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

Citation

Field, J and Shahijanian, F and Schibeci, S and Johnson, L and Gresle, M and Laverick, L and Parnell, G and Stewart, G and McKay, F and Kilpatrick, T and Butzkueven, H and Booth, D and Charlesworth, JC and Taylor, B, Australia and New Zealand MS Genetics Consortium (ANZgene), 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) Article e0127080. ISSN 1932-6203 (2015) [Refereed Article]


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Copyright Statement

2015 Field et al. Licenced under Creative Commons Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/

DOI: doi:10.1371/journal.pone.0127080

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.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Central Nervous System
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Charlesworth, JC (Dr Jac Charlesworth)
Author:Taylor, B (Professor Bruce Taylor)
ID Code:102098
Year Published:2015
Web of Science® Times Cited:9
Deposited By:Menzies Institute for Medical Research
Deposited On:2015-07-28
Last Modified:2017-11-06
Downloads:127 View Download Statistics

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