The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function

Judith Field, Fernando Shahijanian, Stephen Schibeci, Australia and New Zealand MS Genetics Consortium, Alan Baxter, Allan G. Kermode, Bruce Taylor, David R. Booth, Deborah Mason, Graeme J. Stewart, Helmut Butzkueven, Jac Charlesworth, James Wiley, Jeannette Lechner-Scott, Judith Field, Lotti Tajouri, Lyn R. Griffiths, Mark Slee, Matthew A. Brown, Pablo MoscatoRodney J. Scott, Simon Broadley, Steve Vucic, Trevor Kilpatrick, William M. Carroll, Laura Johnson, Melissa Gresle, Louise Laverick, Grant Parnell, Graeme Stewart, Fiona McKay, Trevor Kilpatrick, Helmut Butzkueven, David R. Booth

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Abstract

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.

Original languageEnglish
Article numbere0127080
JournalPLoS One
Volume10
Issue number6
DOIs
Publication statusPublished - 11 Jun 2015

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    Field, J., Shahijanian, F., Schibeci, S., Australia and New Zealand MS Genetics Consortium, Baxter, A., Kermode, A. G., Taylor, B., Booth, D. R., Mason, D., Stewart, G. J., Butzkueven, H., Charlesworth, J., Wiley, J., Lechner-Scott, J., Field, J., Tajouri, L., Griffiths, L. R., Slee, M., Brown, M. A., ... Booth, D. R. (2015). The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function. PLoS One, 10(6), [e0127080]. https://doi.org/10.1371/journal.pone.0127080