杰弗里·科恩（Jeffrey I. Cohen）1，*和伊莎贝尔·梅特（Isabelle Meyts）2
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EB病毒(Epstein-Barr Virus，EBV) 是一种人类疱疹病毒，它感染了全世界近95%的人，而且大多数人都不知道他们被感染了，而且从来没有与感染相关的疾病。如果感染推迟到青春期或成年早期，这些人中的大多数会发展为传染性单核细胞增多症。患有某些先天性免疫缺陷的人[例如X-连锁淋巴增生性疾病1(XLP 1)]、获得性免疫缺陷(例如艾滋病)或医源性免疫缺陷(例如器官移植受者)可发展为与原发感染或病毒重新激活有关的严重甚至致命的EBV病。这些疾病包括EBV B细胞或T细胞淋巴瘤、淋巴增生性疾病(LPD)、噬血细胞淋巴组织细胞增生症(HLH)或EBV平滑肌肿瘤。与严重EBV病相关的遗传病包括易感染多种病毒、细菌或真菌(例如GATA 2缺乏)或主要与EBV有关的感染(XLP 1)。这些疾病主要影响T细胞和NK细胞的功能，这些细胞对EBV感染细胞的免疫监测非常重要，而不是病毒感染的B细胞，导致潜伏，并可驱动到LPD。与EBV相关的遗传病的发现进一步加深了我们对细胞蛋白对T细胞和NK细胞的信号传递和效应活性的作用的认识。
收集关于EBV感染和人类原发性免疫缺陷的文章，首先概述T细胞对病毒的反应。[tr]Long等人[tr]本文强调T细胞对EBV的反应在症状性、无症状性原发感染和持续感染中的重要性。作者还描述了组织驻留记忆T细胞、γδT细胞和NKT细胞对控制EBV感染的贡献。[tr]拉图尔和温特[tr]提供对易患EBV LPD的免疫缺陷的概述。这包括影响T细胞增殖的蛋白质的突变，B细胞与T细胞的相互作用，以及T细胞和NK细胞的细胞毒性。本系列的其他文章集中于与严重EBV病相关的特定免疫缺陷。[tr]Ghosh等人[tr]IL-2诱导激酶(ITK)缺乏症的研究报告。ITK有缺陷的患者可表现为EBV阳性的霍奇金淋巴瘤、LPD和HLH。[tr]Panchal等人[tr]回顾XLP 1患者在SAP中出现B细胞淋巴瘤、HLH和/或胃动球蛋白血症的功能缺失突变的结果。SAP是一种重要的适配蛋白，对SLAM家族成员的激活和T和NK细胞的信号传递具有重要意义。SAP突变患者T、NK细胞功能受损。[tr]Arjun araja等人[tr]与CARD 11功能增益突变相关的NF-κB和T细胞无能性疾病B细胞扩增的报道。这些患者有B细胞淋巴细胞增多，T和NK细胞减少，低级别持续性EBV病毒血症和NF-κB的构成性激活。[tr]Caorsi等人[tr]描述一位CD 70缺乏症患者，他表现为周期性发热、扁桃体炎、颈淋巴结炎和EBV病毒血症。CD 70在抗原提呈细胞(包括B细胞)上表达，是CD 27的配体，在T细胞上表达，这种相互作用对细胞毒性T细胞的激活具有重要意义。[tr]Hoeger等人[tr]报道活化B细胞核因子κ-轻链增强子1(NF-κB1)单倍体功能不全与常见的变异型免疫缺陷样B细胞病、反复肺部感染和EBVLPD有关。NF-κB1在细胞毒性T细胞和B细胞NF-κB信号转导中起重要作用。[tr]卡皮尔和卢卡斯[tr]活化PI3Kδ综合征(Apds)的研究进展PI3K3CD[tr]或PIK3R[tr]或功能缺失突变PTEN[tr]。这些突变导致PI3K与衰老的CD8 T细胞共同激活，并增加终末效应细胞CD8 T细胞的数量。病人经常出现心肺感染，EBV病毒血症，LPD，淋巴瘤，以及巨细胞病毒病毒血症和淋巴结炎。[tr]木村和科恩[tr]描述慢性活动性EBV病，患者循环T或NK细胞(或B细胞较少)存在较高水平的EBV，浸润组织，经常导致EBV淋巴瘤或HLH。其中一些患者的EBV阳性T或NK细胞有体细胞突变，通常与驱动基因突变相关，如DDX3X[tr]和BCOR.
伴有严重EBV的遗传病患者可发生HLH。[tr]马什[tr]据报道，HLH患者表现为发热、脾肿大、红细胞、白细胞或血小板减少，并常伴有肝炎。HLH患者的细胞毒性T细胞或NK细胞具有明显的脱颗粒或细胞毒性，并存在持续的炎症反应。HLH合并严重EBV病与SH2D1A，BIRC 4，CD 27，ITK[tr]，和MAGT 1[tr]。虽然EBV阳性平滑肌肿瘤最初在实体器官移植受者或艾滋病患者中被报道，[tr]Magg等人[tr]据报道，这些肿瘤存在与EBV相关的免疫缺陷，包括GATA 2或CARMIL 2缺陷、共济失调、毛细血管扩张症以及与突变相关的严重联合免疫缺陷。阿达角[tr]，或IL2RG[tr]。虽然造血干细胞移植(HSCT)已被用于纠正许多EBV相关的遗传病，但许多患者在移植前存在严重的病毒感染，增加了与HSCT相关的发病率，有些患者可能在HSCT后复发EBV病。[tr]McLaughlin等人[tr]报道说，使用EBV特异性细胞毒性T细胞，无论是在HSCT之前获得更好的感染控制，还是在移植后治疗持续性EBV疾病，都是有效的。来自HSCT供体或第三方HLA匹配细胞的EBV特异性T细胞是有效的.
本系列中的文章描述了许多与EBV相关的遗传病，新的疾病仍在继续被发现。这些疾病继续告诉我们T或NK细胞与EBV感染的B细胞之间相互作用的重要性，以及我们的免疫系统如何控制唯一在B细胞中建立潜伏期并诱导B细胞淋巴增殖的人类病毒。更好地理解单个T和NK细胞蛋白在控制EBV中的作用，可能会导致对EBV病和癌症的免疫基础治疗的改进。此外，识别对T细胞和NK细胞功能重要的关键蛋白可为免疫抑制药物提供新的靶点。
作者贡献 列出的所有作者都为该作品作出了重大、直接和智力上的贡献，并批准其出版。
利益冲突 提交人宣布，这项研究是在没有任何商业或金融关系的情况下进行的，这种关系可能被解释为潜在的利益冲突。
供资 这项工作得到了国家过敏和传染病研究所内研究项目的支持。
以下是作者原文：
Editorial: EBV Infection and Human Primary Immune Deficiencies
Jeffrey I. Cohen1,* and Isabelle Meyts2
Author information Article notes Copyright and License information Disclaimer
Epstein-Barr virus (EBV) is a human herpes virus that infects nearly 95% of individuals worldwide and most persons are unaware that they are infected and never have disease associated with the infection. If infection is delayed until adolescence or early adulthood, most of these persons will develop infectious mononucleosis. Persons with certain congenital immunodeficiencies [e.g., X-linked lymphoproliferative disease 1 (XLP1)], acquired immunodeficiencies (e.g., AIDS), or iatrogenic immunodeficiencies (e.g., organ transplant recipients) can develop severe or even fatal EBV disease associated with primary infection or reactivation of the virus. These diseases include EBV B cell or T cell lymphoma, lymphoproliferative disease (LPD), hemophagocytic lymphohistiocytosis (HLH), or EBV smooth muscle tumors. Genetic disorders associated with severe EBV disease include those that predispose to infections with multiple viruses, bacteria, or fungi (e.g., GATA2 deficiency) or infection primarily associated with EBV alone (XLP1). These disorders primarily affect the function of T cells and NK cells which are important for immune surveillance against EBV-infected cells, rather than B cells that the virus infects, establishes latency in, and can drive to LPD. Identification of genetic disorders associated with EBV has furthered our knowledge of the role of the functions of cellular proteins important for signaling and effector activity of T cells and NK cells.
The collection of articles on EBV Infectious and Human Primary Immune Deficiencies begins with an overview of T cell responses to the virus by Long et al. This review emphasizes the importance of T cell responses to EBV during symptomatic and asymptomatic primary infection and during persistent infection. The authors also describe the contributions of tissue resident memory T cells, γδ T cells, and NKT cells for control of EBV infection. Latour and Winter provide an overview of immune deficiencies that predispose to EBV LPD. These include mutations in proteins that impair T cell proliferation, B cell-T cell interactions, and T cell and NK-cell cytotoxicity. Additional articles in this collection focus on specific immune deficiencies associated with severe EBV disease. Ghosh et al. report on IL-2 inducible kinase (ITK) deficiency which is critical for T cell signaling. Patients with defects in ITK can present with EBV-positive Hodgkin and non-Hodgkin lymphoma, LPD, and HLH. Panchal et al. review findings in patients with XLP1 who have loss-of-function mutations in SAP that present with B cell lymphoma, HLH, and/or dysgammaglobulinemia. SAP is an adapter protein important for activation of SLAM family members and signaling in T and NK cells. Patients with mutations in SAP have impaired T and NK cell function. Arjunaraja et al. report on B cell expansion with NF-κB and T cell anergy (BENTA) disease which is associated with gain-of-function mutations in CARD11. These patients have B cell lymphocytosis, reduced numbers of T and NK cells, low grade persistent EBV viremia, and constitutive activation of NF-κB. Caorsi et al. describe a patient with CD70 deficiency who presented with periodic fever, tonsillitis, cervical lymphadenitis, and EBV viremia. CD70 is expressed on antigen presenting cells (including B cells) and is the ligand for CD27 which is expressed on T cells; this interaction is important for cytotoxic T cell activation. Hoeger et al. report that nuclear factor kappa-light-chain-enhancer of activated B cells 1 (NF-κB1) haploinsufficiency is associated with common variable immunodeficiency-like B cell disease, recurrent pulmonary infections, and EBV LPD. NF-κB1 is important for NF-κB signaling in both cytotoxic T cells and in B cells. Carpier and Lucas review activated PI3Kδ syndrome (APDS) which is due to gain-of-function mutations in PI3K3CD or PIK3R or loss-of-function mutations in PTEN. These mutations result in constitutive activation of PI3K with senescent CD8 T cells and increased numbers of terminal effector CD8 T cells. Patients present with frequent sinopulmonary infections, EBV viremia, LPD, and lymphoma, as well as cytomegalovirus viremia and lymphadenitis. Kimura and Cohen describe chronic active EBV disease in which patients have high levels of EBV in circulating T or NK cells (or less commonly in B cells) which infiltrate the tissues and often result in EBV lymphoma or HLH. Some of these patients have somatic mutations in their EBV-positive T or NK cells, usually associated with driver mutations in genes such as DDX3X and BCOR.
Patients with genetic disorders associated with severe EBV can develop HLH. Marsh reports that patients with HLH present with fever, splenomegaly, reduced numbers of erythrocytes, leukocytes, or platelets, and often hepatitis. Cytotoxic T cells or NK cells from patients with HLH have impaired degranulation or cytotoxicity, and persistent hyperinflammation is present. HLH with severe EBV disease has been associated with mutations in SH2D1A, BIRC4, CD27, ITK, and MAGT1. While EBV-positive smooth muscle tumors were initially reported in solid organ transplant recipients or patients with AIDS, Magg et al. report that these tumors have been reported in immune deficiencies associated with EBV, including GATA2 or CARMIL2 deficiency, ataxia telangiectasia, and severe combined immune deficiency associated with mutations in ADA, ZAP70, or IL2RG. While hematopoietic stem cell transplantation (HSCT) has been used to correct many EBV-associated genetic disorders, many of these patients have severe viral infections prior to transplant which increases the morbidity associated with HSCT, and some may have relapses of EBV disease after HSCT. McLaughlin et al. report that the use of EBV-specific cytotoxic T cells either before HSCT to gain better control of infections, or after transplant to treat persistent EBV disease, has been effective. EBV-specific T cells derived from the HSCT donor or third-party HLA-matched cells have been effective.
The articles in this collection describe many of the genetic disorders associated with EBV; new disorders continue to be discovered. These diseases continue to inform us about the importance of interactions between T or NK cells and EBV-infected B cells and how the only human virus that establishes latency in B cells and induces B cell lymphoproliferation is controlled by our immune system. Better understanding of the role of individual T and NK cell proteins in controlling EBV may lead to improved immunologic-based treatments for both EBV disease as well as for cancer. In addition, identification of key proteins important for T cell and NK cell function could lead to novel targets for immune suppressive medications.
[size=15.9991px]Author ContributionsAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
Conflict of InterestThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. [size=15.9991px]
Footnotes
Funding. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.
Articles from Frontiers in Immunology are provided here courtesy of Frontiers Media SA
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发表于 2020-4-1 08:48
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