Cerebrospinal Fluid IgM Levels in Association With Inflammatory Pathways in Multiple Sclerosis Patients

Abstract

Background: Intrathecal 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. Methods: Using 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. Results: A 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. Conclusion: IgMs 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.

Effects of Natalizumab Therapy on Intrathecal Immunoglobulin G Production Indicate Targeting of Plasmablasts

“…Details of the intrathecal Ig production in MS are useful for distinguishing MS from other neuroinflammatory diseases 1,4 and are of prognostic relevance: intrathecal IgM production is linked to conversion of clinically isolated syndrome to MS 21 and correlates with disease activity 22 ; in addition, intrathecal IgG production is associated with worsening. 23 Here, we present a comprehensive analysis of the effects of long-term NTZ therapy on different features of intrathecal Ig production and show that α4-integrin is expressed more highly on plasmablasts than on naive and memory B cells.…”

The survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5

“…B-cells activate and support the T-cell response through secretion of pro-inflammatory cytokines and were suggested to act as antigen-presenting cells (APC) 2 . In addition, autoantibodies against elements of the CNS are found in the cerebrospinal fluid (CSF) of MS patients 3 , 4 and serve as a biomarker for the disease 5 . These immunoglobulins (Ig) were shown to localize within lesions and near damaged myelin and were demonstrated, ex vivo and in vitro, to cause axonal damage by inducing complement-mediated tissue injury 3 , 6 .…”

Antibodies from serum and CSF of multiple sclerosis patients bind to oligodendroglial and neuronal cell-lines

“…Therefore, IgG (predominantly IgG1), and IgM are considered the major contributors to the OCB formation in the CSF. 26 , 27 Elevated intrathecal IgM synthesis has been associated with worse disease evolution. 27 The detection of IgM OCBs in CIS patients was associated with higher risks of conversion to clinically definite MS and in RRMS patients predicted a higher probability of converting to SPMS.…”