A1 Refereed original research article in a scientific journal
Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis
Authors: Ponath G, Lincoln MR, Levine-Ritterman M, Park C, Dahlawi S, Mubarak M, Sumida T, Airas L, Zhang S, Isitan C, Nguyen TD, Raine CS, Hafler DA, Pitt D
Publication year: 2018
Journal: Nature Communications
Journal name in source: Nature Communications
Article number: 5337
Volume: 9
Number of pages: 9
ISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-018-07785-8
Web address : https://doi.org/10.1038/s41467-018-07785-8
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/37049444
Epigenetic annotation studies of genetic risk variants for multiple sclerosis (MS) implicate dysfunctional lymphocytes in MS susceptibility; however, the role of central nervous system (CNS) cells remains unclear. We investigated the effect of the risk variant, rs7665090G, located near NFKB1, on astrocytes. We demonstrated that chromatin is accessible at the risk locus, a prerequisite for its impact on astroglial function. The risk variant was associated with increased NF-κB signaling and target gene expression, driving lymphocyte recruitment, in cultured human astrocytes and astrocytes within MS lesions, and with increased lesional lymphocytic infiltrates and lesion sizes. Thus, our study establishes a link between genetic risk for MS (rs7665090G) and dysfunctional astrocyte responses associated with increased CNS access for peripheral immune cells. MS may therefore result from variant-driven dysregulation of the peripheral immune system and of the CNS, where perturbed CNS cell function aids in establishing local autoimmune inflammation.
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