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IL-6, IL-12, and IL-23 STAT-Pathway Genetic Risk and Responsiveness of Lymphocytes in Patients with Multiple Sclerosis

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  1. Exposure to passive smoking during adolescence is associated with an increased risk of developing multiple sclerosis

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  2. Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta: a GWAS

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  3. Biomarkers of inflammation and epithelial barrier function in multiple sclerosis

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  4. Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium

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  5. Multiplex assessment of cerebrospinal fluid biomarkers in multiple sclerosis

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Multiple sclerosis (MS) is an immune-mediated demyelinating disease characterized by central nervous system (CNS) lymphocyte infiltration, abundant production of pro-inflammatory cytokines, and inappropriate activation of Th1 and Th17 cells, B cells, and innate immune cells. The etiology of MS is complex, and genetic factors contribute to disease susceptibility. Genome-wide association studies (GWAS) have revealed numerous MS-risk alleles in the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways implicated in the differentiation of Th1 and Th17 cells. In this study, we investigated the signaling properties of these pathways in T, B, and NK cells from patients with relapsing-remitting MS (RRMS) and healthy controls, and assessed the genetic contribution to the activity of the pathways. This revealed a great variability in the level of STAT-pathway molecules and STAT activation between the cell types investigated. We also found a strong donor variation in IL-6, IL-12, and IL-23 responsiveness of primed CD4+ T cells. This variation could not be explained by a single MS-risk variant in a pathway component, or by an accumulation of multiple STAT-pathway MS-risk SNPs. The data of this study suggests that other factors in cohesion with the genetic background contribute to the responsiveness of the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways.

Original languageEnglish
JournalCells
Volume8
Issue number3
ISSN2073-4409
DOIs
Publication statusPublished - 26 Mar 2019

    Research areas

  • Adult, Alleles, Case-Control Studies, Cross-Priming/immunology, Female, Genetic Predisposition to Disease, Humans, Interleukin-12/metabolism, Interleukin-23/metabolism, Interleukin-6/metabolism, Interleukins/metabolism, Lymphocytes/immunology, Male, Middle Aged, Multiple Sclerosis/genetics, Receptors, Interleukin/metabolism, Risk Factors, STAT Transcription Factors/metabolism, Signal Transduction

ID: 58578183