BAFF Index and CXCL13 levels in the cerebrospinal fluid associate respectively with intrathecal IgG synthesis and cortical atrophy in multiple sclerosis at clinical onset

Abstract

Background: B lymphocytes are thought to play a relevant role in multiple sclerosis (MS) pathology. The in vivo analysis of intrathecally produced B cell-related cytokines may help to clarify the mechanisms of B cell recruitment and immunoglobulin production within the central nervous system (CNS) in MS. Methods: Paired cerebrospinal fluid (CSF) and serum specimens from 40 clinically isolated syndrome suggestive of MS or early-onset relapsing-remitting MS patients (CIS/eRRMS) and 17 healthy controls (HC) were analyzed for the intrathecal synthesis of IgG (quantitative formulae and IgG oligoclonal bands, IgGOB), CXCL13, BAFF, and IL-21. 3D-FLAIR, 3D-DIR, and 3D-T1 MRI sequences were applied to evaluate white matter (WM) and gray matter (GM) lesions and global cortical thickness (gCTh). Results: Compared to HC, CIS/eRRMS having IgGOB (IgGOB+, 26 patients) had higher intrathecal IgG indexes (p<0.01), lower values of BAFF Index (11.9±6.1 vs 17.5±5.2, p<0.01), and higher CSF CXCL13 levels (27.7±33.5 vs 0.9±1.5, p<0.005). In these patients, BAFF Index but not CSF CXCL13 levels inversely correlated with the intrathecal IgG synthesis (r>0.5 and p<0.05 for all correlations). CSF leukocyte counts were significantly higher in IgGOB+ compared to IgGOB- (p<0.05) and HC (p<0.01), and correlated to CSF CXCL13 concentrations (r 0.77, p<0.001). The gCTh was significantly lower in patients with higher CSF CXCL13 levels (2.41±0.1 vs 2.49±0.1mm, p<0.05), while no difference in MRI parameters of WM and GM pathology was observed between IgGOB+ and IgGOB-. Conclusions: The intrathecal IgG synthesis inversely correlated with BAFF Index and showed no correlation with CSF CXCL13. These findings seem to indicate that intrathecally synthesized IgG are produced by long-term PCs that have entered the CNS from the peripheral blood, rather than produced by PCs developed in the meningeal follicle-like structures (FLS). In this study, CXCL13 identifies a subgroup of MS patients characterized by higher leukocyte counts in the CSF and early evidence of cortical thinning, further suggesting a role for this chemokine as a possible marker of disease severity.