固有免疫在HBV感染發(fā)病和治療中的作用

屈曉晶 張璐 李明慧 謝堯

100015 北京，首都醫(yī)科大學(xué)附屬北京地壇醫(yī)院肝病中心肝病二科，北京市醫(yī)院管理局重點(diǎn)醫(yī)學(xué)專業(yè)發(fā)展計(jì)劃

·綜述·

固有免疫在HBV感染發(fā)病和治療中的作用

屈曉晶 張璐 李明慧 謝堯

100015 北京，首都醫(yī)科大學(xué)附屬北京地壇醫(yī)院肝病中心肝病二科，北京市醫(yī)院管理局重點(diǎn)醫(yī)學(xué)專業(yè)發(fā)展計(jì)劃

乙型肝炎病毒(HBV)感染的發(fā)病機(jī)制是宿主免疫系統(tǒng)和HBV之間復(fù)雜的相互作用，宿主免疫系統(tǒng)包括固有免疫和適應(yīng)性免疫?，F(xiàn)在認(rèn)為，宿主對(duì)病毒及其蛋白的免疫反應(yīng)是決定病毒清除、感染慢性化和肝細(xì)胞損傷的主要因素。固有免疫是宿主對(duì)抗病毒感染的第一道防線，但許多研究顯示HBV可以逃避固有免疫識(shí)別、干擾固有免疫信號(hào)通路并介導(dǎo)免疫抑制。對(duì)固有免疫在HBV感染過(guò)程中的作用和狀態(tài)研究有助于開發(fā)新的治療方法，以達(dá)到根除HBV。本文對(duì)固有免疫反應(yīng)的模式識(shí)別受體(PRRs)、樹突狀細(xì)胞(DCs)、自然殺傷(NK)細(xì)胞/自然殺傷T(NKT)細(xì)胞、調(diào)節(jié)性T細(xì)胞(Tregs)和干擾素(IFNs)的近期研究進(jìn)展進(jìn)行了綜述。

Fund programs: Beijing Science and Technology Commission Major Project (D121100003912001)

HBV感染是一項(xiàng)全球范圍內(nèi)的公共健康問(wèn)題，盡管乙肝疫苗已經(jīng)廣泛應(yīng)用并且針對(duì)乙型肝炎具備有效的抗病毒治療，全球仍有2.4億慢性乙型肝炎(Chronic hepatitis B, CHB)患者[1]，一般認(rèn)為HBV不直接對(duì)肝臟造成損傷，其發(fā)病機(jī)制為宿主免疫系統(tǒng)和病毒之間復(fù)雜的相互作用[2,3]。一般認(rèn)為適應(yīng)性免疫反應(yīng)的細(xì)胞毒性T淋巴細(xì)胞(CTLs)在清除HBV方面起非常重要的作用，但有研究顯示HBV特異性T細(xì)胞的功能缺陷可能是病毒不能被清除的主要原因[2]。固有免疫作為宿主對(duì)抗病毒感染的第一道防線，近年來(lái)越來(lái)越多的受到人們重視。固有免疫反應(yīng)的重要組成成分包括模式識(shí)別受體(Pattern-recognition receptors, PRRs)、樹突狀細(xì)胞(Dendritic cells, DCs)、自然殺傷(Natural killer, NK)細(xì)胞/自然殺傷T(Natural killer T, NKT)細(xì)胞、調(diào)節(jié)性T細(xì)胞(T regulatory cells, Tregs)和干擾素(Interferons, IFNs)[4,5]，在HBV感染發(fā)病和治療中起非常重要的作用。

HBV可以逃避、破壞和激活宿主免疫系統(tǒng)，因此不同HBV感染者的臨床結(jié)局不同。首先，HBV本身可以逃避固有免疫的識(shí)別并抑制免疫反應(yīng)。早期實(shí)驗(yàn)發(fā)現(xiàn)，在感染初期，HBV不會(huì)被固有免疫識(shí)別，更不會(huì)激活固有免疫反應(yīng)，因?yàn)檠芯课窗l(fā)現(xiàn)干擾素基因的改變[4，6]。其次，HBV除了能逃避免疫系統(tǒng)識(shí)別，病毒及其蛋白還可以介導(dǎo)免疫抑制。如HBV表面抗原(Hepatitis B surface antigen，HBsAg)可抑制DCs、NKT等多種免疫細(xì)胞[7，9，10]固有免疫反應(yīng)是對(duì)抗HBV感染的重要環(huán)節(jié)，但HBV對(duì)其各個(gè)環(huán)節(jié)的抑制可能是導(dǎo)致HBV感染慢性化的原因。因此，研究固有免疫和HBV之間的相互作用，有助于解析HBV感染的具體發(fā)病機(jī)制，從而有助于研發(fā)有效的免疫治療新藥物。

1 PRRs

PRRs主要分布于固有免疫細(xì)胞表面，可通過(guò)識(shí)別病原體相關(guān)分子模式(Pathogen-associated molecular patterns, PAMPs)激活固有免疫反應(yīng)，促進(jìn)抗病毒和促炎細(xì)胞因子分泌，而且有助于啟動(dòng)適應(yīng)性免疫[11]。PRRs主要包括toll樣受體(Toll-like receptors, TLRs)，比如表達(dá)于細(xì)胞表面的TLR1/2/4/5/6/11/12及表達(dá)于內(nèi)涵體的TLR3/7/9；細(xì)胞質(zhì)受體比如核苷酸結(jié)合寡聚化結(jié)構(gòu)域樣受體(Nucleotide-binding oligomerization domain-like receptors, NLRs)及維甲酸誘導(dǎo)基因-I樣受體(Retinoic acid inducible gene-I like receptors, RLRs)和內(nèi)質(zhì)網(wǎng)跨膜蛋白STING[12，13]。HBV轉(zhuǎn)基因小鼠實(shí)驗(yàn)證實(shí)，靜脈注射TLR3/4/5/7/9特異性配體可以促進(jìn)IFN-α/β分泌，有效控制HBV復(fù)制[14]。TLR7激動(dòng)劑GS-9620短期、有限治療可以在CHB土撥鼠模型上介導(dǎo)持久的抗病毒反應(yīng)[15]。TLR3的激活促進(jìn)IFN-β產(chǎn)生，而且TLR4和TLR2信號(hào)激活肝細(xì)胞內(nèi)通路比如MAPK和PI-3 K/Akt也可促進(jìn)IFN分泌，這些在控制HBV復(fù)制方面有重要意義[16]。

宿主對(duì)抗HBV感染離不開PRRs，但許多研究顯示HBV及其蛋白如HBsAg、HBeAg抑制PRRs的表達(dá)，減弱其介導(dǎo)的抗病毒作用。HepaRG細(xì)胞系研究表明，HBV通過(guò)TLR3和維甲酸誘導(dǎo)基因-I(Retinoic acid inducible gene-I, RIG-I)/黑色素瘤變異相關(guān)基因5(Melanoma differentiation-associated gene 5, MDA5)信號(hào)通路抑制早期固有免疫，導(dǎo)致一些抗病毒和促炎細(xì)胞因子基因表達(dá)下調(diào)[17]。針對(duì)HBV感染者的研究指出，HBsAg抑制TLR9介導(dǎo)的漿細(xì)胞樣樹突狀細(xì)胞(Plasmacytoid DC, pDC)的激活和分泌IFN-α能力[9]。HBeAg能抑制Toll/白介素(Interleukin, IL)-1受體(TIR)和IL-1β介導(dǎo)的炎性轉(zhuǎn)錄因子例如核因子(Nuclear factor, NF)-κB的激活，并抑制NF-κB和IFN-β啟動(dòng)子活性[18]。HBV及其蛋白對(duì)PRRs的抑制，可能導(dǎo)致固有免疫不能被及時(shí)激活，導(dǎo)致HBV感染長(zhǎng)期存在。

2 DCs

DCs是重要的抗原提呈細(xì)胞(Antigen presenting cells, APC)，對(duì)啟動(dòng)適應(yīng)性免疫反應(yīng)起著關(guān)鍵性作用，根據(jù)其來(lái)源不同可分為：髓樣DC(Myeloid dendritic cells，mDC)主要分泌IL-12/IL-15和漿細(xì)胞樣DC(Plasmacytoid dendritic cells, pDC)，主要大量分泌Ⅰ型IFN[19]。早期研究發(fā)現(xiàn)，CHB患者DCs共刺激分子表達(dá)下調(diào)，細(xì)胞因子分泌能力受損。機(jī)制可能為：HBV和HBsAg廢除胞嘧啶-磷酸鹽-鳥嘌呤(cytosine-phosphate-guanine, CpG)-A/TLR9介導(dǎo)的IFN-α基因轉(zhuǎn)錄；病毒樣顆粒(Virus-like Particles, VLPs)，比如 HBV外膜小S蛋白(HBsAgS)損害pDC分泌IFN-α能力；DC表型耐受基因的產(chǎn)生[20-22]。但最近研究發(fā)現(xiàn)，無(wú)論體內(nèi)觀察還是體外刺激，HBV攜帶者循環(huán)總DCs、mDC和pDC的頻數(shù)和功能都未改變[23]。然而，與非活動(dòng)HBsAg攜帶者相比，免疫耐受期患者pDC上CD80/CD86表達(dá)顯著下調(diào)[24]。另一項(xiàng)研究得出類似結(jié)果，在慢性HBV感染，mDC和pDC的頻數(shù)和功能沒(méi)有改變，但pDC分泌的IFN-α減少[25]。產(chǎn)生不同結(jié)果的原因可能與宿主免疫狀態(tài)、抗病毒治療等有關(guān)，但更大的可能為DCs的狀態(tài)決定著宿主對(duì)HBV的免疫反應(yīng)。另外，自體HBsAg激活的DC和細(xì)胞因子介導(dǎo)的殺傷(Cytokine-induced killer, CIK)細(xì)胞回輸CHB患者，可以有效降低病毒載量[26]，這可作為CHB治療的新策略?？傊?，HBV與DCs在宿主的相互作用還需進(jìn)一步探討。

3 NK/NKT細(xì)胞

NK細(xì)胞是固有免疫的主要效應(yīng)細(xì)胞，在清除病原體和異常細(xì)胞方面有重要的作用，根據(jù)其表面CD56的密度不同可分為CD56bright和CD56dim群。CD56dim群主要表達(dá)穿孔素，發(fā)揮直接細(xì)胞毒作用；CD56bright群主要通過(guò)分泌免疫調(diào)節(jié)細(xì)胞因子如IFN-γ、腫瘤壞死因子α(Tumor necrosis factor-α, TNF-α)、轉(zhuǎn)化生長(zhǎng)因子β(Transforming growth factor, TGF-β)、粒細(xì)胞-巨噬細(xì)胞集落刺激因子(Granulocyte-macrophage colony-stimulating factor, GM-CSF)和IL-10發(fā)揮作用[27]。

NK細(xì)胞雖然是固有免疫的主要效應(yīng)細(xì)胞，但在清除HBV的同時(shí)，也會(huì)造成肝細(xì)胞損傷，對(duì)臨床結(jié)局起決定性作用。研究顯示，免疫清除期患者NK細(xì)胞CD69和CD107表達(dá)上調(diào)，分泌IFN-γ和TNF-α增加，而且NK細(xì)胞活性的增強(qiáng)與肝臟損傷呈正相關(guān)[28]。HBsAg轉(zhuǎn)基因小鼠實(shí)驗(yàn)也證明，NK細(xì)胞和其分泌IFN-γ引起肝臟損傷[29]。

一項(xiàng)急性HBV感染研究顯示，CD56+CD3-NK和CD56+CD3+NKT細(xì)胞在HBV感染早期階段能快速發(fā)揮抗病毒作用，并及時(shí)地觸發(fā)適應(yīng)性免疫[30]。然而CHB患者NK細(xì)胞似乎受到抑制，導(dǎo)致病毒不能被清除。無(wú)論HBV感染的小鼠還是患者，NK細(xì)胞上抑制性受體NKG2A表達(dá)均上調(diào)，這可能與肝內(nèi)調(diào)節(jié)性CD4+CD25+T細(xì)胞分泌的IL-10增加有關(guān)。而且，小鼠體內(nèi)阻斷NKG2A表達(dá)可以激活NK細(xì)胞，有助于HBV清除[31]。研究顯示，在慢性HBV感染患者，外周血NK細(xì)胞的數(shù)量和細(xì)胞毒活性不改變，但其分泌細(xì)胞因子(如IFN-γ和TNF-α)能力受損[32，33].。然而，HBV相關(guān)慢加急性肝衰竭(HBV-ACLF)患者NK細(xì)胞上激活受體NKG2D、NKp30、NKp44和NKp46表達(dá)上調(diào)，CD56brightCD16-群頻數(shù)增加，但細(xì)胞毒性CD56dimCD16bright群頻數(shù)和功能均降低[34]，這可能是CD56dimCD16brightNK細(xì)胞的耗竭所致，也可能是受到自體的保護(hù)性抑制。在HBV感染發(fā)病過(guò)程中，似乎是激活的NK細(xì)胞損傷肝細(xì)胞，而肝細(xì)胞損傷又誘導(dǎo)抑制性細(xì)胞因子產(chǎn)生，反過(guò)來(lái)抑制NK細(xì)胞的活性，從而減輕肝臟損傷，但這種抑制也使NK細(xì)胞的清除病毒能力減弱。NK細(xì)胞的這些改變是HBV直接作用還是HBV介導(dǎo)的細(xì)胞因子間接作用，亦或是NK細(xì)胞的耗竭所致仍需進(jìn)一步探討。

NKT細(xì)胞是T淋巴細(xì)胞里較特殊的一群，既表達(dá)NK細(xì)胞標(biāo)記物CD56又表達(dá)T細(xì)胞受體CD3，識(shí)別主要組織相容性復(fù)合體Ⅰ類分子(MHC class I-like molecule)提成的脂類抗原。NKT細(xì)胞可分為Ⅰ型和Ⅱ型NKT 細(xì)胞。Ⅰ型NKT細(xì)胞又叫經(jīng)典NKT或恒定NKT(Invariant NKT, iNKT)細(xì)胞表達(dá)恒定的T細(xì)胞受體α(TCR-α)，占肝臟總NKT細(xì)胞的95%；Ⅱ型NKT細(xì)胞表達(dá)多種TCR，占肝臟總NKT 細(xì)胞的5%[35]。激活的iNKT細(xì)胞可以分泌大量的細(xì)胞因子如IFN-γ、TNF-α、IL-4、IL-13、IL-17等和細(xì)胞毒性介質(zhì)如穿孔素。NKT細(xì)胞和NK細(xì)胞一樣，在HBV感染早期被激活，在控制病毒復(fù)制和觸發(fā)適應(yīng)性免疫反應(yīng)有重要作用[26]。

實(shí)驗(yàn)證明，非經(jīng)典NKT細(xì)胞上NKG2D和其配體介導(dǎo)HBV轉(zhuǎn)基因小鼠的急性肝損傷，阻斷NKG2D和其配體結(jié)合，可以阻止非經(jīng)典NKT細(xì)胞介導(dǎo)的急性肝炎和肝損傷[36]。在小鼠研究，iNKT細(xì)胞可以優(yōu)先增強(qiáng)CD8α+DC群分泌Ⅰ型IFN的能力[37]。

NKT細(xì)胞和NK細(xì)胞在抗HBV感染方面的作用基本一致，但NKT細(xì)胞似乎表現(xiàn)出不一樣的抑制肝臟再生和促纖維化作用。小鼠研究表明受損的肝臟再生能力可因?yàn)镹KT細(xì)胞而不是NK細(xì)胞的耗竭而明顯改善，阻斷CD1d-NKT細(xì)胞作用可以有效提升肝細(xì)胞再生能力，顯示NKT細(xì)胞抑制肝臟再生能力。NKT細(xì)胞分泌IL-4、IL-13、hedgehog配體和骨橋蛋白，促進(jìn)肝纖維化，而NK細(xì)胞卻能早期選擇性的殺傷或加快肝星形細(xì)胞(Hepatic stellate cell, HSCs)衰老，并分泌IFNγ，從而抑制肝纖維化[38]。NK和NKT細(xì)胞在乙肝疫苗接種方面也起著重要作用。[39]。

4 Tregs

CD4+CD25+Tregs分泌抑制性細(xì)胞因子如IL-10和TGF-β，保持對(duì)自身和外部抗原的免疫耐受，許多研究證實(shí)CD4+CD25+Tregs與HBV感染的免疫耐受密切相關(guān)[40]。但也有報(bào)道，與健康對(duì)照和痊愈的HBV感染者相比，CHB患者CD4+CD25+Tregs數(shù)量顯著升高，且這種升高與病毒載量一致[41，42]，在HBV相關(guān)肝衰竭患者也發(fā)現(xiàn)Tregs顯著升高[43]，小鼠實(shí)驗(yàn)也得出類似結(jié)果，CD4+Foxp3+Tregs通過(guò)增加TGF-β分泌和增強(qiáng)枯否細(xì)胞分泌IL-10對(duì)抗polyI:C/d-GalN介導(dǎo)的爆發(fā)性肝炎[44]。Tregs上膜結(jié)合TGF-β(mTGF-β)和OX40的表達(dá)上調(diào)可以抑制NK細(xì)胞介導(dǎo)的肝細(xì)胞損傷[45]。Tregs在抑制免疫介導(dǎo)的肝損傷的同時(shí)，同樣會(huì)抑制免疫細(xì)胞的抗病毒作用，導(dǎo)致HBV不能被清除。比如Tregs抑制HBV抗原介導(dǎo)的單核細(xì)胞增殖和分泌IFN-γ能力[46]。CD4+CD25+Tregs分泌的IL-10抑制NK細(xì)胞和CD8+ T細(xì)胞的抗病毒作用[47]。轉(zhuǎn)基因鼠實(shí)驗(yàn)指出，熱休克蛋白gp96可以一定程度上減少Tregs數(shù)量，提升抗病毒免疫[48]，間接證明Tregs對(duì)免疫細(xì)胞的抑制作用。Tregs在HCV感染的研究卻得到不同結(jié)果，Tregs上PD-1的表達(dá)水平與適應(yīng)性免疫造成的損傷程度相關(guān)[49]，CD4+FoxP3+Treg的大量激活可以使感染局部化，而且可能限制肝纖維化進(jìn)展[50]。所以，Tregs在HBV感染中作用還需進(jìn)一步研究。

5 IFNs

IFNs主要分為I型IFN(IFN-α和IFN-β)、Ⅱ型IFN(IFN-γ)和Ⅲ型(IFN-λ1、2和3)，發(fā)揮著抗病毒、調(diào)節(jié)免疫、抑制增殖和抗腫瘤等作用。IFN-α主要由pDC產(chǎn)生，mDC也可產(chǎn)生IFN-α。大多數(shù)細(xì)胞在接觸病原體后會(huì)產(chǎn)生IFN-β。I型IFN可以影響dsRNA依賴蛋白酶R(dsRNA-dependent protein kinase R, PKR)、2＇5＇腺苷酸合成酶(2＇5＇adenylatesynthetase, 2＇5＇OAS))系統(tǒng)和Mx蛋白等，在病毒生命周期的各個(gè)階段發(fā)揮抗病毒作用[9]。I型IFN可以提升NK細(xì)胞的活性，上調(diào)MHC表達(dá)，影響T細(xì)胞和B細(xì)胞的發(fā)育并調(diào)控DC功能。IFN-γ主要由T細(xì)胞產(chǎn)生，也可以由NK和NKT細(xì)胞產(chǎn)生，發(fā)揮免疫調(diào)節(jié)的作用。IFN-λ由細(xì)胞毒性T淋巴細(xì)胞(Cytotoxic T-lymphocytes, CTLs)產(chǎn)生，可抑制HBV復(fù)制，其作用的分子機(jī)制與IFN-α類似[51]。

研究發(fā)現(xiàn)，HCV感染的黑猩猩大量干擾素調(diào)節(jié)基因(IFN regulated genes，IRG)被快速喚起，然而急性HBV感染的黑猩猩并沒(méi)有發(fā)現(xiàn)固有免疫相關(guān)基因的改變[52，53]，作者認(rèn)為HBV不觸發(fā)固有免疫反應(yīng)可能是因?yàn)镠BV在感染初期表現(xiàn)為隱形病毒角色。敲除IFN-λ和IFN-α/β受體的小鼠，HBV復(fù)制水平明顯比正常小鼠高[54]，證實(shí)了這些細(xì)胞因子在控制HBV復(fù)制的重要作用。但許多研究發(fā)現(xiàn)HBV感染過(guò)程IFN反應(yīng)受到抑制。TLR刺激實(shí)驗(yàn)證明，CHB患者NK細(xì)胞產(chǎn)生IFN-γ能力受損。在HBV轉(zhuǎn)基因小鼠NKT細(xì)胞的頻數(shù)降低，產(chǎn)生IFN-γ能力也受損[55，56]。出現(xiàn)這些現(xiàn)象的原因可能為HBV及其蛋白介導(dǎo)的免疫抑制。HBeAg可能通過(guò)IL-18抑制NK細(xì)胞產(chǎn)生IFN-γ的能力[57]。HBV可能通過(guò)IL-8啟動(dòng)子的表觀遺傳調(diào)控激活I(lǐng)L-8基因表達(dá)，IL-8反過(guò)來(lái)降低HBV對(duì)IFN-α的敏感性[58]。

IFN-α可以通過(guò)表觀遺傳調(diào)控(如激活I(lǐng)RG)，還可以加強(qiáng)固有免疫和適應(yīng)性免疫發(fā)揮抗病毒作用，因此被廣泛用于抗HBV治療。一項(xiàng)研究顯示，Peg-IFNα治療可以早期激活DCs，使CD56brightNK細(xì)胞大量擴(kuò)增，增強(qiáng)CD56dimNK細(xì)胞活性和功能，而且使輔助性T細(xì)胞Th1和Th1定向的HBV特異性CD4/CD8T細(xì)胞頻數(shù)增加[59]。有研究發(fā)現(xiàn)，替諾福韋(Tenofovirdisoproxilfumarate, TDF)早期使HBV復(fù)制的降低可以增強(qiáng)Peg-IFNα對(duì)固有免疫的激活[60]，強(qiáng)調(diào)了對(duì)基線HBV載量高患者聯(lián)合治療的必要性。研究顯示，NK細(xì)胞的激活限制CD8+T細(xì)胞免疫反應(yīng)，增加免疫損傷，使感染慢性化，但I(xiàn)型IFN的治療可以保護(hù)NK細(xì)胞對(duì)CD8+T細(xì)胞的這種限制[61，62]。

對(duì)于IFN-λ的研究相對(duì)較少，但因其與IFN-α類似的抗病毒機(jī)制，受到越來(lái)越多的關(guān)注。早期研究提示，IFN-λ用于治療兩個(gè)HBV感染的人類肝細(xì)胞衍生細(xì)胞系，雖然兩個(gè)細(xì)胞系IFN-λ受體的表達(dá)和IFN-λ介導(dǎo)的抗病毒蛋白水平相似，但只有一個(gè)細(xì)胞系的HBV受抑制，所以認(rèn)為IFN-λ在人體抗HBV作用可能有限[63]。最近一項(xiàng)臨床研究顯示，IFN-λ治療HBeAg(+)CHB患者早期HBV DNA和HBsAg的下降程度比IFN-α治療組更明顯，兩組的48周HBeAg血清學(xué)轉(zhuǎn)換率相似，但治療后續(xù)的HBeAg血清學(xué)轉(zhuǎn)換率不如IFN-α高，而且與IFN-α相比，IFN-λ的副反應(yīng)相對(duì)更大[64]。

6 小結(jié)

雖然許多固有免疫成分有強(qiáng)有力的抗病毒作用，但HBV本身或者通過(guò)干擾信號(hào)通路和介導(dǎo)抑制性細(xì)胞因子產(chǎn)生等策略抑制固有免疫成分，造成固有免疫反應(yīng)不能被激活，適應(yīng)性免疫不能及時(shí)觸發(fā)，HBV感染持續(xù)存在。而消除這些抑制可部分重塑固有免疫反應(yīng)，有助于HBV的清除?？傊?，宿主和HBV之間的免疫反應(yīng)是一個(gè)復(fù)雜的過(guò)程，了解其具體機(jī)制有助于未來(lái)免疫治療新策略的研發(fā)。

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The roll of innate immunity in the pathogenesis and treatment of HBV infectionQu

Xiaojing,ZhangLu,LiMinghui,XieYao

SecondDivisionofLiverDiseasesCenter,BeijingDitanHospital,CapitalMedicalUniversity,BeijingMunicipalAdministrationofHospitalsClinicalMedicineDevelopmentofSpecialFunding,Beijing100015,ChinaCorrespondingauthor:XieYao,Email:xieyao00120184@sina.com

Objective The pathogenesis of HBV infection is the result of a complex interactions between the host immune system and the virus, the host immune system involves innate immune and adaptive immune. Now, it is thought that host immune responses to viral particles and proteins are important factors that determine whether HBV is cleared or persists and hepatocytes injured. Innate immune system is the first defending line of host against viral infection. However, many studies have shown that HBV can develop tactics to escape innate immune recognition and interfere with innate immune signaling pathways and induce immunosuppression. It is necessary to analysis the functions and status of host innate immunity in HBV infection which may contribute to find novel approaches to eliminate HBV. This review will present the current understanding of innate immune components including pattern-recognition receptors(PRRs)、dendritic cells(DCs)、natural killer(NK)/natural killer T(NKT)cells、T regulatory cells(Tregs) and interferons(IFNs).

Hepatitis B virus; Host; Innate immunity; Immunosuppression

北京市科學(xué)技術(shù)委員會(huì)重大項(xiàng)目(D121100003912001)

謝堯，Email:xieyao00120184@sina.com

10.3760/cma.j.issn.1003-9279.2017.01.018

肝炎病毒，乙型；宿主；固有免疫；免疫抑制

2016-11-08)