Title | Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis. |
Publication Type | Journal Article |
Year of Publication | 2018 |
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 |
Journal | Nat Commun |
Volume | 9 |
Issue | 1 |
Pagination | 5337 |
Date Published | 2018 12 17 |
ISSN | 2041-1723 |
Keywords | Astrocytes, Cells, Cultured, Central Nervous System, Genetic Predisposition to Disease, Humans, Multiple Sclerosis, NF-kappa B p50 Subunit, Polymorphism, Single Nucleotide, Risk Factors, Transcription Factor RelA |
Abstract | 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, rs7665090, 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 (rs7665090) 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. |
DOI | 10.1038/s41467-018-07785-8 |
Alternate Journal | Nat Commun |
PubMed ID | 30559390 |
PubMed Central ID | PMC6297228 |
Grant List | U19 AI070352 / AI / NIAID NIH HHS / United States R01 NS102267 / NS / NINDS NIH HHS / United States P01 AI039671 / AI / NIAID NIH HHS / United States P01 AI045757 / AI / NIAID NIH HHS / United States U19 AI046130 / AI / NIAID NIH HHS / United States R01 NS090464 / NS / NINDS NIH HHS / United States |
Related Institute:
MRI Research Institute (MRIRI)