Abstract
Epigenetic annotation studies of genetic variants associated with multiple sclerosis (MS) risk suggest that dysfunctional lymphocyte responses drive MS susceptibility. It remains unclear whether MS risk variants impact cellular function in the central nervous system (CNS) and whether this plays a role in MS susceptibility. Here, we investigated the effect of the risk variant, rs7665090-G, located near the NFKB1 gene, on astrocyte function. In human fetal astrocytes, we found that chromatin was accessible at the rs7665090 locus, suggesting a potential impact of the risk variant on astroglial function. In astrocytes differentiated from MS patient-derived induced pluripotent stem cells (iPSCs), and in astrocytes within autopsied MS lesions, the risk variant was associated with increased NF-κB signaling and expression of NF-κB target genes that promote lymphocyte recruitment and neurotoxicity. Consistent with these findings, infiltrating lymphocytes were increased in MS lesions homozygous for the risk variant. Moreover, in MS patients, the rs7665090 risk variant was associated with increased total lesion volumes on magnetic resonance imaging (MRI).
Overall, our work establishes that the rs7665090-G variant directly perturbs CNS cell function, resulting in enhanced lymphocyte recruitment and reduced thresholds for lesion formation. Thus, MS may be triggered by a complex interplay between the peripheral immune system and the CNS, where dysfunctional peripheral immune responses are targeted to the CNS e.g. through enhanced astrocytic responses.
One Sentence Summary The NF-κB relevant multiple sclerosis risk variant, rs7665090-G, drives astrocyte responses that promote lesion formation.