Jordan, Margaret A., Gresle, Melissa M., Gemiarto, Adrian T., Stanley, Dragana, Smith, Letitia D., Laverick, Louise, Spelman, Tim, Stankovich, Jim, Willson, Annie M.L., Dinh, Xuyen T., Johnson, Laura, Robertson, Kylie, Reid, Christopher A.R., Field, Judith, Butzkueven, Helmut, and Baxter, Alan G. (2024) Transcriptional network analysis of peripheral blood leukocyte subsets in multiple sclerosis identifies a pathogenic role for a cytotoxicity‐associated gene network in myeloid cells. Immunology & Cell Biology. (In Press)

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Abstract

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.

Item ID:	83028
Item Type:	Article (Research - C1)
ISSN:	0818-9641
Copyright Information:	© 2024 The Author(s). Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Date Deposited:	26 Jun 2024 22:50
FoR Codes:	32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320404 Cellular immunology @ 100%
SEO Codes:	20 HEALTH > 2001 Clinical health > 200101 Diagnosis of human diseases and conditions @ 100%
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