表達(dá)上調(diào)的現(xiàn)象[37]，患者血清中可檢測到炎性細(xì)胞因子(TNF-α、IL-1、IL-6等)及抗炎細(xì)胞因子(IL-10、IL-6等)表達(dá)均顯著上升，兩者相互作用往往導(dǎo)致廣泛的肺組織水腫、感染性肺炎、肺泡出血等癥狀，許多病例由此發(fā)展成急性呼吸窘迫綜合征(acute respiratory distress syndrome，ARDS)，甚至死亡。

“細(xì)胞因子風(fēng)暴”最初由外周血 IL-6、TNF-α高表達(dá)引起[37]。上皮細(xì)胞發(fā)生凋亡后，被招募至感染部位的巨噬細(xì)胞被子代病毒感染而發(fā)生凋亡[38]，同時誘導(dǎo)大量炎性細(xì)胞因子產(chǎn)生，引起機(jī)體發(fā)熱、厭食、關(guān)節(jié)痛、中性粒細(xì)胞增多、血流動力學(xué)異常改變等[39]。這些炎性細(xì)胞的大量出現(xiàn)會加重病情，引發(fā)嚴(yán)重的呼吸道功能失調(diào)及致死性的肺部病理損傷，并通過誘導(dǎo)包括T細(xì)胞、B細(xì)胞、中性粒細(xì)胞在內(nèi)的相關(guān)血液單核細(xì)胞活化并遷移至感染部位，促進(jìn)肺部免疫病理損傷。另外，由IL-1、TNF-α等誘導(dǎo)而高表達(dá)的IL-8、巨噬細(xì)胞炎性蛋白10(macrophage inflammatory protein 10，MIP-10)等趨化因子可活化中性粒細(xì)胞并遷移至感染部位，進(jìn)一步造成疾病惡化。IL-8屬于趨化因子CXC家族，是一種強(qiáng)力的中性粒細(xì)胞趨化和活化介質(zhì)，可誘導(dǎo)其變形、趨化、脫顆粒，胞質(zhì)內(nèi)鈣短暫上升，生物活性脂類合成，整合素上調(diào)，呼吸爆發(fā)等[40]。外周血IL-8表達(dá)水平在感染、創(chuàng)傷及某些自身免疫性疾病中明顯升高，且高濃度IL-8與病死率有關(guān)。有研究指出，中性粒細(xì)胞的炎性浸潤與病原體造成的肺部損傷相關(guān)[41]，中性粒細(xì)胞產(chǎn)生的髓過氧化物酶和彈性蛋白酶會造成急性肺部損傷。外周血IL-8表達(dá)上調(diào)，可激活中性粒細(xì)胞運動裝置，使其能定向游走，促使表達(dá)黏附分子，并促進(jìn)中性粒細(xì)胞溶酶體酶(髓過氧化物酶、彈性蛋白酶、β葡萄糖醛酸酶)釋放[42]。

3 結(jié)語

綜上所述，細(xì)胞因子在機(jī)體抗流感免疫調(diào)節(jié)過程中發(fā)揮作用。研究證實，在此過程中，由細(xì)胞因子介導(dǎo)的免疫病理損傷確實存在。通過這方面的研究，可了解甲型流感病毒的致病原理，探索流感病毒如何致宿主嚴(yán)重呼吸道感染，揭示呼吸道感染性疾病的發(fā)病機(jī)制，為制定甲型流感防控措施提供一定的科學(xué)依據(jù)。

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