Cerebrospinal fluid immunoglobulin light chain ratios predict disease progression in multiple sclerosis

Abstract

ObjectiveTo determine whether the ratio of cerebrospinal fluid (CSF) immunoglobulin kappa to lambda light chains at time of multiple sclerosis (MS) diagnosis predicts disease progression and whether this was intrinsic to CSF plasmablasts.MethodsCSF and peripheral blood were obtained from patients undergoing elective diagnostic lumbar puncture and included clinically isolated syndrome (CIS) (n=43), relapsing remitting MS (RRMS; n=50), primary progressive MS (PPMS; n=20) and other neurological disease controls, both inflammatory (ONID; n=23) and non-inflammatory (OND; n=114). CSF samples were assayed for free and immunoglobulin-associated light chains and on B cells and plasmablasts. Clinical follow-up data were collected during a 5-year follow-up period where available.ResultsThere was an increased median CSF κ:λ free light chain (FLC) in all MS groups (CIS: 18.2, 95% CI 6.8 to 30.3; RRMS: 4.4, 95% CI 2.7 to 11.4; PPMS: 12.0, 95% CI 3.6 to 37.1) but not controls (OND: 1.61, 95% CI 1.4 to 1.9; ONID: 1.7, 95% CI 1.3 to 2.2; p<0.001). This ratio predicted Expanded Disability Status Scores (EDSS) progression at 5 years, with a lower median EDSS in the group with high (>10) CSF κ:λ FLC (0.0, 95% CI 0 to 2.5 vs 2.5, 95% CI 0 to 4, high vs low; p=0.049). CSF κ:λ FLC correlated with CSF IgG1 κ:λ (r=0.776; p<0.0001) and was intrinsic to CSF plasmablasts (r=0.65; p=0.026).ConclusionsThese data demonstrate that CSF immunoglobulin κ:λ ratios, determined at the time of diagnostic lumbar puncture, predict MS disease progression and may therefore be useful prognostic markers for early therapeutic stratification.

Preservation of cerebrospinal fluid cells to investigate intrathecal immunity in neurodegeneration

“…CSF cells, on the other hand, provide a way to directly study immunology in the central nervous system. Indeed, recent studies of intrathecal immunity by us and others have shown this understudied immune compartment to be relevant to the pathobiology of neurodegenerative diseases (3,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Yet CSF cells have been widely understudied because of the invasive method of CSF extraction (typically lumbar puncture), and because cells are often discarded for proteomic analysis.…”

“…To our knowledge, only the multiple sclerosis field has rigorously evaluated live CSF cells (3,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), with sparse investigations in the context of AD (15,16), narcolepsy (17), Rasmussen encephalitis (18), and paraneoplastic cerebellar degeneration (19). Lueg et al report increased activation of CD4 + and CD8 + T cells in patients with AD and mild cognitive impairment (MCI) (16).…”

“…Most of the aforementioned studies have relied on freshy isolated CSF cells (3,5,6,(9)(10)(11)(12)(13)(14)(16)(17)(18)(19)(20), or merely extraction of genomic DNA or RNA from frozen cells (7,8). Analyzing fresh CSF cells provides the highest number of viable cells and the closest approximation of their endogenous physiology, but introduces batch effects and time restrictions.…”

Search for a prognostic biomarker in multiple sclerosis: a step in the right direction?

“…In the journal, Rathbone et al 1 provide further evidence to support the utility of the ratio of cerebrospinal fluid (CSF) immunoglobulin kappa to lambda free light chains (FLC κ:λ ratio), measured at diagnostic lumbar puncture (LP) at the time of CIS, in predicting multiple sclerosis (MS) disease progression out to 5 years post-CIS.…”

Oligoclonal IgG and free light chains – comparison between agarose and polyacrylamide isoelectric focusing

“…Tento test je používán vzácně vzhledem ke své větší pracnosti, zejména ve srovnání s novými automatizovanými kvantitativními metodami. U RS byla popsána také intratékální syntéza fLC typu lambda (free lambda light chains; fLLC) a přestože je nacházena vzácněji než intratékální syntéza IgG a fKLC [5, 7,8], recentní studie ukazují, že současná analýza fKLC a fLLC může mít prognostický význam [9][10][11].…”