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1.
Genome Med ; 11(1): 26, 2019 04 30.
Article in English | MEDLINE | ID: mdl-31039804

ABSTRACT

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.


Subject(s)
B-Lymphocytes/metabolism , CD4 Antigens/genetics , Herpesvirus 4, Human/physiology , Multiple Sclerosis/genetics , Polymorphism, Single Nucleotide , TNF Receptor-Associated Factor 3/genetics , B-Lymphocytes/virology , Cells, Cultured , Endonucleases/genetics , Herpesvirus 4, Human/pathogenicity , Humans , Quantitative Trait Loci , Transcriptome , Virus Latency , Virus Replication
2.
Clin Immunol ; 163: 96-107, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26762769

ABSTRACT

Multiple Sclerosis (MS) is an autoimmune disease treated by therapies targeting peripheral blood cells. We previously identified that expression of two MS-risk genes, the transcription factors EOMES and TBX21 (ET), was low in blood from MS and stable over time. Here we replicated the low ET expression in a new MS cohort (p<0.0007 for EOMES, p<0.028 for TBX21) and demonstrate longitudinal stability (p<10(-4)) and high heritability (h(2)=0.48 for EOMES) for this molecular phenotype. Genes whose expression correlated with ET, especially those controlling cell migration, further defined the phenotype. CD56+ cells and other subsets expressed lower levels of Eomes or T-bet protein and/or were under-represented in MS. EOMES and TBX21 risk SNP genotypes, and serum EBNA-1 titres were not correlated with ET expression, but HLA-DRB1*1501 genotype was. ET expression was normalised to healthy control levels with natalizumab, and was highly variable for glatiramer acetate, fingolimod, interferon-beta, dimethyl fumarate.


Subject(s)
Multiple Sclerosis/genetics , T-Box Domain Proteins/genetics , Adult , Aged , CD56 Antigen , Case-Control Studies , Cell Movement , Dimethyl Fumarate/therapeutic use , Epstein-Barr Virus Nuclear Antigens/blood , Female , Fingolimod Hydrochloride/therapeutic use , Gene Expression Regulation , Genetic Predisposition to Disease , Glatiramer Acetate/therapeutic use , HLA-DRB1 Chains/genetics , Humans , Immunologic Factors/therapeutic use , Immunosuppressive Agents/therapeutic use , Interferon-beta/therapeutic use , Longitudinal Studies , Male , Middle Aged , Multiple Sclerosis/drug therapy , Natalizumab/therapeutic use , Polymorphism, Single Nucleotide , Young Adult
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