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, Australian and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene), Laura Johnson, Melissa Gresle, Louise Laverick, Grant Parnell, Graeme J. Stewart, Fiona McKay, Trevor Kilpatrick, Helmut Butzkueven, David Booth, Alan Baxter, Allan G. Kermode, Bruce Taylor, David R. Booth, Deborah Mason, Graeme J. Stewart, Jac CharlesworthJames Wiley, Jeannette Lechner-Scott, Lotti Tajouri, Lyn Griffiths, Mark Slee, Matthew A. Brown, Pablo Moscato, Rodney J. Scott, Simon Broadley, Steve Vucic, William M. Carroll

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    22 Citations (Scopus)

    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
    Number of pages14
    JournalPLoS One
    Volume10
    Issue number6
    DOIs
    Publication statusPublished - 11 Jun 2015

    Bibliographical note

    This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PLOS applies the Creative Commons Attribution (CC BY) license to articles and other works we publish.

    Keywords

    • costimulatory molecule CD40
    • multiple sclerosis (MS)
    • T-allele

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    Field, J., Shahijanian, F., Schibeci, S., Australian and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene), Johnson, L., Gresle, M., Laverick, L., Parnell, G., Stewart, G. J., McKay, F., Kilpatrick, T., Butzkueven, H., Booth, D., Baxter, A., Kermode, A. G., Taylor, B., Booth, D. R., Mason, D., Stewart, G. J., ... Carroll, W. M. (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