New Insights into Risk Genes and Their Candidates in Multiple Sclerosis

Abstract

Oligodendrocytes are central nervous system glial cells that wrap neuronal axons with their differentiated myelin membranes as biological insulators. There has recently been an emerging concept that multiple sclerosis could be triggered and promoted by various risk genes that appear likely to contribute to the degeneration of oligodendrocytes. Despite the known involvement of vitamin D, immunity, and inflammatory cytokines in disease progression, the common causes and key genetic mechanisms remain unknown. Herein, we focus on recently identified risk factors and risk genes in the background of multiple sclerosis and discuss their relationships.

Keywords: multiple sclerosis; oligodendrocyte; risk gene.

Figure 1

Schematic diagram of some putative major factors associated with multiple sclerosis. Deficiency of vitamin D results in demyelination. The levels of 25-OH-D, a metabolite from vitamin D, is one of the risks of MS. MAG proteins, as well as signaling molecules around immune cells, are also related to MS demyelination.

Figure 2

JAK/STAT signaling pathway associated with MS. Cytokines, through JAK/STAT signaling, especially in Th1 and Th17 cells, are putatively considered responsible for the progression of MS.

Figure 3

Interaction of some receptors with their cognate ligands induces the expression of pro-inflammatory cytokines in immune cells. Pathogen-associated molecular patterns interaction with TLRs, SOCS3 activation by cytokine receptors, microbe-associated molecular patterns or damage-associated molecular patterns binding to pattern recognition receptors, and/or activation through NF-κB are involved in the regulation of the expression of inflammatory cytokines, which are responsible for MS, in immune cells.

Figure 4

Abnormal autoimmune reaction and neuroinflammation in MS. Altered Foxp3 expression in Treg cells induces an abnormal autoimmune reaction. Expression levels of vascular endothelial growth factors and matrix metallopeptidases are increased, probably disrupting the blood–brain barrier. This disruption allows immune cells to infiltrate. Phosphorylation of RIPK1 in astrocytes and microglia is involved in the promotion of the neuroinflammatory program.