Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis. Academic Article uri icon

Overview

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.

publication date

  • December 17, 2018

Research

keywords

  • Astrocytes
  • Central Nervous System
  • Multiple Sclerosis
  • NF-kappa B p50 Subunit

Identity

PubMed Central ID

  • PMC6297228

Scopus Document Identifier

  • 85058724570

Digital Object Identifier (DOI)

  • 10.1038/nature11632

PubMed ID

  • 30559390

Additional Document Info

volume

  • 9

issue

  • 1