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 Moscato & 14 others Rodney 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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antigen-presenting cells
sclerosis
Antigen-Presenting Cells
Cell membranes
Multiple Sclerosis
cell membranes
Genes
Alleles
Cell Membrane
alleles
Lymphocytes
genes
Membrane Proteins
Genotype
surface proteins
cells
dendritic cells
Messenger RNA
T-cells
Dendritic Cells

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Field, J., Shahijanian, F., Schibeci, S., Australia and New Zealand MS Genetics Consortium, Baxter, A., Kermode, A. G., ... 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
Field, Judith ; Shahijanian, Fernando ; Schibeci, Stephen ; Australia and New Zealand MS Genetics Consortium ; Baxter, Alan ; Kermode, Allan G. ; Taylor, Bruce ; Booth, David R. ; Mason, Deborah ; Stewart, Graeme J. ; Butzkueven, Helmut ; Charlesworth, Jac ; Wiley, James ; Lechner-Scott, Jeannette ; Field, Judith ; Tajouri, Lotti ; Griffiths, Lyn R. ; Slee, Mark ; Brown, Matthew A. ; Moscato, Pablo ; Scott, Rodney J. ; Broadley, Simon ; Vucic, Steve ; Kilpatrick, Trevor ; Carroll, William M. ; Johnson, Laura ; Gresle, Melissa ; Laverick, Louise ; Parnell, Grant ; Stewart, Graeme ; McKay, Fiona ; Kilpatrick, Trevor ; Butzkueven, Helmut ; Booth, David R. / 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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title = "The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function",
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 {Australia and New Zealand MS Genetics Consortium} and Alan Baxter and Kermode, {Allan G.} and Bruce Taylor and Booth, {David R.} and Deborah Mason and Stewart, {Graeme J.} and Helmut Butzkueven and Jac Charlesworth and James Wiley and Jeannette Lechner-Scott and Judith Field and Lotti Tajouri and Griffiths, {Lyn R.} and Mark Slee and Brown, {Matthew A.} and Pablo Moscato and Scott, {Rodney J.} and Simon Broadley and Steve Vucic and Trevor Kilpatrick and Carroll, {William M.} 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 Booth, {David R.}",
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Field, J, Shahijanian, F, Schibeci, S, Australia and New Zealand MS Genetics Consortium, Baxter, A, Kermode, AG, Taylor, B, Booth, DR, Mason, D, Stewart, GJ, Butzkueven, H, Charlesworth, J, Wiley, J, Lechner-Scott, J, Field, J, Tajouri, L, Griffiths, LR, Slee, M, Brown, MA, Moscato, P, Scott, RJ, Broadley, S, Vucic, S, Kilpatrick, T, Carroll, WM, Johnson, L, Gresle, M, Laverick, L, Parnell, G, Stewart, G, McKay, F, Kilpatrick, T, Butzkueven, H & Booth, DR 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; Australia and New Zealand MS Genetics Consortium; Baxter, Alan; Kermode, Allan G.; Taylor, Bruce; Booth, David R.; Mason, Deborah; Stewart, Graeme J.; Butzkueven, Helmut; Charlesworth, Jac; Wiley, James; Lechner-Scott, Jeannette; Field, Judith; Tajouri, Lotti; Griffiths, Lyn R.; Slee, Mark; Brown, Matthew A.; Moscato, Pablo; Scott, Rodney J.; Broadley, Simon; Vucic, Steve; Kilpatrick, Trevor; Carroll, William M.; Johnson, Laura; Gresle, Melissa; Laverick, Louise; Parnell, Grant; Stewart, Graeme; McKay, Fiona; Kilpatrick, Trevor; Butzkueven, Helmut; Booth, David R.

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

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells

T2 - Implications for gene function

AU - Field, Judith

AU - Shahijanian, Fernando

AU - Schibeci, Stephen

AU - Australia and New Zealand MS Genetics Consortium

AU - Baxter, Alan

AU - Kermode, Allan G.

AU - Taylor, Bruce

AU - Booth, David R.

AU - Mason, Deborah

AU - Stewart, Graeme J.

AU - Butzkueven, Helmut

AU - Charlesworth, Jac

AU - Wiley, James

AU - Lechner-Scott, Jeannette

AU - Field, Judith

AU - Tajouri, Lotti

AU - Griffiths, Lyn R.

AU - Slee, Mark

AU - Brown, Matthew A.

AU - Moscato, Pablo

AU - Scott, Rodney J.

AU - Broadley, Simon

AU - Vucic, Steve

AU - Kilpatrick, Trevor

AU - Carroll, William M.

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 R.

PY - 2015/6/11

Y1 - 2015/6/11

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, Australia and New Zealand MS Genetics Consortium, Baxter A, Kermode AG 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