Intrathecal K free light chain synthesis in multiple sclerosis at clinical onset associates with local IgG production and improves the diagnostic value of cerebrospinal fluid examination

Abstract

Background: The pathological significance and the diagnostic usefulness of intrathecal κ and λ free light chain (FLC) synthesis in Multiple Sclerosis (MS) are debated.

Methods: Paired cerebrospinal fluid (CSF) and serum specimens from 70 relapsing remitting MS (RRMS), 40 with and 30 without CSF restricted IgG Oligoclonal Band (IgGOB), and 37 from healthy controls (HC) were analyzed. IgG, IgM, κFLC and λFLC concentrations and indexes were evaluated. All RRMS performed MRI to estimate white and grey matter (WM) pathology.

Results: In HC, no intrathecal κ or λ FLC synthesis was found, and κFLC and λFLC Indexes were reciprocally correlated (r = 0.67, p < 0.001). In RRMS, intrathecal κFLC or λFLC synthesis was demonstrated in respectively 66% and 43% of the cases, the Q_κ/λ ratio was significantly higher compared to HC (17.0 ± 31.3 vs 0.79 ± 0.20, p < 0.001) and the correlation between κFLC Index and λFLC Index was weak (r:0.38, p < 0.05). Intrathecal IgG synthesis was associated with κFLC Index (IgG Index: r2 = 0.53, β = 0.73, p < 0.001; IgG_LOC: r² = 0.37, β = 0.61, p < 0.001; IgG_IF: r² = 0.69, β = 0.83, p < 0.001), but not with λFLC Index, while intrathecal IgM synthesis correlated with λFLC Index (IgM Index: r = 0.41, p < 0.001; IgM_LOC: r = 0.34, p < 0.005; IgM_IF: r = 0.45, p < 0.001), but not with κFLC Index. 26% of RRMS patients without CSF-restricted IgGOB had increased κFLC_LOC. Finally, no associations were observed between any CSF and MRI parameters.

Conclusions: The demonstration of intrathecal κFLC synthesis may further improve the diagnostic usefulness of CSF examination in RRMS. The marked increased in Q_κ/λ further suggests a deregulated B-cell activation in MS pathology.

Keywords: Intrathecal IgG synthesis; Kappa free light chains; Lambda free light chains; Multiple sclerosis.