Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis
Sumida T; Mubarak M; Pitt D; Ponath G; Airas L; Isitan C; Levine-Ritterman M; Nguyen TD; Dahlawi S; Lincoln MR; Park C; Hafler DA; Raine CS; Zhang S
Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis
Sumida T
Mubarak M
Pitt D
Ponath G
Airas L
Isitan C
Levine-Ritterman M
Nguyen TD
Dahlawi S
Lincoln MR
Park C
Hafler DA
Raine CS
Zhang S
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042720367
https://urn.fi/URN:NBN:fi-fe2021042720367
Tiivistelmä
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.
Kokoelmat
- Rinnakkaistallenteet [19207]