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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: 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.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.

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 protein is under- expressed in B lymphocytes of MS patients.B lymphocyte subsets from healthy controls (n = 86) and MS patients (n = 24) were identified by flow cytometry and CD40 expression determined relative to an isotype control (relative fluorescence intensity; RFI). Surface levels of CD40 were compared in total B-lymphocytes (A), B lymphocytes from rs1883832 CC individuals (B; n = 49 healthy controls, n = 12 MS patients), naïve B lymphocytes (C), classical memory B lymphocytes (D) and IgM memory B lymphocytes (E). P-values were determined using Mann—Whitney test.
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pone.0127080.g003: CD40 protein is under- expressed in B lymphocytes of MS patients.B lymphocyte subsets from healthy controls (n = 86) and MS patients (n = 24) were identified by flow cytometry and CD40 expression determined relative to an isotype control (relative fluorescence intensity; RFI). Surface levels of CD40 were compared in total B-lymphocytes (A), B lymphocytes from rs1883832 CC individuals (B; n = 49 healthy controls, n = 12 MS patients), naïve B lymphocytes (C), classical memory B lymphocytes (D) and IgM memory B lymphocytes (E). P-values were determined using Mann—Whitney test.

Mentions: Comparison of B lymphocyte expression of CD40 in MS patients failed to show a significant effect of genotype on surface CD40 expression levels in total B lymphocytes (Fig 2F), naïve B lymphocytes (Fig 2G) or classical memory B lymphocytes (Fig 2H). However, comparison of cell surface CD40 expression on B-lymphocytes between healthy controls and MS patients (Fig 3) showed that CD40 expression was significantly lower in MS patients compared to healthy controls in all CD19+ B-lymphocytes (Fig 3A; p <0.0001), as well as in the naïve B lymphocytes\ (Fig 3C; p <0.0001), classical memory B-lymphocyte (Fig 3D; p = 0.0001) and IgM memory B lymphocyte subsets (Fig 3E; p = 0.0004). A subset comparison of patients and unaffected controls homozygous for the rs1883832 C allele (CC) also demonstrated a significant decrease in CD40 expression on the total B—lymphocytes of MS patients compared to controls (Fig 3B; p <0.0001) The relative proportions of total B-lymphocytes and subsets as a percentage of total white cells were not affected by genotype or phenotype (data not shown).


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 protein is under- expressed in B lymphocytes of MS patients.B lymphocyte subsets from healthy controls (n = 86) and MS patients (n = 24) were identified by flow cytometry and CD40 expression determined relative to an isotype control (relative fluorescence intensity; RFI). Surface levels of CD40 were compared in total B-lymphocytes (A), B lymphocytes from rs1883832 CC individuals (B; n = 49 healthy controls, n = 12 MS patients), naïve B lymphocytes (C), classical memory B lymphocytes (D) and IgM memory B lymphocytes (E). P-values were determined using Mann—Whitney test.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0127080.g003: CD40 protein is under- expressed in B lymphocytes of MS patients.B lymphocyte subsets from healthy controls (n = 86) and MS patients (n = 24) were identified by flow cytometry and CD40 expression determined relative to an isotype control (relative fluorescence intensity; RFI). Surface levels of CD40 were compared in total B-lymphocytes (A), B lymphocytes from rs1883832 CC individuals (B; n = 49 healthy controls, n = 12 MS patients), naïve B lymphocytes (C), classical memory B lymphocytes (D) and IgM memory B lymphocytes (E). P-values were determined using Mann—Whitney test.
Mentions: Comparison of B lymphocyte expression of CD40 in MS patients failed to show a significant effect of genotype on surface CD40 expression levels in total B lymphocytes (Fig 2F), naïve B lymphocytes (Fig 2G) or classical memory B lymphocytes (Fig 2H). However, comparison of cell surface CD40 expression on B-lymphocytes between healthy controls and MS patients (Fig 3) showed that CD40 expression was significantly lower in MS patients compared to healthy controls in all CD19+ B-lymphocytes (Fig 3A; p <0.0001), as well as in the naïve B lymphocytes\ (Fig 3C; p <0.0001), classical memory B-lymphocyte (Fig 3D; p = 0.0001) and IgM memory B lymphocyte subsets (Fig 3E; p = 0.0004). A subset comparison of patients and unaffected controls homozygous for the rs1883832 C allele (CC) also demonstrated a significant decrease in CD40 expression on the total B—lymphocytes of MS patients compared to controls (Fig 3B; p <0.0001) The relative proportions of total B-lymphocytes and subsets as a percentage of total white cells were not affected by genotype or phenotype (data not shown).

Bottom Line: 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.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.

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