Deltombe Matthieu, Stölting Anna, Maggi Pietro, van Pesch Vincent
Laboratory of Neurochemistry, Institute of Neuroscience, Université Catholique de Louvain (UCLouvain), Brussels, Belgium.
Neuroinflammation Imaging Lab (NIL), Institute of Neuroscience, Université Catholique de Louvain (UCLouvain), Brussels, Belgium; and.
Neurol Neuroimmunol Neuroinflamm. 2025 Nov;12(6):e200485. doi: 10.1212/NXI.0000000000200485. Epub 2025 Sep 26.
Fc receptor-like 5 (FCRL5) is an IgG-binding receptor frequently reported to be highly expressed on double-negative and atypical memory B cells, both of which are frequently expanded in inflammatory conditions. However, its expression profile in multiple sclerosis (MS) remains unclear. This study aims to characterize FCRL5 expression in CSF, serum, and peripheral blood mononuclear cells (PBMC) of patients with MS and to define the phenotypic and transcriptional features of FCRL5 B cells in MS.
A proximity extension assay-based proteomic analysis was conducted on the CSF of patients with relapsing-remitting MS (RRMS, n = 59) and controls (n = 29). The observed FCRL5 upregulation was validated using single-molecule array analysis in a cohort comprising patients with RRMS (n = 40), controls (n = 30), and individuals with other inflammatory neurologic diseases (OIND, n = 20). Serum FCRL5 levels were also assessed in a cohort of patients with MS characterized by 3T MRI (n = 58). In addition, flow cytometry-based techniques and RNA sequencing were performed on PBMC from patients with RRMS and controls to investigate the phenotype and transcriptional profiles of FCRL5 B cells. Finally, the effect of Bruton tyrosine kinase inhibitors (BTKi) on FCRL5 regulation was also evaluated in vitro.
FCRL5 was significantly upregulated in the CSF of patients with RRMS compared with that in controls and OIND. Elevated CSF FCRL5 levels were associated with an increased risk of new brain lesions within 24 months. Serum FCRL5 levels were not correlated with CSF measurements but were inversely correlated with the cortical and juxtacortical lesion burdens. Moreover, flow cytometry analysis revealed that peripheral CD19FCRL5 B cells of patients with RRMS differed from those of controls by their strong CD11c expression. The transcriptional profiles of CD19CD11cFCRL5 cells also differed significantly between the 2 groups, characterized by reduced expression of humoral response genes and enhanced inflammatory signaling. In addition, FCRL5 regulation was found to be BTK-dependent.
The soluble form of FCRL5 can be measured in the CSF and could serve as a promising biomarker for MS diagnosis and disease activity prediction. In addition, this study highlights that CD19CD11cFCRL5 B cells in MS display a distinct transcriptional profile compared with controls.
Fc受体样5（FCRL5）是一种IgG结合受体，经常报道其在双阴性和非典型记忆B细胞上高表达，这两种细胞在炎症条件下常大量扩增。然而，其在多发性硬化症（MS）中的表达谱仍不清楚。本研究旨在描述MS患者脑脊液、血清和外周血单个核细胞（PBMC）中FCRL5的表达情况，并确定MS中FCRL5⁺ B细胞的表型和转录特征。
对复发缓解型MS（RRMS，n = 59）患者和对照者（n = 29）的脑脊液进行基于邻近延伸分析的蛋白质组学分析。在一个包括RRMS患者（n = 40）、对照者（n = 30）和其他炎性神经系统疾病（OIND，n = 20）个体的队列中，使用单分子阵列分析验证观察到的FCRL5上调情况。还在一组经3T MRI检查的MS患者（n = 58）中评估血清FCRL5水平。此外，对RRMS患者和对照者的PBMC进行基于流式细胞术的技术和RNA测序，以研究FCRL5⁺ B细胞的表型和转录谱。最后，还在体外评估布鲁顿酪氨酸激酶抑制剂（BTKi）对FCRL5调节的影响。
与对照者和OIND患者相比，RRMS患者脑脊液中的FCRL5显著上调。脑脊液中FCRL5水平升高与24个月内出现新脑损伤的风险增加相关。血清FCRL5水平与脑脊液测量值无关，但与皮质和皮质下病变负荷呈负相关。此外，流式细胞术分析显示，RRMS患者的外周CD19⁺FCRL5⁺ B细胞与对照者的不同，其CD11c表达较强。两组之间CD19⁺CD11c⁺FCRL5⁺细胞的转录谱也有显著差异，其特征是体液反应基因表达降低和炎症信号增强。此外，发现FCRL5调节依赖于BTK。
FCRL5的可溶性形式可在脑脊液中检测到，有望作为MS诊断和疾病活动预测的生物标志物。此外，本研究强调，与对照者相比，MS中的CD19⁺CD11c⁺FCRL5⁺ B细胞表现出独特的转录谱。
