Intrathecal Kappa Free Light Chains in Relation to IgM Synthesis and MRZH Reaction in a Mixed Neurological Cohort

Intrathecal immunoglobulin synthesis is a hallmark of neuroinflammatory diseases. Free kappa light chains (FLCK) in cerebrospinal fluid (CSF) have emerged as a sensitive biomarker of B-cell activity in the central nervous system (CNS), yet their relationship to immunoglobulin M (IgM) synthesis and polyspecific antiviral responses remains unclear. We aimed to delineate the diagnostic and immunological significance of FLCK in relation to intrathecal IgM production and the measles-rubella-zoster-herpes (MRZH) antibody reaction across a broad neurological spectrum. We retrospectively analyzed paired CSF and serum samples from 240 patients showing evidence of intrathecal immune activity, defined by oligoclonal bands (OCB), MRZH positivity, or IgM intrathecal fraction (IF) ≥ 10%. Intrathecal synthesis of immunoglobulin classes and FLCK was quantified using Reiber's hyperbolic reference functions. Patients were classified into multiple sclerosis (MS), noninfectious inflammatory neurological disease (NI-IND), infectious neurological disease (IND), neurodegenerative disease (NDD), tumor disease (TUM), and other neurological disease (OND). FLCK intrathecal synthesis (IF ≥ 10%) was detected in 81.7% of patients, including 98% of MS cases. FLCK levels were significantly higher in inflammatory and infectious diseases compared with non-inflammatory conditions (p < 0.001). A subset of OCB-negative but FLCK-positive patients exhibited intrathecal IgM synthesis, suggesting that FLCK capture non-IgG immune responses. In infectious diseases, high FLCK IF correlated with IgM synthesis, whereas in MS and autoimmune disorders, additional immunoglobulin classes likely contributed. FLCK levels also paralleled MRZH reactivity and were highest in patients with multiple viral antibody indices, particularly measles. These findings position FLCK as a quantitative and broadly applicable marker of intrathecal immunoglobulin synthesis across diverse CNS pathologies. FLCK may extend diagnostic sensitivity beyond IgG-based assays and aid in the integrative evaluation of cerebrospinal fluid biomarkers. Prospective studies should evaluate their prognostic value and specificity across neuroinflammatory and infectious diseases.