C-X-C chemokine ligand 13 (CXCL13) is frequently elevated in cerebrospinal fluid (CSF) in a variety of inflammatory central nervous system (CNS) diseases, has been detected in meningeal B cell aggregates in brain tissues of multiple sclerosis patients, and proposedly recruits B cells into the inflamed CNS. Besides B cells also follicular helper T (Tfh) cells express the cognate receptor C-X-C chemokine receptor type 5 (CXCR5) and follow CXCL13 gradients in lymphoid tissues. These highly specialized B cell helper T cells are indispensable for B cell responses to infection and vaccination and involved in autoimmune diseases. Phenotypically and functionally related circulating CXCR5+CD4 T cells occur in blood. Their co-recruitment to the inflamed CSF is feasible but unresolved. We approached this question with a retrospective study including data of all patients between 2017 and 2019 of whom immune phenotyping data of CXCR5 expression and CSF CXCL13 concentrations were available. Discharge diagnoses and CSF laboratory parameters were retrieved from records. Patients were categorized as pyogenic/aseptic meningoencephalitis (ME, n = 29), neuroimmunological diseases (NIMM, n = 22), and non-inflammatory neurological diseases (NIND, n = 6). ANOVA models and Spearman’s Rank-Order correlation were used for group comparisons and associations of CXCL13 levels with immune phenotyping data. In fact, intrathecal CXCL13 elevations strongly correlated with CXCR5+CD4 T cell frequencies in the total cohort (p < 0.0001, r = 0.59), and ME (p = 0.003, r = 0.54) and NIMM (p = 0.043, r = 0.44) patients. Moreover, the ratio of CSF-to-peripheral blood (CSF/PB) frequencies of CXCR5+CD4 T cells strongly correlated with CXCL13 levels both in the total cohort (p = 0.001, r = 0.45) and ME subgroup (p = 0.005, r = 0.50), indicating selective accumulation. ME, NIMM and NIND groups differed with regard to CSF cell counts, albumin quotient, intrathecal IgG, CXCL13 elevations and CXCR5+CD4 T cells, which were higher in inflammatory subgroups. The observed link between intrathecal CXCL13 elevations and CXCR5+CD4 T cell frequencies does not prove but suggests recruitment of possible professional B cell helpers to the inflamed CSF. This highlights CSF CXCR5+CD4 T cells a key target and potential missing link to the poorly understood phenomenon of intrathecal B cell and antibody responses with relevance for infection control, chronic inflammation and CNS autoimmunity.

中文翻译：

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神经炎症中的 CXCL13/CXCR5-趋化因子轴：CXCR5+CD4 T 细胞募集到 CSF 的证据

CXC 趋化因子配体 13 (CXCL13) 在多种炎症性中枢神经系统 (CNS) 疾病的脑脊液 (CSF) 中经常升高，已在多发性硬化症患者脑组织的脑膜 B 细胞聚集体中检测到，并建议招募 B 细胞进入发炎的中枢神经系统。除 B 细胞外，滤泡辅助 T (Tfh) 细胞还表达同源受体 CXC 趋化因子受体 5 型 (CXCR5) 并在淋巴组织中遵循 CXCL13 梯度。这些高度特化的 B 细胞辅助 T 细胞对于 B 细胞对感染和疫苗接种的反应是必不可少的，并参与自身免疫性疾病。表型和功能相关的循环 CXCR5+CD4 T 细胞出现在血液中。他们共同招募发炎的脑脊液是可行的，但尚未解决。我们通过一项回顾性研究来解决这个问题，该研究包括 2017 年至 2019 年间所有患者的数据，其中 CXCR5 表达和脑脊液 CXCL13 浓度的免疫表型数据可用。从记录中检索出院诊断和脑脊液实验室参数。患者分为化脓性/无菌性脑膜脑炎（ME，n = 29）、神经免疫疾病（NIMM，n = 22）和非炎症性神经疾病（NIND，n = 6）。ANOVA 模型和 Spearman 的 Rank-Order 相关性用于 CXCL13 水平与免疫表型数据的组比较和关联。事实上，鞘内 CXCL13 升高与整个队列中的 CXCR5+CD4 T 细胞频率密切相关（p < 0.0001，r = 0.59），以及 ME（p = 0.003，r = 0.54）和 NIMM（p = 0.043，r = 0.44） ） 耐心。而且，在总队列（p = 0.001，r = 0.45）和 ME 亚组（p = 0.005，r = 0.50），表明选择性积累。ME、NIMM 和 NIND 组在 CSF 细胞计数、白蛋白商、鞘内 IgG、CXCL13 升高和 CXCR5+CD4 T 细胞方面存在差异，这些在炎症亚组中较高。鞘内 CXCL13 升高与 CXCR5+CD4 T 细胞频率之间观察到的联系并不能证明，但表明可能为发炎的 CSF 募集了专业的 B 细胞辅助细胞。这突显了 CSF CXCR5+CD4 T 细胞是一个关键靶点，并且可能与鞘内 B 细胞和与感染控制、慢性炎症和 CNS 自身免疫相关的抗体反应这一知之甚少的现象缺乏联系。