Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis
Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis
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DOI：
10.1073/pnas.0402455101
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发表时间：
2004-07-27
影响因子：
11.1
通讯作者：
Pistoia, V
中科院分区：
文献类型：
--
作者：
Corcione, A;Casazza, S;Pistoia, V
在多发性硬化（MS）患者的CNS中检测到携带IG可变（V）区基因体细胞突变的克隆扩增B细胞群，表明CNS内可能发生B细胞亲和力成熟过程，随后产生潜在致病性自身抗体。在这里，我们的特点是B细胞亚群存在于脑脊液（CSF）的MS患者和其他炎症性神经系统疾病的个人通过流式细胞术。CD 19（+）CD 38（高+）CD 77（+）、Ki 67（+）、Bcl-2（-）中心母细胞，即，一种仅在次级淋巴器官中发现的B细胞亚群，在CSF中检测到，但在两个患者组的配对外周血中未检测到。CD 27（+）IgD（-）记忆B细胞，即，具有高度突变的IgV基因的细胞在CSF中相对于配对的外周血中显著增加，并且在两个患者组中显示出CD 80和CD 86共刺激分子以及CC趋化因子受体（CCR）1、CCR 2和CCR 4的上调。多发性硬化和其他炎性神经系统疾病患者的脑脊液中存在淋巴新生的关键介质-α-光毒素、CXC配体（CXCL）12和CXCL 13，并在多发性硬化脑组织中表达，选择性定位于毛细血管壁的外层。总之，本研究表明，在持续的炎症反应期间，通过在次级淋巴器官中观察到的B细胞分化的所有阶段的重演，在CNS内发生了区室化的B细胞反应。中枢神经系统中淋巴毒素-α、CXCL 12和CXCL 13的存在可能为这些事件提供有利的微环境条件。
Clonally expanded populations of B cells carrying somatic mutations of Ig variable (V) region genes have been detected in the CNS of subjects with multiple sclerosis (MS), suggesting that a process of B cell affinity maturation with ensuing production of potentially pathogenic autoantibodies may occur inside the CNS. Here, we have characterized the B cell subsets present in the cerebrospinal fluid (CSF) of MS patients and of individuals with other inflammatory neurological disorders by flow cytometry. CD19(+)CD38(high+)CD77(+), Ki67(+), Bcl-2(-) centroblasts, i.e., a B cell subset found exclusively in secondary lymphoid organs, were detected in the CSF but not in paired peripheral blood from both patient groups. CD27(+)IgD(-) memory B cells, i.e., cells with hyper-mutated IgV genes, were significantly increased in the CSF vs. paired peripheral blood and displayed up-regulation of the CD80 and CD86 costimulatory molecules and of CC chemokine receptor (CCR) 1, CCR2, and CCR4 in both patient groups. Lymphotoxin-a, CXC ligand (CXCL) 12, and CXCL13, key mediators of lymphoid neogenesis, were present in the CSF from patients with MS and other inflammatory neurological disorders and were expressed in MS brain tissue, with selective localization in the outer layer of the capillary vessel wall. In conclusion, this study suggests that a compartmentalized B cell response occurs within the CNS during an ongoing inflammatory reaction, through a recapitulation of all stages of B cell differentiation observed in secondary lymphoid organs. The presence of lymphotoxin-alpha, CXCL12, and CXCL13 in the CNS may provide favorable microenvironmental conditions for these events.