The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function
Field, J., Shahijanian, F., Schibeci, S., Johnson, L., Gresle, M., Laverick, L., Parnell, G., Stewart, G., McKay, F., Kilpatrick, T., Butzkueven, H., Booth, D., Baxter, A., Kermode, A.G., Taylor, B., Booth, D.R., Mason, D., Stewart, G.J., Charlesworth, J., Wiley, J., Lechner-Scott, J., Tajouri, L., Griffiths, L.R., Slee, M., Brown, M.A., Moscato, P., Scott, R.J., Broadley, S., Vucic, S., & 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).
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. © 2015 Field et al.
Impact and interest:
Citation counts are sourced monthly from and citation databases.
These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.
Citations counts from theindexing service can be viewed at the linked Google Scholar™ search.
Full-text downloads displays the total number of times this work’s files (e.g., a PDF) have been downloaded from QUT ePrints as well as the number of downloads in the previous 365 days. The count includes downloads for all files if a work has more than one.
|Item Type:||Journal Article|
|Additional Information:||Funding Details: 1065157, NHMRC, National Health and Medical Research Council
Funding Details: 633275, NHMRC, National Health and Medical Research Council
|Keywords:||CD19 antigen, CD27 antigen, CD40 antigen, immunoglobulin D, immunoglobulin M, adult, allele, antigen presenting cell, Article, B lymphocyte, CD40 gene, cell membrane, clinical article, controlled study, dendritic cell, down regulation, female, flow cytometry, gene expression, gene expression regulation, gene frequency, gene function, genetic association, genetic variability, genotype, human, human cell, lymphocyte subpopulation, male, memory cell, monocyte, multiple sclerosis, neuroprotection, protein expression, protein function, single nucleotide polymorphism, T lymphocyte activation, Animalia|
|Divisions:||Current > Schools > School of Biomedical Sciences
Current > Institutes > Institute of Health and Biomedical Innovation
|Copyright Owner:||© 2015 Field et al.|
|Copyright Statement:||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
|Deposited On:||21 Sep 2015 07:12|
|Last Modified:||14 Nov 2016 01:03|
Repository Staff Only: item control page