B-cell populations discriminate between pediatric- and adult-onset multiple sclerosis

Abstract

Objective:To comparatively assess the B-cell composition in blood and CSF of patients with pediatric-onset multiple sclerosis (pedMS) and adult-onset multiple sclerosis (adMS).Methods:In this cross-sectional study, we obtained blood and CSF samples from 25 patients with pedMS (8–18 years) and 40 patients with adMS (23–65 years) and blood specimens from 66 controls (1–55 years). By using multicolor flow cytometry, we identified naive, transitional, isotype class-switched memory, nonswitched memory, and double-negative memory B-cell subsets as well as plasmablasts (PB) and terminally differentiated plasma cells (PC). Flow cytometric data were compared to concentrations of B-cell-specific cytokines in serum and CSF as determined by ELISA.Results:Frequencies of circulating naive B-cells decreased with higher age in controls but not in patients with multiple sclerosis (MS). B-cell patterns in CSF differed between pedMS and adMS with an acute relapse: in pedMS-derived CSF samples, high frequencies of nonswitched memory B cells and PB were present, whereas class-switched memory B cells and PC dominated in the CSF of patients with adMS. In pedMS, PB were also elevated in the periphery. Accumulation of PB in the CSF correlated with high intrathecal CXCL-13 levels and augmented intrathecal synthesis of immunoglobulin G and immunoglobulin M.Conclusions:We demonstrate distinct changes in intrathecal B-cell homeostasis in patients with pedMS during active disease, which differ from those in adults by an expansion of plasmablasts in blood and CSF and similarly occur in prototypic autoantibody-driven autoimmune disorders. This emphasizes the particular importance of activated B-lymphocyte subsets for disease progression in the earliest clinical stages of MS.

Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells

“…Therefore, cladribine may control MS via an action on both T and B lymphocytes, notably as T cell activities are integrally involved in B cell function. However, the importance of memory B cells is consistent with the potential genetic and infectious aetiology of MS [ 36 ]; the pathology that is associated with memory B cell accumulation during attacks [ 27 , 37 ], the generation of nerve and oligodendrocyte cytotoxic molecules and ectopic B cell follicle formation [ 4 , 27 , 38 ]; and importantly the response to effective DMT [ 4 ]. Epstein Barr Virus is believed to be an aetiological trigger of MS and drives the production of memory B cells, which may become relatively T cell-independent, and perhaps more autoimmune prone, due to B the antigen receptor and CD40-signalling mimics created by the virus [ 36 , 39 ].…”

Promise, Progress, and Pitfalls in the Search for Central Nervous System Biomarkers in Neuroimmunological Diseases: A Role for Cerebrospinal Fluid Immunophenotyping

“…28,73–76 Although there were no data from adults with NMO, AE, or NPSLE in adults, there were case reports of increased CSF B cell percentage for each disorder in pediatric-onset counterparts. 77–79 One adult with PCD paraneoplastic syndrome exhibited elevated CSF B cell frequency, though the T cell abnormalities were the focus of the report.…”

“…Flow cytometric CSF immunophenotyping has been used successful in the analysis of pediatric-onset neuroinflammatory disorders. 28,73,76,81,84,90 The need for it stems from concern that different developmental stages of the pediatric immune system (and the brain) and what impact they may have on the appropriateness of treatment decisions. Although lumbar puncture in healthy children is not considered ethical, several sources of non-inflammatory neurological disorders (NIND) are used for comparisons.…”

“…In contrast, the frequency and absolute counts of peripheral blood mononuclear cells (PBMN) changes so dramatically over time 91,92 as to complicate the search for immunologic biomarkers. CSF immunophenotyping has revealed that B cell populations discriminate between pediatric- and adult-onset MS. 76 …”

Safety and efficacy of rituximab in multiple sclerosis: A retrospective observational study

“…There is increasing evidence that B cells and humoral immunity play a key role in the pathogenesis of multiple sclerosis (MS) [1]. Rituximab is an anti-CD 20 chimeric monoclonal antibody that effectively depletes circulating B cells [2].…”