FCRL5, a B-Cell Marker With Novel Diagnostic and Prognostic Value for Multiple Sclerosis

Area of Science:

• Immunology
• Neuroimmunology
• Biomarker Discovery

Background:

• Fc receptor-like 5 (FCRL5) is implicated in inflammatory conditions.
• Its role in multiple sclerosis (MS) pathogenesis is not well understood.
• Characterizing FCRL5 in MS is crucial for understanding disease mechanisms.

Purpose of the Study:

• To investigate FCRL5 expression in cerebrospinal fluid (CSF), serum, and peripheral blood mononuclear cells (PBMC) of MS patients.
• To define the phenotypic and transcriptional characteristics of FCRL5-positive (FCRL5+) B cells in MS.
• To explore FCRL5 as a potential biomarker for MS diagnosis and activity.

Main Methods:

• Proteomic analysis (proximity extension assay) of CSF from relapsing-remitting MS (RRMS) patients and controls.
• Validation of FCRL5 levels using single-molecule array in expanded cohorts.
• Flow cytometry and RNA sequencing of PBMC to analyze FCRL5+ B cell phenotype and transcriptome.
• In vitro assessment of Bruton tyrosine kinase inhibitors (BTKi) on FCRL5 regulation.

Main Results:

• FCRL5 was significantly upregulated in the CSF of RRMS patients compared to controls and other inflammatory neurologic diseases (OIND).
• Elevated CSF FCRL5 correlated with increased risk of new brain lesions.
• Peripheral CD19+FCRL5+ B cells in MS patients exhibited increased CD11c expression and distinct transcriptional profiles with reduced humoral response and enhanced inflammatory signaling.
• FCRL5 regulation was found to be dependent on Bruton tyrosine kinase (BTK).

Conclusions:

• Soluble FCRL5 in CSF shows potential as a biomarker for MS diagnosis and disease activity prediction.
• MS-associated CD19+CD11c+FCRL5+ B cells possess a unique transcriptional signature.
• FCRL5 expression and regulation are linked to BTK activity in MS B cells.