Cannabinoids and B cells: emerging targets for treating progressive multiple sclerosis

2011 ◽  
Vol 17 (3) ◽  
pp. 259-261 ◽  
Author(s):  
Gavin Giovannoni
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Progressive Multiple Sclerosis

scholarly journals Systemic Inflammation in Progressive Multiple Sclerosis Involves Follicular T-Helper, Th17- and Activated B-Cells and Correlates with Progression

PLoS ONE ◽  
2013 ◽  
Vol 8 (3) ◽  
pp. e57820 ◽  
Author(s):  
Jeppe Romme Christensen ◽  
Lars Börnsen ◽  
Rikke Ratzer ◽  
Fredrik Piehl ◽  
Mohsen Khademi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Systemic Inflammation ◽  
Progressive Multiple Sclerosis ◽  
T Helper ◽  
Activated B Cells

scholarly journals The Role of B Cells in Primary Progressive Multiple Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jameson P. Holloman ◽  
Robert C. Axtell ◽  
Nancy L. Monson ◽  
Gregory F. Wu
Keyword(s):  
Multiple Sclerosis ◽  
Cell Differentiation ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cytokine Production ◽  
Progressive Multiple Sclerosis ◽  
T Cell Differentiation ◽  
Primary Progressive Multiple Sclerosis ◽  
Antibody Synthesis

The success of ocrelizumab in reducing confirmed disability accumulation in primary progressive multiple sclerosis (PPMS) via CD20-targeted depletion implicates B cells as causal agents in the pathogenesis of PPMS. This review explores the possible mechanisms by which B cells contribute to disease progression in PPMS, specifically exploring cytokine production, antigen presentation, and antibody synthesis. B cells may contribute to disease progression in PPMS through cytokine production, specifically GM-CSF and IL-6, which can drive naïve T-cell differentiation into pro-inflammatory Th1/Th17 cells. B cell production of the cytokine LT-α may induce follicular dendritic cell production of CXCL13 and lead indirectly to T and B cell infiltration into the CNS. In contrast, production of IL-10 by B cells likely induces an anti-inflammatory effect that may play a role in reducing neuroinflammation in PPMS. Therefore, reduced production of IL-10 may contribute to disease worsening. B cells are also capable of potent antigen presentation and may induce pro-inflammatory T-cell differentiation via cognate interactions. B cells may also contribute to disease activity via antibody synthesis, although it's unlikely the benefit of ocrelizumab in PPMS occurs via antibody decrement. Finally, various B cell subsets likely promulgate pro- or anti-inflammatory effects in MS.

scholarly journals B Cells in the CNS at Postmortem Are Associated With Worse Outcome and Cell Types in Multiple Sclerosis

2021 ◽  
Vol 9 (1) ◽  
pp. e1108
Author(s):  
Marcello Moccia ◽  
Lukas Haider ◽  
Arman Eshaghi ◽  
Steven Harry Pieter van de Pavert ◽  
Vincenzo Brescia Morra ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
T Lymphocytes ◽  
Regression Models ◽  
Cox Regression ◽  
Age At Onset ◽  
Brain Slices ◽  
Anion Channel ◽  
Progressive Multiple Sclerosis ◽  
Voltage Dependent Anion Channel

Background and ObjectivesTo define the clinical and pathologic correlations of compartmentalized perivascular B cells in postmortem progressive multiple sclerosis (MS) brains.MethodsBrain slices were acquired from 11 people with secondary progressive (SP) MS, 5 people with primary progressive (PP) MS, and 4 controls. Brain slices were immunostained for B lymphocytes (CD20), T lymphocytes (CD3), cytotoxic T lymphocytes (CD8), neuronal neurofilaments (NF200), myelin (SMI94), macrophages/microglia (CD68 and IBA1), astrocytes (glial fibrillary acidic protein [GFAP]), and mitochondria (voltage-dependent anion channel and cytochrome c oxidase subunit 4). Differences in CD20 immunostaining intensity between disease groups and associations between CD20 immunostaining intensity and both clinical variables and other immunostaining intensities were explored with linear mixed regression models and Cox regression models, as appropriate.ResultsCD20 immunostaining intensity was higher in PPMS (Coeff = 0.410; 95% confidence interval [CI] = 0.046, 0.774; p = 0.027) and SPMS (Coeff = 0.302; 95% CI = 0.020, 0.585; p = 0.036) compared with controls. CD20 immunostaining intensity was higher in cerebellar, spinal cord, and pyramidal onset (Coeff = 0.274; 95% CI = 0.039, 0.510; p = 0.022) compared with optic neuritis and sensory onset. Higher CD20 immunostaining intensity was associated with younger age at onset (hazard ratio [HR] = 1.033; 95% CI = 1.013, 1.053; p = 0.001), SP conversion (HR = 1.056; 95% CI = 1.022, 1.091; p = 0.001), wheelchair dependence (HR = 1.472; 95% CI = 1.108, 1.954; p = 0.008), and death (HR = 1.684; 95% CI = 1.238, 2.291; p = 0.001). Higher immunostaining intensity for CD20 was associated with higher immunostaining intensity for CD3 (Coeff = 0.114; 95% CI = 0.005, 0.224; p = 0.040), CD8 (Coeff = 0.275; 95% CI = 0.200, 0.350; p < 0.001), CD68 (Coeff = 0.084; 95% CI = 0.023, 0.144; p = 0.006), GFAP (Coeff = 0.002; 95% CI = 0.001, 0.004; p = 0.030), and damaged mitochondria (Coeff = 3.902; 95% CI = 0.891, 6.914; p = 0.011).DiscussionPerivascular B cells were associated with worse clinical outcomes and CNS-compartmentalized inflammation. Our findings further support the concept of targeting compartmentalized B-cell inflammation in progressive MS.

Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration

2013 ◽  
Vol 20 (3) ◽  
pp. 304-312 ◽  
Author(s):  
Silvia Rossi ◽  
Caterina Motta ◽  
Valeria Studer ◽  
Francesca Barbieri ◽  
Fabio Buttari ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Neuronal Damage ◽  
Brain Slices ◽  
Progressive Multiple Sclerosis ◽  
Cell Swelling ◽  
Necrosis Factor

Background: Chronic inflammation leads to gray matter damage in progressive multiple sclerosis (MS), but the mechanism linking inflammation and neurodegeneration is unclear. Objective: The objective of this paper is to investigate the synaptic mechanism of inflammatory neurodegeneration in progressive forms of MS. Methods: Cytokine and neurofilament-light were determined in cerebrospinal fluid (CSF) of MS patients. In vitro electrophysiology and cell swelling experiments were performed to measure the effects of inflammatory cytokines in the CSF of MS patients on synaptic transmission and neuronal integrity. Results: Tumor necrosis factor-α (TNF) was higher in CSF of progressive MS subjects, and caused excitotoxic neuronal death in vitro. In murine brain slices incubated in the presence of CSF from progressive MS, in fact, we observed increased spontaneous excitatory postsynaptic currents (sEPSCs) and glutamate-mediated neuronal swelling through a mechanism dependent on enhanced TNF signaling. We also suggested a pathogenic role of B cells in TNF CSF increase, exacerbation of glutamatergic transmission and neuronal damage, since CNS depletion of B cells with intrathecal rituximab caused a dramatic reduction of TNF levels, of TNF-induced sEPSC alterations, and of neurofilament CSF concentrations in a patient with progressive MS. Conclusion: Our results point to TNF as a primary neurotoxic molecule in progressive forms of MS.

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