PDF(Pubmed)
Abstract：
BACKGROUND: In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk factors. Studies on monozygotic twins discordant for MS offer a unique way to reduce this complexity and reveal discrepant subsets.
METHODS: In this study, we analyzed B cell subsets in blood samples of monozygotic twins with and without MS using publicly available data. We verified functional characteristics by exploring the role of therapy and performed separate analyses in unrelated individuals.
RESULTS: The frequencies of CXCR3+ memory B cells were reduced in the blood of genetically identical twins with MS compared to their unaffected twin siblings. Natalizumab (anti-VLA-4 antibody) was the only treatment regimen under which these frequencies were reversed. The CNS-homing features of CXCR3+ memory B cells were supported by elevated CXCL10 levels in MS cerebrospinal fluid and their in vitro propensity to develop into antibody-secreting cells.
CONCLUSIONS: Circulating CXCR3+ memory B cells are affected by non-heritable cues in people who develop MS. This underlines the requirement of environmental risk factors such as Epstein-Barr virus in triggering these B cells. We propose that after CXCL10-mediated entry into the CNS, CXCR3+ memory B cells mature into antibody-secreting cells to drive MS.
BACKGROUND: This work was supported by Nationaal MS Fonds (OZ2021-016), Stichting MS Research (19-1057 MS, 20-490f MS, and 21-1142 MS), the European Research Council (ERC) under the European Union\'s Horizon 2020 research and innovation program grant agreement no. 882424, and the Swiss National Science Foundation (733 310030_170320, 310030_188450, and CRSII5_183478).
METHODS: In this study, we analyzed B cell subsets in blood samples of monozygotic twins with and without MS using publicly available data. We verified functional characteristics by exploring the role of therapy and performed separate analyses in unrelated individuals.
RESULTS: The frequencies of CXCR3+ memory B cells were reduced in the blood of genetically identical twins with MS compared to their unaffected twin siblings. Natalizumab (anti-VLA-4 antibody) was the only treatment regimen under which these frequencies were reversed. The CNS-homing features of CXCR3+ memory B cells were supported by elevated CXCL10 levels in MS cerebrospinal fluid and their in vitro propensity to develop into antibody-secreting cells.
CONCLUSIONS: Circulating CXCR3+ memory B cells are affected by non-heritable cues in people who develop MS. This underlines the requirement of environmental risk factors such as Epstein-Barr virus in triggering these B cells. We propose that after CXCL10-mediated entry into the CNS, CXCR3+ memory B cells mature into antibody-secreting cells to drive MS.
BACKGROUND: This work was supported by Nationaal MS Fonds (OZ2021-016), Stichting MS Research (19-1057 MS, 20-490f MS, and 21-1142 MS), the European Research Council (ERC) under the European Union\'s Horizon 2020 research and innovation program grant agreement no. 882424, and the Swiss National Science Foundation (733 310030_170320, 310030_188450, and CRSII5_183478).
摘要：
背景：在多发性硬化症（MS）中，B细胞被认为是该病的主要诱因,可能是遗传和环境风险因素之间复杂相互作用的结果。对MS不一致的单卵双胞胎的研究提供了一种独特的方法来降低这种复杂性并揭示不同的子集。
方法：在本研究中，我们使用公开的数据分析了有MS和无MS的单卵双胞胎血液样本中的B细胞亚群.我们通过探索治疗的作用来验证功能特征，并在无关个体中进行单独分析。
结果：与未受影响的双胞胎兄弟姐妹相比，患有MS的同卵双胞胎的血液中CXCR3记忆B细胞的频率降低。那他珠单抗(抗VLA-4抗体)是这些频率被逆转的唯一治疗方案。CXCR3记忆B细胞的CNS归巢特征得到了MS脑脊液中CXCL10水平升高及其体外发育为抗体分泌细胞的倾向的支持。
结论：正在循环的CXCR3+记忆B细胞受非遗传线索的影响。这强调了在触发这些B细胞时需要环境风险因素，例如爱泼斯坦-巴尔病毒。我们建议在CXCL10介导的进入中枢神经系统后，CXCR3+记忆B细胞成熟为抗体分泌细胞驱动MS。
背景：这项工作得到了国家MSFonds（OZ2021-016）的支持，StichtingMSResearch(19-1057MS，20-490fMS,和21-1142MS），欧洲研究理事会(ERC)根据欧盟“地平线2020”研究和创新计划授予协议编号。882424和瑞士国家科学基金会（733310030_170320、310030_188450和CRSII5_183478）。
方法：在本研究中，我们使用公开的数据分析了有MS和无MS的单卵双胞胎血液样本中的B细胞亚群.我们通过探索治疗的作用来验证功能特征，并在无关个体中进行单独分析。
结果：与未受影响的双胞胎兄弟姐妹相比，患有MS的同卵双胞胎的血液中CXCR3记忆B细胞的频率降低。那他珠单抗(抗VLA-4抗体)是这些频率被逆转的唯一治疗方案。CXCR3记忆B细胞的CNS归巢特征得到了MS脑脊液中CXCL10水平升高及其体外发育为抗体分泌细胞的倾向的支持。
结论：正在循环的CXCR3+记忆B细胞受非遗传线索的影响。这强调了在触发这些B细胞时需要环境风险因素，例如爱泼斯坦-巴尔病毒。我们建议在CXCL10介导的进入中枢神经系统后，CXCR3+记忆B细胞成熟为抗体分泌细胞驱动MS。
背景：这项工作得到了国家MSFonds（OZ2021-016）的支持，StichtingMSResearch(19-1057MS，20-490fMS,和21-1142MS），欧洲研究理事会(ERC)根据欧盟“地平线2020”研究和创新计划授予协议编号。882424和瑞士国家科学基金会（733310030_170320、310030_188450和CRSII5_183478）。
