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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.

Field J, Shahijanian F, Schibeci S, Australia and New Zealand MS Genetics Consortium (ANZgene)Johnson L, Gresle M, Laverick L, Parnell G, Stewart G, McKay F, Kilpatrick T, Butzkueven H, Booth D - PLoS ONE (2015)

Bottom Line: Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS.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.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.

View Article: PubMed Central - PubMed

Affiliation: Multiple Sclerosis Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria., Australia.

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.

No MeSH data available.


Related in: MedlinePlus

CD40 expression is higher in differentiated dendritic cell subsets.CD40 expression was determined in freshly purified immune cell subsets (B cells, monocytes) or in vitro differentiated dendritic cells (DC1, DC2) from healthy controls. Gene expression by RT-PCR (A; n = 49) and relative fluorescence intensity (RFI) by flow cytometry (B; n = 41) are shown; *significantly different from monocytes and DCs; **significantly different from B cells and monocytes (A) or from monocytes (B); p < 0.05 by Mann-Whitney test.
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pone.0127080.g005: CD40 expression is higher in differentiated dendritic cell subsets.CD40 expression was determined in freshly purified immune cell subsets (B cells, monocytes) or in vitro differentiated dendritic cells (DC1, DC2) from healthy controls. Gene expression by RT-PCR (A; n = 49) and relative fluorescence intensity (RFI) by flow cytometry (B; n = 41) are shown; *significantly different from monocytes and DCs; **significantly different from B cells and monocytes (A) or from monocytes (B); p < 0.05 by Mann-Whitney test.

Mentions: Dendritic cells are the major antigen presenting cells. However, DCs from whole blood are not typical of those in the secondary lymphoid organs and tissues, which are thought to drive T cell activation in autoimmune diseases [29]. Fortunately DCs representative of tissue DCs can be differentiated from monocytes, and have been verified as inflammatory (DC1) or tolerogenic (DC2) on the basis morphology and IL12p40 and IL10 mRNA and protein expression [23]. These DCs express much higher levels of CD40 mRNA and protein than monocytes and B cells (Fig 5). In these cells, CD40 expression was genotype dependent, with reduced expression of the risk allele at the mRNA level in DC2s (Fig 6A, p < 0.011) and at the protein level in both DC phenotypes (Fig 6B; p < 0.0047, DC1s; p < 0.0043, DC2s).


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, Australia and New Zealand MS Genetics Consortium (ANZgene)Johnson L, Gresle M, Laverick L, Parnell G, Stewart G, McKay F, Kilpatrick T, Butzkueven H, Booth D - PLoS ONE (2015)

CD40 expression is higher in differentiated dendritic cell subsets.CD40 expression was determined in freshly purified immune cell subsets (B cells, monocytes) or in vitro differentiated dendritic cells (DC1, DC2) from healthy controls. Gene expression by RT-PCR (A; n = 49) and relative fluorescence intensity (RFI) by flow cytometry (B; n = 41) are shown; *significantly different from monocytes and DCs; **significantly different from B cells and monocytes (A) or from monocytes (B); p < 0.05 by Mann-Whitney test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4465929&req=5

pone.0127080.g005: CD40 expression is higher in differentiated dendritic cell subsets.CD40 expression was determined in freshly purified immune cell subsets (B cells, monocytes) or in vitro differentiated dendritic cells (DC1, DC2) from healthy controls. Gene expression by RT-PCR (A; n = 49) and relative fluorescence intensity (RFI) by flow cytometry (B; n = 41) are shown; *significantly different from monocytes and DCs; **significantly different from B cells and monocytes (A) or from monocytes (B); p < 0.05 by Mann-Whitney test.
Mentions: Dendritic cells are the major antigen presenting cells. However, DCs from whole blood are not typical of those in the secondary lymphoid organs and tissues, which are thought to drive T cell activation in autoimmune diseases [29]. Fortunately DCs representative of tissue DCs can be differentiated from monocytes, and have been verified as inflammatory (DC1) or tolerogenic (DC2) on the basis morphology and IL12p40 and IL10 mRNA and protein expression [23]. These DCs express much higher levels of CD40 mRNA and protein than monocytes and B cells (Fig 5). In these cells, CD40 expression was genotype dependent, with reduced expression of the risk allele at the mRNA level in DC2s (Fig 6A, p < 0.011) and at the protein level in both DC phenotypes (Fig 6B; p < 0.0047, DC1s; p < 0.0043, DC2s).

Bottom Line: Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS.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.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.

View Article: PubMed Central - PubMed

Affiliation: Multiple Sclerosis Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria., Australia.

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.

No MeSH data available.


Related in: MedlinePlus