Dissecting the "killer module" and its role in Multiple Sclerosis

Background: Multiple Sclerosis (MS) is a complex genetic disease associated with both environmental and genetic risk factors. In most cases, the risk factors’ individual associations with MS are so weak that any meaningful understanding of the disease will require the identification of molecular pathways that contribute to MS liability. Objective: To identify molecular pathways associated with MS in five lymphocyte populations, NK cells, monocytes, B cells, and CD4 and CD8 T cells, and then functionally test their role using a mouse model of disease, Experimental Autoimmune Encephalomyelitis (EAE). Design Methods: We generated a weighted gene co-expression network based on 712 pooled Affymetrix Human Gene 1.0 ST array analyses of magnetic bead sorted lymphocytes from 67 relapsing/remitting MS patients and 102 Healthy unaffected individuals (HC). For each leukocyte population, the strength of differential expression between patients and HC was assessed, and each transcript was tested across the network to identify modules of interest which were tested in vivo and in vitro to elucidate their role in MS. Results: We identified a major networked module of genes involved in cell-mediated cytotoxicity that is downregulated in the monocytes and NK cells of MS patients. Three genes were elucidated that, when modulated in vitro, affected expression across the entire module. Furthermore, their targeted deletion resulted in more severe EAE. Conclusions: While there is strong data identifying NK cell deficiencies in MS patients, and key roles for monocytes in myelin and axon destruction and autoantigen presentation, this research identifies a new role for monocytes in immunomodulation by cytotoxicity. Further dissection of this “killer module” should elucidate its role in MS.