Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis

Gerald Ponath, Matthew R. Lincoln, Maya Levine-Ritterman, Calvin Park, Somiah Dahlawi, Mayyan Mubarak, Tomokazu Sumida, Laura Airas, Shun Zhang, Cigdem Isitan, Thanh D. Nguyen, Cedric S. Raine, David A. Hafler and David Pitt ()
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Gerald Ponath: Yale School of Medicine
Matthew R. Lincoln: Yale School of Medicine
Maya Levine-Ritterman: Yale School of Medicine
Calvin Park: Yale School of Medicine
Somiah Dahlawi: Yale School of Medicine
Mayyan Mubarak: Yale School of Medicine
Tomokazu Sumida: Yale School of Medicine
Laura Airas: University of Turku
Shun Zhang: Weill Cornell Medical College
Cigdem Isitan: Yale School of Medicine
Thanh D. Nguyen: Weill Cornell Medical College
Cedric S. Raine: Albert Einstein College of Medicine
David A. Hafler: Yale School of Medicine
David Pitt: Yale School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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, 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.

Date: 2018
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DOI: 10.1038/s41467-018-07785-8

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