Multiple sclerosis associated SNPs influencing B cell expression of co-stimulatory receptors and T cell proliferation and cytokine secretion profile
ECTRIMS Online Library. He D. Oct 12, 2018; 232052; 299
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Abstract: 299

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics

Objectives: Although more than 200 susceptibility loci for multiple sclerosis (MS) have been identified, our understanding of the molecular mechanisms underlying these associations remains limited. We have previously shown that that the MS associated SNPs rs9282641 and rs4810485 respectively influence the ex vivo expression of CD86 and CD40 in B cells. To elucidate the molecular mechanisms behind these genotypic effects, we employed an in vitro B cell activation model using CD40L-expressing cell line, and a B/T cell co-culture system.
Methods: Peripheral blood was collected from 108 healthy volunteers (recruited via the Cambridge BioResource according to their genotypes). Peripheral blood mononuclear cells (PBMCs) were isolated from these samples and cultured with CD40L-transfected L cells for three days. In an independent second experiment 28 volunteers (carrying either AA or GG at rs9282641) were also recruited. From these purified B cells and naïve T cells were co-cultured for 12 days. Relevant surface and intracellular markers, and cell proliferation, were then measured by flow cytometry.
Results: The carriage of the risk allele T at rs4810485 decreases the proportion of naïve B cells expressing CD40 with (p=0.0001) and without (p=0.0016) CD40L stimulation after three days' culture, whereas carrying the risk allele G at rs9282641 increases the proportion of naïve B cells expressing CD86 with (p=0.0047) and without (p=0.0022) stimulation. In the 12-day culture experiment interim analysis shows that carrying the risk allele at rs9282641 demonstrated a trend towards higher cell proliferation ratio and CD86 expression. The stimulated T cells displayed significantly higher proliferation and IFN-y production but lower IL-10 production as compared with the unstimulated, and stimulated B cells showed higher proliferation and CD80, IL-6 expression but lower CD40 and IL-10.
Conclusions: Our study shows that the two MS associated SNPs alter the expression of co-stimulatory receptors in B cells under cultured condition, which further influenced T cell proliferation and cytokine production profile.
Disclosure: The study was supported by a grant from the Multiple Sclerosis Society UKDi He: PhD study supported by China Scholarship Council and Cambridge Trust
Maria Ban: nothing to disclose
Stephen Sawcer: nothing to disclose

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