Multi-omic analysis of NFkB-mediated signaling in multiple sclerosis

The NFκB family of transcription factors are central mediators of critical cell signaling events related to inflammation. We have shown that multiple sclerosis (MS) risk variants discovered in genome-wide association studies (GWAS) are enriched near NFκB binding sites active in CD4+ T cells, and that the MS risk haplotype in the NFKB1 locus markedly increases TNFα-dependent NFkB phosphorylation levels in naïve CD4+ T cells. We hypothesize that the MS risk variant in the NFKB1 locus (rs228614) induces stable changes to CD4+ T cell stimulus response, driven by altered NFκB-mediated signaling and characterized by: (i) a lower CD4+ T cell stimulus-dependent activation threshold; (ii) non-contextual gene activation; and (iii) consequently, increased rates of cell survival and proliferation upon stimulus. We will test this hypothesis by quantitating stimulus-dependent NFκB activation in CD4+ T cells with multi-omic approach in healthy donors and MS patients with different rs228614 genotypes, and consequent changes to gene regulatory programs and functional CD4+ T cell responses. We hypothesize that there is a dose-response relationship between NFκB phosphorylation levels and target gene activation. Thus, increased NFκB phosphorylation levels lower the activation threshold of CD4+ T cells and increase their survival and proliferation, effectively producing a ""hair trigger"" state which increases risk for multiple sclerosis.