Cerebrospinal fluid kappa free light chains as biomarker in multiple sclerosis-from diagnosis to prediction of disease activity

Abstract

Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system that shows a high interindividual heterogeneity, which frequently poses challenges regarding diagnosis and prediction of disease activity. In this context, evidence of intrathecal inflammation provides an important information and might be captured by kappa free light chains (κ-FLC) in the cerebrospinal fluid (CSF). In this review, we provide an overview on what is currently known about κ‑FLC, its historical development, the available assays and current evidence on its diagnostic and prognostic value in MS. Briefly, intrathecal κ‑FLC synthesis reaches similar diagnostic accuracy compared to the well-established CSF-restricted oligoclonal bands (OCB) to identify patients with MS, and recent studies even depict its value for prediction of early MS disease activity. Furthermore, detection of κ‑FLC has significant methodological advantages in comparison to OCB detection.

Keywords: Clinically isolated syndrome; FLC index; Oligoclonal bands; Progression; Relapse.

Fig. 1

Schematic illustration of the molecular structure of immunoglobulins and free light chains. B cells produce (a) intact immunoglobulins and (b) in excess free light chains. Both immunoglobulins and FLC serve as biomarker for B cell activity. a Immunoglobulins consist of two identical heavy chains (blue) and two identical light chains (green). Each heavy chain consists of four immunoglobulin domains linked by a hinge region. Differences in the structure of the constant regions (C_H1, C_H2 and C_H3) determine the isotype (IgG, M, A, D, E) and subclass of the immunoglobulin (e.g., IgG1–4), while the variable domain (V_H) contributes to the antigen binding site. Each light chain consists of two immunoglobulin domains. Differences in the structure of the constant region (C_L) determine the isotype of free light chain (either κ or λ), while the variable domain (V_L) contributes to the antigen binding site. Accordingly, both the heavy chains and light chains form the amino-terminal variable (V) regions responsible for antigen recognition; the carboxyl-terminal constant (C) regions mediate effector functions. b Free light chains show the same structure as light chains bound within the intact immunoglobulin. FLC have a molecular weight of approximately 24 kD and consist of the two immunoglobulin domains C_L and V_L. Differences in the structure of the constant region (C_L) determine the isotype of the free light chain (either κ or λ). Whereas κ‑FLC mainly exist in the form of monomers, λ‑FLC are present as covalent dimers. C_H constant heavy chain domain, C_L constant light chain domain, Fab fragment antibody binding, Fc fragment crystallisable, FLC free light chain, V_H variable heavy chain domain, V_L variable light chain domain