Transcriptional network analysis of peripheral blood leukocyte subsets in multiple sclerosis identifies a pathogenic role for a cytotoxicity‐associated gene network in myeloid cells
Journal Publication ResearchOnline@JCUAbstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system affecting predominantly adults. It is a complex disease associated with both environmental and genetic risk factors. Although over 230 risk single-nucleotide polymorphisms have been associated with MS, all are common human variants. The mechanisms by which they increase the risk of MS, however, remain elusive. We hypothesized that a complex genetic phenotype such as MS could be driven by coordinated expression of genes controlled by transcriptional regulatory networks. We, therefore, constructed agene coexpression network from microarray expression analyses of five purifiedperipheral blood leukocyte subsets of 76 patients with relapsing remitting MS and 104 healthy controls. These analyses identified a major network (ormodule) of expressed genes associated with MS that play key roles in cell-mediated cytotoxicity which was downregulated in monocytes of patients with MS. Manipulation of the module gene expression was achieved in vitro through small interfering RNA gene knockdown of identified drivers. In a mouse model, network gene knockdown modulated the autoimmuneinflammatory MS model disease—experimental autoimmune encephalomyelitis.This research implicates a cytotoxicity-associated gene network in myeloid cells in the pathogenesis of MS.
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Immunology & Cell Biology
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0818-9641
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Pages Count
19
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Publisher
Wiley
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DOI
10.1111/imcb.12793