BACKGROUND Genome wide association studies have identified > 200 susceptibility loci accounting for much of the heritability of multiple sclerosis (MS). Epstein-Barr virus (EBV), a memory B cell tropic virus, has been identified as necessary but not sufficient for development of MS. The molecular and immunological basis for this has not been established. Infected B cell proliferation is driven by signalling through the EBV produced cell surface protein LMP1, a homologue of the MS risk gene CD40. METHODS We have investigated transcriptomes of B cells and EBV-infected B cells at Latency III (LCLs) and identified MS risk genes with altered expression on infection and with expression levels associated with the MS risk genotype (LCLeQTLs). The association of LCLeQTL genomic burden with EBV phenotypes in vitro and in vivo was examined. The risk genotype effect on LCL proliferation with CD40 stimulation was assessed. RESULTS These LCLeQTL MS risk SNP:gene pairs (47 identified) were over-represented in genes dysregulated between B and LCLs (p < 1.53 × 10-4), and as target loci of the EBV transcription factor EBNA2 (p < 3.17 × 10-16). Overall genetic burden of LCLeQTLs was associated with some EBV phenotypes but not others. Stimulation of the CD40 pathway by CD40L reduced LCL proliferation (p < 0.001), dependent on CD40 and TRAF3 MS risk genotypes. Both CD40 and TRAF3 risk SNPs are in binding sites for the EBV transcription factor EBNA2, with expression of each correlated with EBNA2 expression dependent on genotype. CONCLUSIONS These data indicate targeting EBV may be of therapeutic benefit in MS.

中文翻译：

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来自全基因组关联研究的证据表明，在多发性硬化症易感性方面，爱泼斯坦-巴尔病毒感染的控制减少。

背景技术全基因组关联研究已确定> 200个易感基因座，占多发性硬化症（MS）遗传力的大部分。爱泼斯坦-巴尔病毒（EBV）是一种记忆性B细胞嗜性病毒，已被确定为必要的但不足以发展MS。尚未建立其分子和免疫学基础。感染的B细胞增殖是通过EBV产生的细胞表面蛋白LMP1（MS风险基因CD40的同源物）发出的信号驱动的。方法我们研究了在潜伏期III（LCL）的B细胞和EBV感染的B细胞的转录组，并鉴定了感染后表达改变且与MS风险基因型（LCLeQTLs）相关的表达水平的MS风险基因。在体外和体内，研究了LCLeQTL基因组负担与EBV表型之间的关系。评估了风险基因型对CD40刺激对LCL增殖的影响。结果这些LCLeQTL MS风险SNP：基因对（已鉴定47个）在B和LCL之间失调的基因中过分表达（p <1.53×10-4），并作为EBV转录因子EBNA2的靶基因座（p <3.17×10 -16）。LCLeQTL的总体遗传负担与某些EBV表型相关，而与其他EBV表型无关。CD40L刺激CD40途径可降低LCL增殖（p <0.001），具体取决于CD40和TRAF3 MS风险基因型。CD40和TRAF3风险SNP都位于EBV转录因子EBNA2的结合位点，每种表达都与EBNA2的表达相关，取决于基因型。结论这些数据表明靶向EBV在MS中可能具有治疗益处。结果这些LCLeQTL MS风险SNP：基因对（已鉴定47个）在B和LCL之间失调的基因中过分表达（p <1.53×10-4），并作为EBV转录因子EBNA2的靶基因座（p <3.17×10 -16）。LCLeQTL的总体遗传负担与某些EBV表型相关，而与其他EBV表型无关。CD40L刺激CD40途径可降低LCL增殖（p <0.001），具体取决于CD40和TRAF3 MS风险基因型。CD40和TRAF3风险SNP都位于EBV转录因子EBNA2的结合位点，每种表达都与EBNA2的表达相关，取决于基因型。结论这些数据表明靶向EBV在MS中可能具有治疗益处。结果这些LCLeQTL MS风险SNP：基因对（已鉴定47个）在B和LCL之间失调的基因中过分表达（p <1.53×10-4），并作为EBV转录因子EBNA2的靶基因座（p <3.17×10 -16）。LCLeQTL的总体遗传负担与某些EBV表型相关，而与其他EBV表型无关。CD40L刺激CD40途径可降低LCL增殖（p <0.001），具体取决于CD40和TRAF3 MS风险基因型。CD40和TRAF3风险SNP都位于EBV转录因子EBNA2的结合位点，每种表达都与EBNA2的表达相关，取决于基因型。结论这些数据表明靶向EBV在MS中可能具有治疗益处。并作为EBV转录因子EBNA2的靶基因座（p <3.17×10-16）。LCLeQTL的总体遗传负担与某些EBV表型相关，而与其他EBV表型无关。CD40L刺激CD40途径可降低LCL增殖（p <0.001），具体取决于CD40和TRAF3 MS风险基因型。CD40和TRAF3风险SNP都位于EBV转录因子EBNA2的结合位点，每种表达都与EBNA2的表达相关，取决于基因型。结论这些数据表明靶向EBV在MS中可能具有治疗益处。并作为EBV转录因子EBNA2的靶基因座（p <3.17×10-16）。LCLeQTL的总体遗传负担与某些EBV表型相关，而与其他EBV表型无关。CD40L刺激CD40途径可降低LCL增殖（p <0.001），具体取决于CD40和TRAF3 MS风险基因型。CD40和TRAF3风险SNP都位于EBV转录因子EBNA2的结合位点，每种表达都与EBNA2的表达相关，取决于基因型。结论这些数据表明靶向EBV在MS中可能具有治疗益处。CD40和TRAF3风险SNP都位于EBV转录因子EBNA2的结合位点，每种表达都与EBNA2的表达相关，取决于基因型。结论这些数据表明靶向EBV在MS中可能具有治疗益处。CD40和TRAF3风险SNP都位于EBV转录因子EBNA2的结合位点，每种表达都与EBNA2的表达相关，取决于基因型。结论这些数据表明靶向EBV在MS中可能具有治疗益处。