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, The Australia and New Zealand MS Genetics Consortium, Laura Johnson, Melissa Gresle, Louise Laverick, Grant Parnell, Graeme Stewart, Helmut Butzkueven, David 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
Number of pages14
JournalPLoS ONE
Volume10
Issue number6
DOIs
Publication statusPublished - 11 Jun 2015
Externally publishedYes

Cite this

Field, J., Shahijanian, F., Schibeci, S., The Australia and New Zealand MS Genetics Consortium, Johnson, L., Gresle, M., ... Booth, D. (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
Field, Judith ; Shahijanian, Fernando ; Schibeci, Stephen ; The Australia and New Zealand MS Genetics Consortium ; Johnson, Laura ; Gresle, Melissa ; Laverick, Louise ; Parnell, Grant ; Stewart, Graeme ; Butzkueven, Helmut ; Booth, David. / The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells : Implications for gene function. In: PLoS ONE. 2015 ; Vol. 10, No. 6.
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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.",
author = "Judith Field and Fernando Shahijanian and Stephen Schibeci and {The Australia and New Zealand MS Genetics Consortium} and Laura Johnson and Melissa Gresle and Louise Laverick and Grant Parnell and Graeme Stewart and Fiona McKay and Trevor Kilpatrick and Helmut Butzkueven and David Booth and Alan Baxter and Kermode, {Allan G.} and Bruce Taylor and Booth, {David R.} and Deborah Mason and Stewart, {Graeme J.} and Jac Charlesworth and James Wiley and Jeannette Lechner-Scott and Lotti Tajouri and Lyn Griffiths and Mark Slee and Brown, {Matthew A.} and Pablo Moscato and Scott, {Rodney J.} and Simon Broadley and Steve Vucic and Carroll, {William M.}",
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Field, J, Shahijanian, F, Schibeci, S, The Australia and New Zealand MS Genetics Consortium, Johnson, L, Gresle, M, Laverick, L, Parnell, G, Stewart, G, Butzkueven, H & Booth, D 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, vol. 10, no. 6, e0127080. https://doi.org/10.1371/journal.pone.0127080

The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells : Implications for gene function. / Field, Judith; Shahijanian, Fernando; Schibeci, Stephen; The Australia and New Zealand MS Genetics Consortium; Johnson, Laura; Gresle, Melissa; Laverick, Louise; Parnell, Grant; Stewart, Graeme; Butzkueven, Helmut; Booth, David.

In: PLoS ONE, Vol. 10, No. 6, e0127080, 11.06.2015.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Field, Judith

AU - Shahijanian, Fernando

AU - Schibeci, Stephen

AU - The Australia and New Zealand MS Genetics Consortium

AU - Johnson, Laura

AU - Gresle, Melissa

AU - Laverick, Louise

AU - Parnell, Grant

AU - Stewart, Graeme

AU - McKay, Fiona

AU - Kilpatrick, Trevor

AU - Butzkueven, Helmut

AU - Booth, David

AU - Baxter, Alan

AU - Kermode, Allan G.

AU - Taylor, Bruce

AU - Booth, David R.

AU - Mason, Deborah

AU - Stewart, Graeme J.

AU - Charlesworth, Jac

AU - Wiley, James

AU - Lechner-Scott, Jeannette

AU - Tajouri, Lotti

AU - Griffiths, Lyn

AU - Slee, Mark

AU - Brown, Matthew A.

AU - Moscato, Pablo

AU - Scott, Rodney J.

AU - Broadley, Simon

AU - Vucic, Steve

AU - Carroll, William M.

PY - 2015/6/11

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N2 - 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.

AB - 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.

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Field J, Shahijanian F, Schibeci S, The Australia and New Zealand MS Genetics Consortium, Johnson L, Gresle M et al. 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. https://doi.org/10.1371/journal.pone.0127080