Contributions
Abstract: P465
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
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 (SNP) rs4810485, which maps within the CD40 gene, and rs9282641, which maps within the CD86 gene. We found that carrying the risk allele at rs4810485*T lowers the cell-surface expression of CD40 in all tested B cells sub-types (in total B cells p ≤ 5.10 x 10-5 in patients and ≤ 4.09 x 10-6 in controls), while carrying the risk allele at 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 x 10-5 in controls). In concordance with these results analysis of RNA expression demonstrated that the risk allele of 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 x 10-7). Finally, we also observed that the risk allele of rs4810485*T is 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 role in the pathogenesis of multiple sclerosis.
Disclosure:
Ide Smets: nothing to disclose.
Barnaby Fiddes: supported by a Raymond and Beverly Sackler Student Studentship
Josselyn Garcia-Perez: nothing to disclose.
Di He: nothing to disclose.
Klara Mallants: nothing to disclose.
Wenjia Liao: nothing to disclose.
James Dooley: nothing to disclose.
George Wang: nothing to disclose.
Stephanie Humblet-Baron: nothing to disclose.
Bénédicte Dubois: consulting fees and/or funding from Bayer, Biogen Idec, BSP, Merck, Sanofi-Aventis, Serono, Teva and Novartis, clinical Investigator of the Research Foundation Flanders (FWO).
Alastair Compston: nothing to disclose.
Joanne Jones: nothing to disclose.
Alasdair Coles: nothing to disclose.
Adrian Liston: funding from Novartis. The spouse of AL is an ex-employee of UCB.
Maria Ban: nothing to disclose.
An Goris: funding from Novartis.
Stephen Sawcer: nothing to disclose.
This study was supported by the Research Fund KU Leuven (C24/16/045), the Research Foundation Flanders (FWO G.07334.15), the Belgian Charcot Foundation, the MS Liga Vlaanderen, a research grant from Novartis, the UK MS Society (ref11/955), UK Medical Council (G1100125) and the National Institute for Health Research Cambridge Biomedical Research Centre.
Abstract: P465
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
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 (SNP) rs4810485, which maps within the CD40 gene, and rs9282641, which maps within the CD86 gene. We found that carrying the risk allele at rs4810485*T lowers the cell-surface expression of CD40 in all tested B cells sub-types (in total B cells p ≤ 5.10 x 10-5 in patients and ≤ 4.09 x 10-6 in controls), while carrying the risk allele at 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 x 10-5 in controls). In concordance with these results analysis of RNA expression demonstrated that the risk allele of 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 x 10-7). Finally, we also observed that the risk allele of rs4810485*T is 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 role in the pathogenesis of multiple sclerosis.
Disclosure:
Ide Smets: nothing to disclose.
Barnaby Fiddes: supported by a Raymond and Beverly Sackler Student Studentship
Josselyn Garcia-Perez: nothing to disclose.
Di He: nothing to disclose.
Klara Mallants: nothing to disclose.
Wenjia Liao: nothing to disclose.
James Dooley: nothing to disclose.
George Wang: nothing to disclose.
Stephanie Humblet-Baron: nothing to disclose.
Bénédicte Dubois: consulting fees and/or funding from Bayer, Biogen Idec, BSP, Merck, Sanofi-Aventis, Serono, Teva and Novartis, clinical Investigator of the Research Foundation Flanders (FWO).
Alastair Compston: nothing to disclose.
Joanne Jones: nothing to disclose.
Alasdair Coles: nothing to disclose.
Adrian Liston: funding from Novartis. The spouse of AL is an ex-employee of UCB.
Maria Ban: nothing to disclose.
An Goris: funding from Novartis.
Stephen Sawcer: nothing to disclose.
This study was supported by the Research Fund KU Leuven (C24/16/045), the Research Foundation Flanders (FWO G.07334.15), the Belgian Charcot Foundation, the MS Liga Vlaanderen, a research grant from Novartis, the UK MS Society (ref11/955), UK Medical Council (G1100125) and the National Institute for Health Research Cambridge Biomedical Research Centre.