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.

Transition to secondary progression in relapsing-onset multiple sclerosis: Definitions and risk factors

2020 ◽  
pp. 135245852097436
Author(s):  
Pietro Iaffaldano ◽  
Giuseppe Lucisano ◽  
Francesco Patti ◽  
Vincenzo Brescia Morra ◽  
Giovanna De Luca ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Protective Factor ◽  
Cox Regression ◽  
Age At Onset ◽  
Progressive Multiple Sclerosis ◽  
Disease Modifying Therapy ◽  
Relapsing Remitting ◽  
Definition Of ◽  
Relapsing Remitting Multiple Sclerosis

Background: No uniform criteria for a sensitive identification of the transition from relapsing–remitting multiple sclerosis (MS) to secondary-progressive multiple sclerosis (SPMS) are available. Objective: To compare risk factors of SPMS using two definitions: one based on the neurologist judgment (ND) and an objective data-driven algorithm (DDA). Methods: Relapsing-onset MS patients ( n = 19,318) were extracted from the Italian MS Registry. Risk factors for SPMS and for reaching irreversible Expanded Disability Status Scale (EDSS) 6.0, after SP transition, were estimated using multivariable Cox regression models. Results: SPMS identified by the DDA ( n = 2343, 12.1%) were older, more disabled and with a faster progression to severe disability ( p < 0.0001), than those identified by the ND ( n = 3868, 20.0%). In both groups, the most consistent risk factors ( p < 0.05) for SPMS were a multifocal onset, an age at onset >40 years, higher baseline EDSS score and a higher number of relapses; the most consistent protective factor was the disease-modifying therapy (DMT) exposure. DMT exposure during SP did not impact the risk of reaching irreversible EDSS 6.0. Conclusion: A DDA definition of SPMS identifies more aggressive progressive patients. DMT exposure reduces the risk of SPMS conversion, but it does not prevent the disability accumulation after the SP transition.

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.

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 Predictors and Conversion Rate of Clinically Isolated Syndrome to Clinically Definite Multiple Sclerosis: A Follow-up Study in Patients Living in the Southern Part of Iran

2020 ◽  
Vol 6 (1) ◽  
pp. 9-15
Author(s):  
Sadegh Izadi ◽  
◽  
Meysam Ahmadi ◽  
Maryam Poursadeghfard ◽  
◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Conversion Rate ◽  
Regression Models ◽  
Cox Regression ◽  
Clinical Course ◽  
Clinically Isolated Syndrome ◽  
Definite Multiple Sclerosis ◽  
Clinically Definite Multiple Sclerosis ◽  
The Mean

Background: Clinical course of Clinically Isolated Syndrome (CIS) is variable, and identifying patients who will eventually develop Multiple Sclerosis (MS) is essential. Objectives: To assess the conversion rate of CIS to Clinically Definite Multiple Sclerosis (CDMS) and its predictors in southern Iran. Materials & Methods: A total of 143 CIS patients registered to Fars Multiple Sclerosis Society (FMSS) were enrolled in the study from 2006 until 2012, and all of them were followed for 5 years. Also, their demographic and MRI data were recorded. The obtained data were analyzed by univariate and multivariable Cox regression models in SPSS v. 17. P<0.05 was considered statistically significant. Results: About 26.6% of patients progressed to MS after a mean duration of 3.4±1.1 years. The conversion rate was 27.6% in patients presented with optic neuritis, and 25.6% in patients presented with spinal cord problems. Although it was not statistically significant (P=0.23), the mean age of the patients who converted to MS was lower at the onset of the presentation (27.6 vs. 29.4 years). In patients who had 3 or more MRI lesions, the conversion rate was 49.2%; however, it was only 9.8% in subjects who had fewer than 3 lesions (OR=8.95, 95% CI=3.69–21.7, P <0.001). Women had higher conversion rate though it was not statistically significant (OR=2.09, 95% CI=0.57–7.64, P=0.26). Conclusion: Our results supported this supposition that the number of MRI lesions at baseline can be used as a predictor of CIS conversion to MS.

scholarly journals Long-term worsening of different body functions in persons with progressive multiple sclerosis

2020 ◽  
Vol 6 (4) ◽  
pp. 205521732096451
Author(s):  
Marco Kaufmann ◽  
Claude Vaney ◽  
Laura Barin ◽  
Xinglu Liu ◽  
Viktor von Wyl
Keyword(s):  
Multiple Sclerosis ◽  
Cox Regression ◽  
Inpatient Rehabilitation ◽  
Progressive Multiple Sclerosis ◽  
Advanced Stage ◽  
Disability Progression ◽  
Mobility Index ◽  
Kaplan Meier ◽  
Valid Predictor

Background It is unclear whether EDSS is responsive to disability worsening in advanced MS. Objective To explore the dynamics of disability worsening in persons with advanced-stage MS (EDSS ≥5.5) using three disability worsening definitions (EDSS, Rivermead Mobility Index (RMI), 9-Hole Peg Test (9-HPT)). Methods EDSS-, RMI- and 9-HPT-based disability worsening were assessed over a minimum of two years in a cohort of 286 persons with advanced MS attending inpatient rehabilitation using Kaplan-Meier Curves and multivariable Cox regression. Furthermore, the correspondence between EDSS-, RMI- and 9-HPT-based disability worsening was analyzed. Results Disability progression was observed in 49% (9-HPT), 52% (EDSS) and 53% (RMI), with 9-HPT-based worsening slightly lagging behind. The Multiple Sclerosis Severity Score (MSSS) was the only consistent factor predicting disability worsening based on all three definitions (EDSS: hazard ratio 1.48 [1.30;1.68]; RMI: 1.12 [0.99;1.27]; 9-HPT: 1.36 [1.18;1.57]). Correspondence between EDSS and the other definitions (9-HPT and RMI) was 44.3% and 55.7% at time of EDSS progression and 65.1% and 72.5% overall, respectively. Conclusion In persons with advanced-stage MS, half still developed disability worsening in different functional systems over a median of 6 years. MSSS seems a valid predictor for disability worsening in all three outcome measures in advanced MS.

The relationship of age with the clinical phenotype in multiple sclerosis

2016 ◽  
Vol 22 (13) ◽  
pp. 1750-1758 ◽  
Author(s):  
A Scalfari ◽  
C Lederer ◽  
M Daumer ◽  
R Nicholas ◽  
GC Ebers ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Age At Onset ◽  
Phase Evolution ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Primary Progressive ◽  
Relapsing Remitting ◽  
Relationship Of ◽  
The Impact ◽  
The Relationship

Background: The multiple sclerosis (MS) clinical course and relapses frequency before progression vary widely. Objective: To investigate the influence of age on the MS phenotype. Methods: Among 751 primary progressive (PP = 217) and secondary progressive (SP = 534) MS patients from the London Ontario database, we assessed the relationship of age on the relapse frequency and on the progressive phase evolution, and the impact of relapses on the age at onset of progression. Results: Age at onset did not influence the early attacks frequency, but patients younger at onset had larger number of total attacks before progression (age = 27.4, 31.0 and 32.8 mean years; ⩾4, 2–3 and 1 relapses, respectively) and longer latency to SP. Although frequent early relapses predicted younger age at SP onset, patients with no attacks (primary progressive multiple sclerosis (PPMS)), or 1, 2–3 and ⩾4 relapses during the relapsing-remitting phase started progressing at similar age (38.6, 41.3, 41.4 and 39.2 mean years, respectively). The age at onset of progressive phase did not affect its evolution. Conclusions: Age strongly influences the phenotype before progression. Relapsing-remitting patients younger at onset are more likely to display a predominantly inflammatory course, yet relapses number does not affect the age at onset of progression.

scholarly journals Massive Restrain of Cytotoxic B cells in the Peripheral Blood During Fingolimod and Natalizumab Treatments in Multiple Sclerosis Patients

2020 ◽  
Author(s):  
Vinícius de Oliveira Boldrini ◽  
Raphael Patrício da Silva Quintiliano ◽  
Adriel dos Santos Moraes ◽  
Carla Stella ◽  
Ana Leda Figueiredo Longhini ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
T Lymphocytes ◽  
Peripheral Blood ◽  
Antibody Therapy ◽  
Healthy Donors ◽  
Relapsing Remitting ◽  
Anti Cd20 ◽  
Multiple Sclerosis Patients

Abstract Background Recently, the success of anti-CD20 monoclonal antibody therapy brought a new light over the role of B cells in multiple sclerosis (MS) pathogenesis. Due to the expression pattern of CD20 during B cells ontogeny, this role seems to be extended beyond the antibodies' production and secretion. Therefore, here we investigated whether not only classical cytotoxic CD8+ T lymphocytes but also non-classical cytotoxic B cells may occur in the peripheral blood from relapsing-remitting MS (RRMS) patients. Methods 104 RRMS patients during different treatment and 58 healthy donors were studied. CD19, GzmB, Runx3 and CD49d expression was assessed by flow cytometry analyses. Results Patients treated with Natalizumab (NTZ) showed an increased percentage of CD8+GzmB+ when compared to other MS therapies, untreated RRMS patients and healthy volunteers. Similarly, and unexpected, massive cytotoxic behavior of B cells CD19+GzmB+ was observed in RRMS patients during Fingolimod (FTY) and NTZ therapies when compared to Glatiramer, Interferonβ, untreated MS patients and healthy donors. Conclusions During different MS treatments, B cells exhibit cytotoxic behavior resembling CD8+ T lymphocytes. This data suggest a possible involvement of “cytotoxic” B cells during MS pathology. Monitoring cytotoxic subsets might become an available marker for the risk of relapses and even for accessing therapeutic effectiveness in MS patients.

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