CD40 reduction in MS

Field J, Shahijanian F, Schibeci S; Australia and New Zealand MS Genetics Consortium (ANZgene), Johnson L, Gresle M, Laverick L, Parnell G, Stewart G, McKay F, Kilpatrick T, Butzkueven H, Booth D. The MS Risk Allele of CD40 Is Associated with Reduced Cell-Membrane Bound Expression in Antigen Presenting Cells: Implications for Gene Function. PLoS One. 2015 Jun 11;10(6):e0127080

Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS.

CD40 is a costimulatory protein found on antigen presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects and this is an MS risk gene. This is associated with reduced CD40 expression ,which happens in MSers. Indeed this low level of CD40 happens in MSers irrespective of whether they have the gene or not. What does it mean? It will result in a reduced immune influence somewhere in
the disease process.

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  • So then the assumption would be that this reduced immune influence is likely on the regulatory cells that tell your immune system, "Whoa! Chill out, dude! That's a friendly! Hold your fire!"? Or does this mean a reduction in the overall strength of the immune response to anything? I always conceptualize MS as an overaggressive immune system, not the other way around.

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