Reactivation of latent Epstein-Barr virus by methotrexate: A potential contributor to methotrexate-associated lymphomas
Reactivation of latent Epstein-Barr virus by methotrexate: A potential contributor to methotrexate-associated lymphomas
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DOI：
10.1093/jnci/djh313
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发表时间：
2004-11-17
影响因子：
10.3
通讯作者：
Kenney, SC
中科院分区：
文献类型：
--
作者：
Feng, WH;Cohen, JI;Kenney, SC
背景：接受甲氨蝶呤(MTX)治疗的类风湿性关节炎或多发性肌炎患者比其他同等免疫抑制方案治疗的患者更容易发生EB病毒(EBV)阳性淋巴瘤。在这里，我们确定了MTX与其他治疗类风湿性关节炎或多发性肌炎的常用药物相比，是否在诱导从潜伏感染的细胞中释放传染性EBV方面是独特的。方法：采用潜伏感染的EBV阳性淋巴母细胞和胃癌细胞株，观察MTX和其他免疫抑制剂对EBV复制的影响。信号转导通路的抑制剂被用来定义诱导溶血性感染的要求。用报告基因分析检测药物对两个EBV即刻早期启动子(BRLF1和BZLF1)转录的影响，以及对缺乏其他效应子激活所需顺式作用序列的启动子结构的影响。接受MTX治疗的类风湿关节炎和多发性肌炎患者的EBV病毒载量与接受其他免疫抑制药物治疗的患者的EBV病毒载量进行了比较。统计检验是两面性的。结果：MTX在体外可激活潜伏感染细胞释放感染性EBV，报告基因检测显示MTX治疗与激活两种病毒即刻早期启动子有关。MTX诱导EBV裂解性感染需要p38 MAP、PI3和MEK通路以及两个病毒即刻早期启动子中的特定顺式作用基序。接受含MTX方案治疗的患者血液中的平均EBV载量显著高于不含MTX的免疫抑制方案的患者(每10(6)个细胞基因组有40个EBV拷贝，而不是5.1个拷贝；拷贝数的几何平均倍数差=10.8，95%，可信区间=3.0至38；P=.011)。结论：MTX可能通过其免疫抑制特性和重新激活潜伏的EBV，促进类风湿关节炎和多发性肌炎患者EBV阳性淋巴瘤的发生。
Background: Patients with rheumatoid arthritis or polymyositis treated with methotrexate (MTX) develop Epstein-Barr virus (EBV)-positive lymphomas more frequently than patients treated with other, equally immunosuppressive regimens. Here we determined whether MTX, in contrast to other commonly used medications for rheumatoid arthritis or polymyositis, is unique in its ability to induce the release of infectious EBV from latently infected cells. Methods: The effect of MTX and other immunosuppressant drugs on EBV replication in vitro was assessed using latently infected EBV-positive lymphoblastoid and gastric carcinoma cell lines. Inhibitors of signal transduction pathways were used to define requirements for induction of lytic infection. Drug effects on transcription of the two EBV immediate-early promoters (BRLF1 and BZLF1) and on promoter constructs lacking cis-acting sequences required for activation by other effectors was examined using reporter gene assays. EBV viral load in rheumatoid arthritis and polymyositis patients receiving MTX was compared with that in patients receiving other immunosuppressive medications. Statistical tests were two-sided. Results: MTX activated the release of infectious EBV from latently infected cell lines in vitro, and MTX treatment was associated with activation of the two viral immediate-early promoters in reporter gene assays. Induction of lytic EBV infection by MTX required the p38 MAP kinase, PI3 kinase, and MEK pathways and specific cisacting motifs in the two viral immediate-early promoters. Patients treated with MTX-containing regimens had statistically significantly higher mean EBV loads in their blood than patients treated with immunosuppressing regimens that did not include MTX (40 EBV copies per 10(6) cellular genomes versus 5.1 copies; geometric mean fold difference in copies = 10.8, 95%, confidence interval = 3.0 to 38; P =.011). Conclusion: MTX may promote EBV-positive lymphomas in rheumatoid arthritis and polymyositis patients by its immunosuppressive properties as well as by reactivating latent EBV.