We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.
To identify differentially expressed genes in multiple sclerosis, microarrays were used in a stringent experimental setting-leukapheresis from disease-discordant monozygotic twins and gene expression profiling in CD4(+) and CD8(+) T-cell subsets. Disease-related differences emerged only in the CD8(+) T-cell subset. The five differentially expressed genes identified included killer cell lectin-like receptor subfamily B, member 1, also known as natural killer receptor protein 1a/CD161, presented by the International Multiple Sclerosis Genetics Consortium as one of the non-MHC candidate loci. Flow cytometric analysis on peripheral blood of healthy donors and patients with multiple sclerosis and rheumatoid arthritis confirmed an upregulation of CD161 at the protein level, showing also a significant excess of CD161(high)CD8(+) T cells in multiple sclerosis. This subset prevalently included chemokine (C-C motif) receptor 6(+), cytokine-producing, effector-memory T cells with proinflammatory profiles. It also included all circulating interleukin-17(+)CD8(+) T cells. In the CD161(high)CD8(+) subset, interleukin-12 facilitated proliferation and interferon-γ production, with CD161 acting as a co-stimulatory receptor. CD161(+)CD8(+)CD3(+) T cells producing interferon-γ were part of intralesional immune infiltrates and ectopic B cell follicles in autopsy multiple sclerosis brains. Variations of CD161 expression on CD8(+) T cells identify a subset of lymphocytes with proinflammatory characteristics that have not been previously reported in multiple sclerosis and are likely to contribute to disease immunopathology.
The relatively high proportion of IP changes in RR-MS patients seems to confirm our work hypothesis and warrants more work to confirm the result on a larger sample, and to understand the implications for related immunological disturbances and intestinal microbiota alterations. Our finding may also have relevance for oral treatments, recently introduced in clinical practice.
Epstein-Barr virus (EBV) is a non-heritable factor that associates with multiple sclerosis (MS). However its causal relationship with the disease is still unclear. The virus establishes a complex co-existence with the host that includes regulatory influences on gene expression. Hence, if EBV contributes to the pathogenesis of MS it may do so by interacting with disease predisposing genes. To verify this hypothesis we evaluated EBV nuclear antigen 2 (EBNA2, a protein that recent works by our and other groups have implicated in disease development) binding inside MS associated genomic intervals. We found that EBNA2 binding occurs within MS susceptibility sites more than expected by chance (factor of observed vs expected overlap [O/E] = 5.392-fold, p < 2.0e-05). This remains significant after controlling for multiple genomic confounders. We then asked whether this observation is significant per se or should also be viewed in the context of other disease relevant gene-environment interactions, such as those attributable to vitamin D. We therefore verified the overlap between EBNA2 genomic occupancy and vitamin D receptor (VDR) binding sites. EBNA2 shows a striking overlap with VDR binding sites (O/E = 96.16-fold, p < 2.0e-05), even after controlling for the chromatin accessibility state of shared regions (p <0.001). Furthermore, MS susceptibility regions are preferentially targeted by both EBNA2 and VDR than by EBNA2 alone (enrichment difference = 1.722-fold, p = 0.0267). Taken together, these findings demonstrate that EBV participates in the gene-environment interactions that predispose to MS.
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