爱泼斯坦-巴尔病毒与免疫抑制患者淋巴瘤中的一种细胞信号通路

Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients.

作者信息

Liebowitz D

机构信息

Marjorie B. Kovler Viral Oncology Laboratories, Department of Medicine, University of Chicago, IL 60637, USA.

出版信息

N Engl J Med. 1998 May 14;338(20):1413-21. doi: 10.1056/NEJM199805143382003.

DOI:10.1056/NEJM199805143382003

PMID:9580648

Abstract

BACKGROUND

Epstein-Barr virus (EBV) is associated with various malignant and benign lymphoproliferative disorders. It also efficiently transforms human B lymphocytes in vitro. The latent membrane protein 1 (LMP1) of EBV-infected cells plays a central part in this process by mimicking members of the family of tumor necrosis factor (TNF) receptors, thereby transmitting growth signals from the cell membrane to the nucleus through cytoplasmic TNF-receptor-associated factors (TRAFs). I sought evidence of LMP1-mediated signal transduction through TRAFs in tumor tissue from patients with post-transplantation lymphoproliferative disease and non-Hodgkin's lymphomas related to the acquired immunodeficiency syndrome (AIDS).

METHODS

The association of LMP1 with TRAF-1 or TRAF-3 in tumor tissue was studied with double-immunofluorescence microscopy and immunoprecipitation assays. Evidence of LMP1-TRAF signaling was sought with an electrophoretic mobility shift assay for the nuclear factor-kappaB (NF-kappaB) transcription factor.

RESULTS

Tumors from eight patients with post-transplantation lymphoproliferative disease, two patients with AIDS-associated non-Hodgkin's lymphoma, and three patients with endemic Burkitt's lymphoma were analyzed. Tumors from six of the patients with post-transplantation lymphoproliferative disease were positive for EBV and expressed LMP1; two samples were EBV-negative. Tumors from both patients with AIDS-associated non-Hodgkin's lymphoma were EBV-positive and expressed LMP1, whereas tumors from all three patients with Burkitt's tumors were positive for EBV but negative for LMP1. Double-immunofluorescence microscopy showed that LMP1 localized with and immunoprecipitated with TRAF-1 and TRAF-3 in all eight of the EBV-positive, LMP1-positive samples. An electrophoretic mobility shift assay revealed activated NF-kappaB in all eight EBV-positive, LMP1-positive samples as well, but not in either of the EBV-negative, LMP1-negative samples or in the three EBV-positive, LMP1-negative samples.

CONCLUSIONS

LMP1-mediated signaling through the TRAF system has a role in the pathogenesis of the EBV-positive lymphomas that arise in immunosuppressed patients.

摘要

背景

爱泼斯坦-巴尔病毒（EBV）与多种恶性和良性淋巴增殖性疾病相关。它还能在体外有效地转化人B淋巴细胞。EBV感染细胞的潜伏膜蛋白1（LMP1）在此过程中起核心作用，它通过模拟肿瘤坏死因子（TNF）受体家族的成员，从而通过细胞质TNF受体相关因子（TRAFs）将生长信号从细胞膜传递到细胞核。我在移植后淋巴增殖性疾病患者以及与获得性免疫缺陷综合征（AIDS）相关的非霍奇金淋巴瘤患者的肿瘤组织中寻找LMP1通过TRAFs介导信号转导的证据。

方法

用双免疫荧光显微镜和免疫沉淀试验研究肿瘤组织中LMP1与TRAF-1或TRAF-3的关联。用针对核因子κB（NF-κB）转录因子的电泳迁移率变动分析寻找LMP1-TRAF信号传导的证据。

结果

分析了8例移植后淋巴增殖性疾病患者、2例AIDS相关非霍奇金淋巴瘤患者和3例地方性伯基特淋巴瘤患者的肿瘤。6例移植后淋巴增殖性疾病患者的肿瘤EBV呈阳性并表达LMP1；2个样本EBV呈阴性。2例AIDS相关非霍奇金淋巴瘤患者的肿瘤EBV均呈阳性并表达LMP1，而3例伯基特肿瘤患者的肿瘤EBV均呈阳性但LMP1呈阴性。双免疫荧光显微镜显示，在所有8个EBV阳性、LMP1阳性样本中，LMP1与TRAF-1和TRAF-3共定位并与之免疫沉淀。电泳迁移率变动分析显示，在所有8个EBV阳性、LMP1阳性样本中也有活化的NF-κB，但在2个EBV阴性、LMP1阴性样本或3个EBV阳性、LMP1阴性样本中均未检测到。