Genetic Risk Variant Tied to Type of CNS Cell Increases Risk of MS, Study Says

A genetic risk variant, rs7665090^G, located near NFKB1, on astrocytes enhances the accessibility of the central nervous system (CNS) to peripheral immune cells, escalating the risk of autoimmune inflammation and multiple sclerosis (MS), according to the results of a recent study.

Astrocyctes are star-shaped glial CNS cells. MS is a genetically mediated disease in which variations in gene regulation lead to increased susceptibility to the condition. One recent finding suggested that changes in immune enhancers such as lymphocytes may disrupt innate and adaptive immune pathways; however, investigators were still unsure whether they affected CNS function and thus increased MS risk. In this study, rs7665090^G was used to determine whether dysregulation in astrocyte function will affect MS risk.

Nuclear factor-κ—light chain enhancer of activated B cells (NF-κB) is an essential part of innate and adaptive immunity and plays a role in autoimmunity. Changes in NF-κB signaling have been associated with cancer and inflammatory and autoimmune diseases. In this study, investigators compared induced pluripotent stem cells (iPSCs)–derived astrocytes from patients who were healthy and patients with MS who were had a homogenous risk variant (rs7665090^GG) or protective variant (rs7665090^AA). In unstimulated astrocytes, both groups had low NF-κB signaling. However, once NF-κB signaling was stimulated using tumor necrosis factor α and IL-1β, NF-κB activation was significantly higher in the astrocytes that carried the risk variant.

The number of NF-κB target genes that were upregulated was also higher in the risk variant group, with 28 upregulated genes compared with only 23 genes for the protective variant. The genes that were differently expressed by 2-fold higher included IL15, ICAM1, CXCL10, CCL5, and C3. The upregulation of these genes indicates greater lymphocyte recruitment and activation in the risk variant astrocytes compared with the protective variant astrocytes.

In MS lesions, significantly elevated expressions of the NF-κB p50 and p65 subunits were seen in astrocytes with the risk variant compared with the protective variant. Similar target genes that were enhanced in iPSC-derived astrocytes were also upregulated for the astrocytes in the MS lesions. Because of the increasing number of infiltrating lymphocytes in the risk variant group, CD3-postive T cells were also elevated in lesions with the risk variant at the active rim. Although lesion sizes have historically increased as a result of the increases in lymphocyte recruitment, lesion loads were not significantly different between the variant and protective groups in this study.

With the enhanced astroglial NF-κB signaling from the variant risk group, peripheral immune cells are more likely to enter the CNS, lowering the threshold of MS lesion formation. Furthermore, many of the upregulation of NF-κB target genes have been shown to drive lymphocyte recruitment and neurotoxicity. Based on the results of the study, investigators concluded that the risk of MS may be higher because of risk variants causing increased NF-κB signaling.

Reference

Ponath G, Lincoln MR, Levine-Ritterman M, et al. Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis. Nat Commun. 2018;9(1):5337. doi: 10.1038/s41467-018-07785-8.