EB病毒相关淋巴瘤研究进展
Research Progress of Epstein Barr Virus Associated Lymphoma

作者: 郝园园 , 林森森 :中国药科大学,江苏 南京;

关键词: Eb病毒伯基特淋巴瘤霍奇金淋巴瘤弥漫大B细胞淋巴瘤Eb Virus Burkitt’s Lymphoma Hodgkin’s Lymphoma Diffuse Large B-Cell Lymphoma

摘要:
Eb病毒(Epstein-Barr virus, EBV)属疱疹病毒群,为双链DNA病毒,超过90%的成年人为EBV健康携带者,尽管在绝大多数携带者中无害,EBV却以不同比例存在于多种免疫力看似正常的不同类型淋巴瘤及上皮细胞肿瘤患者的癌细胞中,包括伯基特淋巴瘤、霍奇金淋巴瘤、弥漫大B细胞淋巴瘤等。EBV相关淋巴瘤的发病机理与病毒基因表达及细胞基因表达间存在着复杂的关系,现就几种常见淋巴瘤中EBV的作用机制及相关研究进展进行综述。

Abstract: Epstein Barr virus (EBV) is a new type of virus. EBV belongs to herpesvirus group, which is double stranded DNA virus. More than 90% of adults are healthy EBV carriers. Although it is harmless in most of the carriers, EBV exists in different proportions in cancer cells of different types of lymphoma and epithelial cell tumor patients with normal immunity, including Burkitt’s lymphoma, Hodgkin’s lymphoma, diffuse large B-cell lymphoma, etc. There is a complex relationship between the pathogenesis of EBV associated lymphoma and the gene expression of virus and cell. This article reviews the mechanism of EBV in several common lymphomas and the related research progress.

1. Epstein-Barr virus概述

Epstein-Barr virus, EBV属于疱疹病毒γ亚科,为双链DNA病毒,是由Epstein和Barr于1964年在Burkitt非洲儿童淋巴瘤细胞中发现的一种亲人类B淋巴细胞的病毒,是最早发现的与人类肿瘤相关的病毒。EBV具有嗜淋巴组织特性,感染后可在人体长期潜伏,超过90%的成年人为EBV健康携带者 [1] [2]。当免疫系统正常时,EBV通常不会危害健康,但是当免疫力受到抑制时,EBV可引发多种恶性淋巴瘤。尽管在绝大多数携带者中无害,EBV却以不同比例存在于多种免疫力看似正常的不同类型淋巴瘤及上皮细胞肿瘤患者的癌细胞中,例如在高发地区的Burkitt淋巴瘤患者中,几乎所有的病人的肿瘤细胞中都存在EBV [3] [4]。

大量研究表明,EBV初次感染及感染后的过程中均受到T淋巴细胞参与的免疫控制 [5] [6]。因此,EBV感染在临床上往往表现为传染性单核细胞增多症,典型症状是由抗原特异性T淋巴细胞引起的发热、咽炎和颈淋巴结肿大,随后,记忆性T淋巴细胞将存储于口咽部淋巴结中持续发挥免疫监控作用 [7] [8]。而当体内T淋巴细胞出现损伤,不受控制的增殖将发展为EBV阳性B淋巴细胞增生性疾病(B-LPD),这一过程通常出现在以下两种免疫功能低下的情况中,包括:1) 干细胞或器官移植。2) T淋巴细胞功能丧失的HIV阳性病人 [9] [10]。

EBV可通过与C3d高度相似的膜糖蛋白Gp350/220与B细胞CR2/CD21分子结合,通过细胞内吞作用进入B细胞 [11]。从B细胞至成熟的记忆B细胞均可在体外被EBV感染并转化为永生化细胞系,这种由EBV感染形成的B细胞系称为淋巴细胞样细胞系。在淋巴细胞样细胞系中,启动子Cp或Wp启动病毒基因组编码下游Mrna及相应蛋白的表达,主要基因产物包括:1) EBV核抗原(Epstein-Barr virus nuclear antigen, EBNA):EBNA1-6,分别称为EBNA1,EBNA2,EBNA3A,EBNA3B,EBNA-LP和EBNA3C。2) EBV潜伏膜蛋白(Epstein-Barr latent membrane protein, LMP),LMP1,LMP2A和LMP2B。除上述蛋白外,感染病毒后,细胞还可产生EBV非编码RNA,包括EBER1,EBER2,BARTs,EBV microRNA。根据特定EBV相关基因表达,可简单分为三种类型,I型(EBNA1),II型(EBNA1,LMP1和LMP2),III型(表达所有潜伏基因)。不同潜伏类型代表着T淋巴细胞对肿瘤的不同免疫应答以及预后状态。在几种主要的EBV相关淋巴瘤中,实际情况更加复杂。I型EBV感染主要出现在伯基特淋巴瘤中,但在不同类型伯基特淋巴瘤中,EBV状态并不相同。赤道非洲儿童中发生率较高的地方性Burkitt淋巴瘤,几乎100%患者携带EBV,但在散发性Burkitt淋巴瘤中,约10%~80%表达EBV [12],而HIV相关的Burkitt淋巴瘤中,约30%~40%的患者可以检出EBV [13]。弥漫大B淋巴瘤(Diffuse large B cell lymphoma, DLBCL)是非霍奇金淋巴瘤中最常见类型,在中国,DLBCL占所有非霍奇金淋巴瘤中的45.8%,占所有淋巴瘤40.1% [14],其中约10%为EBV阳性DLBCL [15],根据表达EBV相关蛋白不同还可分为II型或III型EBV感染。脓胸相关淋巴瘤(Pyothorax-associated lymphoma, PAL)属于慢性炎性相关性DLBCL中的一种,其与EBV感染高度相关,60%为III型EBV潜伏感染。

2. EB病毒与弥漫大B淋巴瘤

弥漫性大B细胞淋巴瘤:是最常见的非霍奇金淋巴瘤。在全球范围内,弥漫性大B细胞淋巴瘤占所有非霍奇金氏恶性淋巴瘤中的比例约为40%,是临床上最常见的恶性淋巴瘤。作为一组临床特征、形态学特点、免疫表型、分子生物学改变各异的肿瘤,DLBCL可被不同的分型标准细分为多种亚型,且不同亚型的DLBCL在临床过程以及对药物治疗的敏感性等方面存在显著差异。2008年世界卫生组织(WHO)根据微阵列基因表达谱将DLBCL分为两种分子亚型:生发中心样弥漫大B细胞淋巴瘤(Germinal centre B-cell-like DLBCL)和活化B细胞样弥漫大B细胞淋巴瘤(Activated B-cell-like DLBCL) [16]。随后,新一代测序证实GCB与ABC型DLBCL存在不同的基因表达特征及基因突变类型 [17]。

2008年版WHO淋巴瘤分类中将“老年性EBV﹢DLBCL”作为一个暂定亚类,将50岁以上的DLBCL伴EBV感染的单克隆B细胞增殖性疾病定义为老年EBV阳性DLBCL,同时需满足免疫功能健全和既往无淋巴瘤病史两个条件,这部分患者预后较EBV阴性DLBCL差 [18]。但近年来发现越来越多的EBV + DLBCL出现在有免疫力年轻患者中,其生物学行为与年龄 > 50岁患者无显著差别 [19] [20]。在M. Cohen等的研究中,阿根廷地区儿童EBV阳性DLBCL发病率与成人近似,甚至更高,这与其他发展中国家儿童非霍奇金淋巴瘤研究结果相同 [21]。因此,2016年版WHO分类明确其为一个疾病实体,并将“老年”改为“非特指(NOS)”,强调需要其他合并EBV感染的大B细胞淋巴瘤不归入此类,如淋巴瘤样肉芽肿 [22]。

在亚洲,老年EBV阳性DLBCL占所有DLBCL的8%~10% [23]。在西方国家,其发生率较低,小于5% [24]。EBV阳性DLBCL患者,无论年龄,均伴有不良的临床特征和病理学特点,且不同年龄组间生存无显著性差异。EBV阳性DLBCL表现为侵袭性的临床过程,超过半数处于疾病进展期及预后较差的国际预后指数(international prognostic index, IPI),中位生存期仅24个月 [25]。

我国是EBV阳性DLBCL发病人数最多的国家,由于EBV阳性DLBCL主要发生在年逾五十的老年群体,随着人口老龄化的不断加剧,EBV阳性DLBCL在我国的发病率将呈持续上升的趋势。前期研究认为老年性EBV阳性DLBCL是由年龄有关的T细胞免疫衰老无法对EB病毒相关免疫发挥有效的免疫作用导致。尽管D. Cárdenas等研究发现EBV阳性DLBCL的发生与EB病毒相关免疫反应发生改变,效应型记忆CD4+和CD8+T淋巴细胞减少有关,但仍需要进一步研究衰老与EBV阳性DLBCL之间的关联 [26]。老年性EBV阳性DLBCL在EBV类型上与B-LPD及AIDS后期EBV阳性弥漫大B相似,通常表现为III型EBV潜伏感染 [27]。有研究表明,EBV编码B细胞转化必须的EBNA3实际上可能会对EBV致癌作用产生抑制,感染EBNA3B缺失病毒的B细胞表现出更强的增值能力 [28]。与老年性DLBCL相比,在更年轻病人,EBV潜伏基因常表现为II型感染,这可能与更复杂的发病机理有关。通常认为,ABC型DLBCL相较于GCG型有着更差的治疗效果,用时EBV更多在结外区域的存在将加剧这一种预后不良。

由于EBV的存在,EBV阳性ABC型DLBCL常出现免疫球蛋白重排的单克隆性增值。与EBV阴性DLBCL相比,EBV阳性DLBCL有着更少的染色体突变出现,细胞遗传学分析表明,除淋巴瘤常见突变MYC,BCL2,BCL6位点外,EBV阳性DLBCL仍未被发现较典型的改变 [29]。ABC型DLBCL中,遗传损伤导致NF-kb通路的持续激活和慢性活化的BCR信号传导通路,这解释了其浆母细胞表型和耐药性 [30]。在正常的B淋巴细胞中,Nf-kb激活靶基因IRF4,随后通过反式激活PRDM1/blimp-1,从而诱导细胞分化。而ABC型DLBCLs中,Nf-kb通路持续激活,但PRDM1则由于基因点突变,缺失或外因等被沉默,因此肿瘤细胞在浆母细胞期持续增殖 [31] [32] [33]。另外,Nf-kb上调抑凋亡蛋白Bcl-XL,cIAP1,cIAP 2将导致化疗难治性 [34]。在大部分EBV阳性DLBCL中存在LMP-1表达,同样将显著的激活Nf-kb通路,这也解释了EBV对DLBCL难治性的另一种影响。Harumi Kato等利用基因富集分析和基因本体分析将老年性EBV阳性DLBCL与EBV-DLBCL进行比对,发现除Nf-kb通路外,EBV阳性肿瘤中还存在着免疫及炎症相关通路的高表达,包括JAK/STAT,NOD受体,Toll样受体信号通路。在其体外研究中,ABC型DLBCL和GCB型DLBCL在EBV感染后,STAT通路和Nf-kb通路均会发生上调 [35]。

脓胸相关淋巴瘤是长期慢性炎症引起的一种比较典型的EBV阳性肿瘤,其发生主要与使用人造气胸治疗结核性胸膜炎导致的长期胸膜腔积脓或胸膜炎有关 [36],由慢性炎症发展到恶性淋巴瘤通常超过10年时间,常发病于65~70岁病人,这一疾病似乎与性别有一定的关联,男性会有更高的发病几率,与女性之间对比大概是4:1。Sanchez-Gonzalez B等研究发现骨骼及关节植入金属所引起的慢性炎症也和EBV阳性DLBCL之间存在一定的关联 [37]。PAL在EBV类型上通常表现为III型潜伏感染,在慢性炎症处,EBV通常通过上调免疫抑制剂IL-10 [38] [39]、自分泌促进因子IL-6 [40],下调MHC Class I表达 [41],以及EBNA3B显性突变使得B细胞发生转化 [42]。此外,微阵列分析表明,与常规DLBCL相比,IFI27是PAL最典型的表达基因之一,IFI27的表达将伴随慢性炎症的整个过程,但关于IFI27在淋巴瘤形成中的作用还仍未得到明确的解释 [43]。

HIV相关DLBCLs,根据细胞形态学,可分为中心母细胞型和免疫母细胞型。免疫母细胞型是发生在ADIS中最常见的类型,其中EBV阳性感染率约为90% [44]。Aaron Arvey等研究发现,在非生发中心型HIV相关DLBCL中,27/48例为EBV阳性,并且在I型、II型、III型EBV潜伏感染中表现出来平均分布的趋势。而在生发中心类型HIV相关DLBCL中,25/98型为EBV阳性,其中76%为I型EBV潜伏感染 [45]。

3. EB病毒与伯基特淋巴瘤

伯基特淋巴瘤:是一种高侵袭性非霍奇金B细胞淋巴瘤,由Denis Parsons Burkitt在 1958年于非洲首先报告。它是最早被证实与EB病毒感染相关的淋巴瘤,也是第一种被发现与病毒相关的人类肿瘤 [46],具有恶性程度高,进展快的特点,其细胞倍增时间通常为24~48 h,常发病于儿童 [47]。根据临床和生物学特征,世界卫生组织将伯基特淋巴瘤划分为三类:地方型、散发型(主要指发生于非疟疾地区)和免疫缺陷相关性。

地方型伯基特淋巴瘤与疟疾感染有很大关联,并且几乎所有地方型BL病例中均可发现EB病毒感染 [3]。有研究称,EB病毒是地方型伯基特淋巴瘤的直接成因。EBV能够引起体外培养B细胞永生化,在肿瘤发生前,通常可在儿童体内发现高水平的EB病毒抗体滴度 [48]。但是,EBV感染B细胞与地方型BL发生之间的相关机制仍未被阐明。在所有地方型BL中,EB病毒均表达EBNA1蛋白,其余潜伏和促细胞溶解转录同样可在部分肿瘤中出现,提示EBNA1在其中起到重要的作用 [49]。缺失的EBNA2能够导致细胞中EBNA3A,EBNA3B,EBNA3C基因的表达 [50],有报道,EBNA2基因缺失的细胞通常表现出更强的抗凋亡能力,因此有可能EBNA2为肿瘤发生提供优势 [51]。在地方型BL中,EB病毒可以通过表达EBNA1蛋白,BHRF1蛋白,EBER转录或后生的改变使得MYC发生转位,随后EBV潜伏膜蛋白LMP1对促凋亡蛋白BIM产生抑制,从而阻止了B细胞发生凋亡 [52] [53]。SA Kamranvar研究发现,EBV能够促进被感染细胞基因不稳定性,端粒功能失常,诱导感染细胞DNA损伤,因此,这也许是促使肿瘤发生的潜在原因 [54]。在最近研究中,EBNA1被认为能够下调多种抑制B细胞生存的基因,同时EBNA1能够抑制细胞凋亡。蛋白质组学研究发现,EBNA1,P53,Mdm2均存在与泛素酶USP7 N端TRAF区域的结合位点 [55] [56] [57],但与P53,Mdm2相比,EBNA1有着更高的亲和力,因此,EBNA1能够竞争性干扰P53,Mdm2活性 [58] [59] [60]。另外,EBNA1还能通过与Sp1宿主蛋白提高B淋巴细胞中生存素水平。通过以上两种方式,EBNA1在B淋巴细胞中抑制细胞凋亡的发生 [61]。

关于伯基特淋巴瘤起始于生发中心B细胞还是记忆B细胞目前还存在争议,这一问题同样与地方型BL中EBV存在相关。在健康宿主中,EBV潜伏感染于人外周血的记忆B细胞当中。Donna Hochberg等的研究发现,当肿瘤起源于EBV潜伏感染记忆B细胞时,肿瘤仅表达EBNA1,这一结果与地方型伯基特淋巴瘤存在着一定的一致性 [62]。

尽管EB病毒存在于大多地方型伯基特淋巴瘤中,在其他类型伯基特淋巴瘤中则更少出现,缺失的EB病毒可能与肿瘤细胞细胞分裂时病毒的丢失有关。在在Cristiana Bellan的研究中,EBV阳性较EBV阴性伯基特淋巴瘤存在更高概率的免疫球蛋白可变区基因的体细胞突变和抗原选择性,因此可能根据EB病毒感染与否,伯基特淋巴瘤起源于不同B细胞类型。一种可能的解释是,EBV阳性伯基特淋巴瘤起源于记忆细胞,而EBV阴性伯基特淋巴瘤起源于生发中心 [63]。

4. EB病毒与霍奇金淋巴瘤

霍奇金淋巴瘤:是近年来发病率较高的一种疾病,同时也是治愈率非常高的淋巴类恶性肿瘤。1832年,Thomas Hodgkin首次发现相关病例。1865年,Wilks将类似病例命名为霍奇金病。在随后的1989年和1902年,Sternberg和Reed分别描述了霍奇金病中肿瘤细胞为一种体积大,常为多核的巨细胞,现称为Sternberg-Reed细胞。2008年版世界卫生组织淋巴瘤分类将霍奇金淋巴类分为经典型霍奇金淋巴瘤(Classical Hodgkin lymphoma, CHL)和结节性淋巴细胞为主型霍奇金淋巴瘤(Nodular lymphocyte predominant HL, NLPHL)。其中,NLPHL较少为EBV阳性。经典型霍奇金淋巴瘤又可分为结节硬化型霍奇金淋巴瘤(Nodular sclerosing HL, NSHL)、混合细胞型霍奇金淋巴瘤(Mixed cellularity type hodgkin lymphoma, MCHL)、富于淋巴细胞性经典霍奇金淋巴瘤(Lymphocyte Rich Hodgkin Lymphoma, LRCHL)、淋巴细胞消减型霍奇金淋巴瘤(Lymphocyte depleted Hodgkin Lymphoma, LDHL) [64],在这四种类型淋巴瘤中,肿瘤组织中霍奇金/里–斯细胞仅占1%~2% [65],其余绝大部分为大量非肿瘤性炎性背景,包括T淋巴细胞、B淋巴细胞、巨噬细胞、嗜酸性粒细胞、纤维母细胞等,因此肿瘤微环境对HL同样至关重要 [66]。

经典型霍奇金淋巴瘤中EB病毒感染率与患者的年龄,性别,种族,地区均存在一定的关联。发达国家中,EB病毒感染率约为30%~50%,在发展中国家中有更高的EB病毒感染率。EBV阳性病例多发生于小于10岁儿童和大于80岁成年当中。其中,儿童可能是由于初次EBV感染并且儿童中,而在老年人当中则可能与免疫力低下有关 [67]。

尽管,cHL并不是AIDS中典型病例,但较正常人群,AIDS患者有着10倍的cHL患病率,并且发生类型多为EBV阳性混合细胞型和淋巴细胞消减型霍奇金淋巴瘤 [44]。cHL在CD4+T细胞数较少的病人中发病晚于HIV相关伯基特淋巴瘤,并且在HAART治疗后,cHL发病率有轻微的升高 [68]。这可能与在伯基特淋巴瘤中,CD4+T抑制EB病毒感染B淋巴细胞,而在cHL中,CD4+T淋巴细胞能够构成肿瘤细胞微环境有关。

EBV阳性cHL中,Eb病毒通常为II型潜伏感染,主要表达EBV核抗原EBNA1,潜伏膜蛋白LMP1和LMP2A,除此之外还转录非编码RNA,EBER和BART。LMP1通过模仿CD40受体,能够激活下游NF-kB,JAK/STAT和PI3K信号传导通路,从而诱导生发中心B淋巴细胞转录改变 [69]。另外,LMP1还可能通过抑制病毒裂解周期的作用,使细胞逃避死亡。Vrzalikova K等研究发现LMP1通过干扰Blimp1转录抑制浆细胞分化 [70]。关于LMP2在霍奇金淋巴瘤的作用,目前还未得到合理的解释,鉴于LMP2类似于BCR通路,而BCR和LMP2在HRS细胞中关键下游通路的缺失,因此认为LMP2可能仅在BCR通路正常的早期HRS前体细胞中发挥作用 [71]。另外,由于LMP2在EBV阳性霍奇金淋巴瘤中较高的阳性比例,也可能LMP2存在除BCR通路外其他重要作用。

尽管EBV阴性与EBV阳性cHL在形态和表型上有一定的相似性,但越来越多发现证明它们发病机理的不同。几乎所有BCR功能缺失的cHL为EBV阳性cHL这一现象表明EB病毒能够使得BCR功能缺失的生发中心B细胞逃避凋亡 [72]。TNFAIP3,编码锌指蛋白A20,是一种新的cHL肿瘤抑制基因,它能够抑制Nf-kb活性。这一基因更频繁的在EBV阴性cHL中发生突变,表明EBV能够功能性的代替突变解除锌指蛋白A20的肿瘤抑制作用 [73] [74]。最后,Leonard S等研究发现,EB病毒感染能够诱导霍奇金淋巴瘤相关的生发中心B细胞表观遗传和转录组的改变 [75]。因此,在病理上,EB病毒通过对关键细胞突变的补偿作用使得肿瘤细胞逃避死亡,并使得HRS前体细胞增殖。

5. 结语和未来展望

近年来,人们认识到,EB病毒与多种疾病发生有关。在淋巴瘤中,EBV阳性病人相对于EBV阴性的预后普遍较差且化疗效果不理想。目前已有多项研究试图从免疫逃避、感染细胞转化等方面阐述EB病毒感染对淋巴瘤发生的影响,但不同EBV阳性肿瘤中EBV表达谱并不一致,EBV影响也不尽相同,因此,关于EBV对淋巴瘤发生的影响仍需要不断的研究。

在治疗EBV阳性淋巴瘤上,除传统化疗、针对EBV的抗病毒治疗外,人们正在探索更加有效的治疗方法,如:过继性CTL治疗、肿瘤疫苗、EBV活化诱导剂等,虽然目前还存着免疫原性较弱、肿瘤细胞耐药、毒副作用强等诸多问题,治疗方案还有待进一步研究,但随着人们对EBV与淋巴瘤关系的了解加深,同时分子生物学研究的不断深入,可以帮助我们更好的选择治疗靶点,动态监测疗效,评估预后,从多角度思考EBV相关淋巴瘤的治疗方向,相信未来终将攻克EBV阳性淋巴瘤这一难治疾病。

NOTES

*通讯作者。

文章引用: 郝园园 , 林森森 (2021) EB病毒相关淋巴瘤研究进展。 世界肿瘤研究, 11, 38-47. doi: 10.12677/WJCR.2021.112006

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