Dynamic relationship between cerebrospinal fluid immune cells and tissue damage markers in multiple sclerosis

Multiple sclerosis (MS) is characterized by immune-mediated demyelination and neurodegeneration. While cerebrospinal fluid (CSF) biomarkers can track tissue damage, the relationship between immune cell populations and tissue damage markers remains poorly understood. We performed comprehensive immunophenotyping of CSF samples from 63 participants [29 relapsing-remitting multiple sclerosis (RRMS), 7 primary progressive multiple sclerosis (PPMS), 27 patients with other suspected neurological diseases (OND)]. CSF levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were measured using single-molecule array technology. Relationships between immune cell populations and biomarkers were assessed using partial correlation and multiple regression analyses, adjusting for age and sex. RRMS patients exhibited expanded lymphocyte populations compared with OND, with elevated CD3+ T cells (+5062 cells/mL, P < 0.0001) and CD19+ B cells (+180 cells/mL, P < 0.0001). Patients with multiple sclerosis showed an age-related shift in monocyte subsets, marked by increased CD14+CD16+ cells [r_SP = 0.670, (95% CI: 0.44-0.81), P = 0.0029]. During active relapse, naive CD4+ T cells demonstrated the strongest association with NfL [cumulative geometric mean ratio = 2.892 (95% CI: 1.352-6.188), P < 0.0001], contrasting with non-relapse states [GMR = 0.689 (95% CI: 0.449-1.057), P = 0.101]. This study identifies distinct immunological signatures in multiple sclerosis and demonstrates disease activity-dependent associations between specific immune cell populations and tissue damage markers. The relationship between classical monocytes and GFAP in controls suggests a previously unrecognized role for myeloid cells in physiological CNS homeostasis.