Abstract
BackgroundGenome 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.MethodsWe 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.ResultsThese 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.ConclusionsThese data indicate targeting EBV may be of therapeutic benefit in MS.
Highlights
Genome wide association studies have identified > 200 susceptibility loci accounting for much of the heritability of multiple sclerosis (MS)
The Lymphoblastoid cell lines (LCL) transcriptome To identify MS risk genes likely to contribute to variation in regulation of Epstein-Barr virus (EBV) infection, we first screened for risk genes with altered regulation in EBV-infected B cells (LCLs) compared to B cells
MS risk genes that are LCL Expression quantitative trait loci (eQTL) Since risk SNPs mainly affects pathogenesis by altering gene expression [16], we identified SNPs associated with gene expression in LCLs
Summary
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 [1] This implies it is necessary to initiate pathogenesis, but the molecular and immunological basis for this has not been established. MS risk SNPs are over-represented as target sites for the EBV transcription factor EBNA2 [11], especially in conjunction with the vitamin D receptor binding sites [12]. These data indicate this near-ubiquitous virus is usually controlled by a sustained immune response and are consistent with the hypothesis that failure of EBV control can induce disease, including MS. There is a higher incidence of spontaneous transforming events in long-term culture of MS B cells [14], together supporting the existence of a higher proportion of latently EBV-infected B cells in MS
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