Abstract
BackgroundIntrathecal immunoglobulin M (IgM) synthesis has been demonstrated in the early disease stages of multiple sclerosis (MS) as a predictor factor of a worsening disease course. Similarly, increased cerebrospinal fluid (CSF) molecules related to B-cell intrathecal activity have been associated with a more severe MS progression. However, whether CSF levels of IgM are linked to specific inflammatory and clinical profile in MS patients at the time of diagnosis remains to be elucidated.MethodsUsing customized Bio-Plex assay, the protein levels of IgG, IgA, IgM, and of 34 other inflammatory molecules, related to B-cell, T-cell, and monocyte/macrophage activity, were analyzed in the CSF of 103 newly diagnosed relapsing–remitting MS patients and 36 patients with other neurological disorders. CSF IgM levels were also correlated with clinical and neuroradiological measures [advanced 3-T magnetic resonance imaging (MRI) parameters], at diagnosis and after 2 years of follow-up.ResultsA 45.6% increase in CSF IgM levels was found in MS patients compared to controls (p = 0.013). CSF IgM levels correlated with higher CSF levels of CXCL13 (p = 0.039), CCL21 (p = 0.023), interleukin 10 (IL-10) (p = 0.025), IL-12p70 (p = 0.020), CX3CL1 (p = 0.036), and CHI3L1 (p = 0.048) and were associated with earlier age of patients at diagnosis (p = 0.008), white matter lesion (WML) number (p = 0.039) and disease activity (p = 0.033) after 2 years of follow-up.ConclusionIgMs are the immunoglobulins mostly expressed in the CSF of naive MS patients compared to other neurological conditions at the time of diagnosis. The association between increased CSF IgM levels and molecules related to both B-cell immunity (IL-10) and recruitment (CXCL13 and CCL21) and to macrophage/microglia activity (IL-12p70, CX3CL1, and CHI3L1) suggests possible correlation between humoral and innate intrathecal immunity in early disease stage. Furthermore, the association of IgM levels with WMLs and MS clinical and MRI activity after 2 years supports the idea of key role of IgM in the disease course.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease that affects the central nervous system (CNS)
The presence of colocalizing immunoglobulins and complement depositions in ongoing MS lesions (Genain et al, 1999) and studies demonstrating that antibodies isolated from the cerebrospinal fluid (CSF) of MS patients induce axonal damage and complement-mediated demyelination when applied to human CNS tissue ex vivo or in vitro (Elliott et al, 2012; Blauth et al, 2015), strongly support a key role of plasma cells and immunoglobulins, in MS pathology
We investigated whether immunoglobulin M (IgM) overexpression in the CSF of MS patients at diagnosis might be associated with a specific inflammatory intrathecal milieu, by analyzing other cytokine/chemokine CSF molecules related to either B cells or other immune cell pathways
Summary
Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease that affects the central nervous system (CNS). Increased CSF expression of similar inflammatory pattern related to B-cell immunity and lymphoid neogenesis was found associated with increased cortical lesion (CL) load, as revealed by advanced 3-T double inversion recovery magnetic resonance imaging (MRI) analysis, in MS patients at time of diagnosis (Magliozzi et al, 2018). These evidences support the hypothesis of complex intrathecal immune interactions and potential correlations between intrathecal antibody syntheses by plasma cells, B cells–related factors release innate immune activities, which occur since early disease stages (Magliozzi et al, 2019). Whether CSF levels of IgM are linked to specific inflammatory and clinical profile in MS patients at the time of diagnosis remains to be elucidated
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