Multiple sclerosis risk variants alter expression of co-stimulatory genes in B cells
| Autor: | Smets, Ide, Fiddes, Barnaby, Garcia-Perez, Josselyn E, He, Di, Mallants, Klara, Liao, Wenjia, Dooley, James, Wang, George, Humblet-Baron, Stephanie, Dubois, Bénédicte, Compston, Alastair, Jones, Joanne, Coles, Alasdair, Liston, Adrian, Ban, Maria, Goris, An, Sawcer, Stephen |
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| Přispěvatelé: | Dooley, James [0000-0003-3154-4708], Jones, Joanna [0000-0003-4974-1371], Coles, Alasdair [0000-0003-4738-0760], Liston, Adrian [0000-0002-6272-4085], Sawcer, Stephen [0000-0001-7685-0974], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
B cells B-Lymphocytes Multiple Sclerosis Genotype hemic and immune systems Original Articles Polymorphism Single Nucleotide susceptibility Interleukin-10 Gene Expression Regulation CD40 Cytokines Humans CD86 Female Genetic Predisposition to Disease B7-2 Antigen CD40 Antigens Correlation of Data |
| Zdroj: | Brain |
| DOI: | 10.1093/brain/awx372 |
| Popis: | Increasing evidence implicates B cells in the pathogenesis of multiple sclerosis. Smets et al. report that the CD40 multiple sclerosis risk allele lowers CD40 expression, whereas the CD86 risk allele increases CD86 expression. B cells may have an important antigen presentation and immunoregulatory role in multiple sclerosis. The increasing evidence supporting a role for B cells in the pathogenesis of multiple sclerosis prompted us to investigate the influence of known susceptibility variants on the surface expression of co-stimulatory molecules in these cells. Using flow cytometry we measured surface expression of CD40 and CD86 in B cells from 68 patients and 162 healthy controls that were genotyped for the multiple sclerosis associated single nucleotide polymorphisms (SNPs) rs4810485, which maps within the CD40 gene, and rs9282641, which maps within the CD86 gene. We found that carrying the risk allele rs4810485*T lowered the cell-surface expression of CD40 in all tested B cell subtypes (in total B cells P ≤ 5.10 × 10−5 in patients and ≤4.09 × 10−6 in controls), while carrying the risk allele rs9282641*G increased the expression of CD86, with this effect primarily seen in the naïve B cell subset (P = 0.048 in patients and 5.38 × 10−5 in controls). In concordance with these results, analysis of RNA expression demonstrated that the risk allele rs4810485*T resulted in lower total CD40 expression (P = 0.057) but with an increased proportion of alternative splice-forms leading to decoy receptors (P = 4.00 × 10−7). Finally, we also observed that the risk allele rs4810485*T was associated with decreased levels of interleukin-10 (P = 0.020), which is considered to have an immunoregulatory function downstream of CD40. Given the importance of these co-stimulatory molecules in determining the immune reaction that appears in response to antigen our data suggest that B cells might have an important antigen presentation and immunoregulatory role in the pathogenesis of multiple sclerosis. |
| Databáze: | OpenAIRE |
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