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Transcriptional network analysis of peripheral blood leukocyte subsets in multiple sclerosis identifies a pathogenic role for a cytotoxicity-associated gene network in myeloid cells.
Jordan, Margaret A; Gresle, Melissa M; Gemiarto, Adrian T; Stanley, Dragana; Smith, Letitia D; Laverick, Louise; Spelman, Tim; Stankovich, Jim; Willson, Annie Ml; Dinh, Xuyen T; Johnson, Laura; Robertson, Kylie; Reid, Christopher Ar; Field, Judith; Butzkueven, Helmut; Baxter, Alan G.
Afiliación
  • Jordan MA; Biomedical Sciences & Molecular Biology, CPHMVS, James Cook University, Townsville, QLD, Australia.
  • Gresle MM; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.
  • Gemiarto AT; The Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
  • Stanley D; Biomedical Sciences & Molecular Biology, CPHMVS, James Cook University, Townsville, QLD, Australia.
  • Smith LD; Central Queensland University, Rockhampton, QLD, Australia.
  • Laverick L; Biomedical Sciences & Molecular Biology, CPHMVS, James Cook University, Townsville, QLD, Australia.
  • Spelman T; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.
  • Stankovich J; Burnett Institute, Melbourne, VIC, Australia.
  • Willson AM; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.
  • Dinh XT; Biomedical Sciences & Molecular Biology, CPHMVS, James Cook University, Townsville, QLD, Australia.
  • Johnson L; Biomedical Sciences & Molecular Biology, CPHMVS, James Cook University, Townsville, QLD, Australia.
  • Robertson K; Hai Duong Medical Technical University, Hai Duong, Vietnam.
  • Reid CA; The Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
  • Field J; Biomedical Sciences & Molecular Biology, CPHMVS, James Cook University, Townsville, QLD, Australia.
  • Butzkueven H; Biomedical Sciences & Molecular Biology, CPHMVS, James Cook University, Townsville, QLD, Australia.
  • Baxter AG; CSL Innovation, Parkville, VIC, Australia.
Immunol Cell Biol ; 102(8): 702-720, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38877291
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 a gene coexpression network from microarray expression analyses of five purified peripheral blood leukocyte subsets of 76 patients with relapsing remitting MS and 104 healthy controls. These analyses identified a major network (or module) 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 autoimmune inflammatory 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Mieloides / Encefalomielitis Autoinmune Experimental / Redes Reguladoras de Genes / Esclerosis Múltiple Límite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Immunol Cell Biol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Mieloides / Encefalomielitis Autoinmune Experimental / Redes Reguladoras de Genes / Esclerosis Múltiple Límite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Immunol Cell Biol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos