Peripheral Regulatory B Cell Phenotype in Multiple Sclerosis Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4843-4843 ◽  
Author(s):  
Jakob Habib ◽  
Jiusheng Deng ◽  
Andrea Pennati ◽  
Neil Lava ◽  
Jacques Galipeau
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Disease Process ◽  
Cell Number ◽  
Intermediate Phenotype ◽  
Cell Phenotype ◽  
Regulatory B Cell ◽  
Multiple Sclerosis Patients

Abstract Abstract 4843 Regulatory B cells (Bregs) are a unique CD5+/CD1d+/IL10+ B cell subtype which has novel immunosuppressive capabilities. It remains to be determined if subjects suffering from autoimmune ailments such as multiple sclerosis (MS) display a defect in number or function of Bregs in association with their disease. Our hypothesis is that total B cell number, and Breg subset in particular, is distinct when comparing peripheral blood B cell populations from MS to healthy controls (HC). This study herein focuses on establishing a phenotypic baseline of the peripheral B cell profile. The total number of CD19+ B cells in HC is 892±816 cells/μL (average ±SD, n=28), of which CD5+/CD1d+ Breg subset is 4.6±5.6 cells/μL. We found a greater number of B cells in MS subjects, 1441±1011 cells/μL (n=22, p<0.05, Student's t-test). However, the number of Bregs in MS patients is not significantly different from HC, 7.5±7.6 cells/μL (p=0.13). We further interrogated the phenotype of B cells in MS subjects and found that there is an increased number of CD27−IgD+ naïve/intermediate phenotype in MS, 1041±794 cells/μL, versus HC, 624±606 cells/μL (p<0.05). Our findings demonstrate that MS is not associated with a deficiency in the absolute number of CD5+/CD1d+ Bregs but rather a 60% increase in CD27−IgD+ B cells. We hypothesize that altered B cell distribution may be functionally associated to the underlying immune disease process of MS. This finding may inform the design of clinical trials examining B cell depletion strategies for treatment of MS. Disclosures: No relevant conflicts of interest to declare.

Contribution of Deregulated miRNAs to the Phenotypic Characteristic of Hodgkin Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 265-265
Author(s):  
Lu Ping Tan ◽  
Bart-Jan Kroesen ◽  
Enrico Tiacci ◽  
Gerben Duns ◽  
Erwin Seinen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Mirna Expression ◽  
Conflicts Of Interest ◽  
System Development ◽  
Cell Phenotype ◽  
Immune System Development

Abstract Abstract 265 In Hodgkin Lymphoma (HL), the Hodgkin Reed-Sternberg (HRS) cells are a minority of large mono- or multi-nucleated B cells characterized by a loss of B cell phenotype, constitutive NF-kB activation, a disturbed cell cycle and anti-apoptotic features. In this study we investigated the role of deregulated miRNA expression in the pathogenesis of HL. MiRNA in situ hybridization (ISH) in HL tissue was performed to determine expression of miRNAs previously reported to be highly abundant in HL cell lines, in HRS cells. Next we identified the miRNA-targetome of two HL cell lines by immunoprecipitation of RISC in untransfected and transfected cell lines. miRNA ISH confirmed expression of miR-17-5p, miR-24, miR-106a, miR-146a, miR-150, miR-155, miR-181b and miR-210 in HRS cells. Ago2-immunoprecipitation followed by microarray analysis of the co-immunoprecipitated mRNA revealed that the miRNA-targetome of HL comprises of about 2,500 genes. Inhibition of the anti-miR-17 seed family revealed that about 500 of these genes are regulated by miRNAs of the miR-17 seed family. Gene ontology (GO) analysis for the total miRNA-targetome of HL showed a significant enrichment of genes involved in the regulation of cell cycle, apoptosis, immune system development and NF-kB cascade. The miRNA-targetome of HL contained several genes known to be mutated in HRS cells, including A20, FAS, NFKB1A, NFKB1E, PERP and SOCS1. Also, using previously reported gene expression data, we defined a set of genes downregulated in HL cell lines (L428 and L1236) compared to germinal center B cells (GCB) and compared them to the miRNA-targetome of the same cell lines. This resulted in the identification of 149 genes in L428 and 183 genes in L1236 that were subjected to miRNA mediated repression. Unexpectedly, only a few of all the reported inactivated genes in HRS cells that might contribute to loss of B cell phenotype (MYBL1 and CXCR4) were found to be regulated by miRNAs in HL. In conclusion, we confirmed the expression of miRNAs in the HRS cells of HL tissue and identified miRNA repressed genes in HL. Our data indicated that aberrant miRNA expression contributes to the deregulation of apoptosis, cell cycle, and NF-kB pathways but not loss of B cell phenotype in HL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis

2020 ◽  
Vol 117 (37) ◽  
pp. 22932-22943 ◽  
Author(s):  
Akshaya Ramesh ◽  
Ryan D. Schubert ◽  
Ariele L. Greenfield ◽  
Ravi Dandekar ◽  
Rita Loudermilk ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Chemokine Receptors ◽  
Plasma Cells ◽  
Cholesterol Biosynthesis ◽  
Memory B Cells ◽  
Cell Phenotype

Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood–brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein–Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.

Fingolimod treatment promotes regulatory B-cell phenotype and function in multiple sclerosis

2014 ◽  
Vol 275 (1-2) ◽  
pp. 42-43
Author(s):  
Berit Grützke ◽  
Stephanie Hucke ◽  
Brigitte Wildemann ◽  
Thomas Dehmel ◽  
Bernd Kieseier ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cell ◽  
Cell Phenotype ◽  
Regulatory B Cell ◽  
And Function

Thymosin-α1 expands deficient IL-10-producing regulatory B cell subsets in relapsing–remitting multiple sclerosis patients

2017 ◽  
Vol 24 (2) ◽  
pp. 127-139 ◽  
Author(s):  
Elena Giacomini ◽  
Fabiana Rizzo ◽  
Marilena P Etna ◽  
Melania Cruciani ◽  
Rosella Mechelli ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Cell Response ◽  
Thymosin Α1 ◽  
Regulatory B Cell ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
B Cell Subsets ◽  
Relapsing Remitting Multiple Sclerosis

Background: B cells are key pathogenic effectors in multiple sclerosis (MS) and several therapies have been designed to restrain B cell abnormalities by directly targeting this lymphocyte population. Objectives: Moving from our data showing a Toll-like receptor (TLR)7-driven dysregulation of B cell response in relapsing–remitting multiple sclerosis (RRMS) and having found a low serum level of Thymosin-α1 (Tα1) in patients, we investigated whether the addition of this molecule to peripheral blood mononuclear cells (PBMCs) would influence the expansion of regulatory B cell subsets, known to dampen autoimmune inflammation. Methods: Serum Tα1 level was measured by enzyme immunoassay. Cytokine expression was evaluated by Cytometric Bead Array (CBA), enzyme-linked immunosorbent assay (ELISA), and real-time reverse transcription polymerase chain reaction (RT-PCR). B cell subsets were analyzed by flow cytometry. Results: Tα1 pre-treatment induces an anti-inflammatory status in TLR7-stimulated RRMS PBMC cultures, reducing the secretion of pro-inflammatory interleukin (IL)-6, IL-8, and IL-1β while significantly increasing the regulatory IL-10 and IL-35. Indeed, Tα1 treatment enhanced expansion of CD19+CD24+CD38hi transitional-immature and CD24low/negCD38hi plasmablast-like regulatory B cell subsets, which likely inhibit both interferon (IFN)-γ and IL-17 production. Conclusion:: Our study reveals a deficient ability of B cells from MS patients to differentiate into regulatory subsets and unveils a novel anti-inflammatory and repurposing potential for Tα1 in MS targeting B cell response.

scholarly journals Natalizumab promotes activation and pro-inflammatory differentiation of peripheral B cells in multiple sclerosis patients

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Jan W. Traub ◽  
Hannah L. Pellkofer ◽  
Katja Grondey ◽  
Ira Seeger ◽  
Christoph Rowold ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Cell Function ◽  
Ethical Review ◽  
Multiple Sclerosis Patients ◽  
Peripheral B Cells

Abstract Background In the past, multiple sclerosis (MS) medications have been primarily designed to modulate T cell properties. Based on the emerging concept that B cells are equally important for the propagation of MS, we compared the effect of four commonly used, primarily T cell-targeting MS medications on B cells. Methods Using flow cytometry, we analyzed peripheral blood mononuclear cells (PBMC) of untreated (n = 19) and dimethyl fumarate (DMF; n = 21)-, fingolimod (FTY; n = 17)-, glatiramer acetate (GA; n = 18)-, and natalizumab (NAT; n = 20)-treated MS patients, focusing on B cell maturation, differentiation, and cytokine production. Results While GA exerted minor effects on the investigated B cell properties, DMF and FTY robustly inhibited pro-inflammatory B cell function. In contrast, NAT treatment enhanced B cell differentiation, activation, and pro-inflammatory cytokine production when compared to both intraindividual samples collected before NAT treatment initiation as well as untreated MS controls. Our mechanistic in vitro studies confirm this observation. Conclusion Our data indicate that common MS medications have differential, in part opposing effects on B cells. The observed activation of peripheral B cells upon NAT treatment may be instructive to interpret its unfavorable effect in certain B cell-mediated inflammatory conditions and to elucidate the immunological basis of MS relapses after NAT withdrawal. Trial registration Protocols were approved by the ethical review committee of the University Medical Center Göttingen (#3/4/14).

scholarly journals Fingolimod alters intrathecal B cell maturation in multiple sclerosis patients

2020 ◽  
Author(s):  
Markus C. Kowarik ◽  
David Astling ◽  
Gildas Lepennetier ◽  
Alanna Ritchie ◽  
Bernhard Hemmer ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Clonal Expansion ◽  
Cell Maturation ◽  
Lymphocyte Migration ◽  
B Cell Maturation ◽  
Natalizumab Treatment ◽  
Multiple Sclerosis Patients

Abstract Background: B cells are postulated to play multiple roles in the pathogenesis of multiple sclerosis (MS) including pathogenic antibody production, antigen-presentation and pro-inflammatory cytokine secretion. Natalizumab and fingolimod are effective MS therapies that disrupt lymphocyte migration but exert differential effects on B cell maturation and trafficking. Herein, we investigated their effects on peripheral blood and cerebrospinal fluid (CSF) B cell repertoires.Methods: Paired CSF and peripheral blood (PB) lymphocytes were collected from MS patients at baseline and after 6 months of treatment with fingolimod (n = 4) or natalizumab (n = 4). B cell subsets including naïve, CD27+ memory, CD27-IgD- double-negative B cells and plasmablasts were collected by FACS and their respective heavy-chain variable region (VH) repertoires assessed by next generation deep sequencing (Illumina MiSeq).Results: Treatment with fingolimod lead to a distinct contraction of the PB B cell pool whereas natalizumab resulted in an expansion of circulating PB B cells. In contrast, CSF B cell numbers remained stable under treatment with fingolimod but decreased following natalizumab therapy. Clonal overlap between CSF and peripheral blood B cells was reduced following natalizumab treatment (-24% reduction of clonal groups) but remained stable with fingolimod therapy. Lineage analyses of CSF B cell repertoires at baseline and following therapy revealed large, clonally expanded B cell clusters in natalizumab-treated MS patients but no intrathecal clonal expansion following fingolimod therapy. Conclusions: Our findings suggest that natalizumab treatment diminishes the exchange of peripheral and intrathecal B cells but does not impact intrathecal clonal expansion. In contrast, fingolimod treatment fails to alter B cell exchange across the blood-brain-barrier but affects intrathecal clonal expansion. Sphingosine-1 phosphate receptor inhibition may impact MS disease progression by inhibiting intrathecal germinal center activity.

Impaired regulatory function and enhanced intrathecal activation of B cells in neuromyelitis optica: distinct from multiple sclerosis

2012 ◽  
Vol 19 (3) ◽  
pp. 289-298 ◽  
Author(s):  
Chao Quan ◽  
Hai Yu ◽  
Jian Qiao ◽  
Baoguo Xiao ◽  
Guixian Zhao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Neuromyelitis Optica ◽  
Regulatory Function ◽  
Enzyme Linked Immunosorbent Assay ◽  
Regulatory B Cell ◽  
Late Antigen ◽  
Csf Levels ◽  
Cell Expression

Background: The effective treatment of neuromyelitis optica (NMO) with rituximab has suggested an important role for B cells in NMO pathogenesis. Objective: To explore the antibody-independent function of B cells in NMO and relapsing–remitting multiple sclerosis (RRMS). Methods: Fifty-one NMO patients and 42 RRMS patients in an acute relapse phase and 37 healthy controls (HC) were enrolled in the study. The B cell expression of B cell activating factor receptor (BAFF-R), CXCR5 and very late antigen-4 (VLA-4), the B cell production of interleukin (IL)-10 and interferon (IFN)-γ and the proportion of circulating memory and CD19+CD24highCD38high regulatory B cells were evaluated by flow cytometry. The cerebrospinal fluid (CSF) levels of BAFF and CXCL13 were determined by enzyme-linked immunosorbent assay (ELISA). Results: The CD19+CD24highCD38high regulatory B cell levels and the B cell expression of IL-10 were significantly lower in NMO patients than in RRMS patients and the HC. In aquaporin-4 antibody (AQP4-ab)-positive NMO patients, the B cell IL-10 production and CD19+CD24highCD38high regulatory B cell levels were even lower than in AQP4-ab-negative NMO patients. The CSF BAFF and CXCL13 levels were significantly higher in NMO patients than in patients with RRMS and other non-inflammatory neurologic diseases (ONDs). Conclusions: The immuno-regulatory properties of B cells are significantly impaired in NMO patients and particularly in AQP4-ab-positive NMO patients. The elevated CSF levels of BAFF and CXCL13 in NMO suggest an enhanced intrathecal B cell recruitment and activation. Our results further define the distinct immunological nature of NMO and RRMS from the B cell perspective.

scholarly journals Autoantibodies against central nervous system antigens in a subset of B cell–dominant multiple sclerosis patients

2020 ◽  
Vol 117 (35) ◽  
pp. 21512-21518 ◽  
Author(s):  
Stefanie Kuerten ◽  
Tobias V. Lanz ◽  
Nithya Lingampalli ◽  
Lauren J. Lahey ◽  
Christoph Kleinschnitz ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
B Cells ◽  
B Cell ◽  
Predictive Biomarker ◽  
Successful Outcome ◽  
Highly Active ◽  
The Central Nervous System ◽  
Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), with characteristic inflammatory lesions and demyelination. The clinical benefit of cell-depleting therapies targeting CD20 has emphasized the role of B cells and autoantibodies in MS pathogenesis. We previously introduced an enzyme-linked immunospot spot (ELISpot)-based assay to measure CNS antigen-specific B cells in the blood of MS patients and demonstrated its usefulness as a predictive biomarker for disease activity in measuring the successful outcome of disease-modifying therapies (DMTs). Here we used a planar protein array to investigate CNS-reactive antibodies in the serum of MS patients as well as in B cell culture supernatants after polyclonal stimulation. Anti-CNS antibody reactivity was evident in the sera of the MS cohort, and the antibodies bound a heterogeneous set of molecules, including myelin, axonal cytoskeleton, and ion channel antigens, in individual patients. Immunoglobulin reactivity in supernatants of stimulated B cells was directed against a broad range of CNS antigens. A group of MS patients with a highly active B cell component was identified by the ELISpot assay. Those antibody reactivities remained stable over time. These assays with protein arrays identify MS patients with a highly active B cell population with antibodies directed against a swathe of CNS proteins.

scholarly journals Memory B Cells in Multiple Sclerosis: Emerging Players in Disease Pathogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Krista D. DiSano ◽  
Francesca Gilli ◽  
Andrew R. Pachner
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Antigen Presentation ◽  
Cytokine Production ◽  
Memory B Cells ◽  
Cell Phenotype ◽  
Effector Functions ◽  
Immunomodulatory Therapies ◽  
Antibody Secreting Cells

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Once thought to be primarily driven by T cells, B cells are emerging as central players in MS immunopathogenesis. Interest in multiple B cell phenotypes in MS expanded following the efficacy of B cell-depleting agents targeting CD20 in relapsing-remitting MS and inflammatory primary progressive MS patients. Interestingly, these therapies primarily target non-antibody secreting cells. Emerging studies seek to explore B cell functions beyond antibody-mediated roles, including cytokine production, antigen presentation, and ectopic follicle-like aggregate formation. Importantly, memory B cells (Bmem) are rising as a key B cell phenotype to investigate in MS due to their antigen-experience, increased lifespan, and rapid response to stimulation. Bmem display diverse effector functions including cytokine production, antigen presentation, and serving as antigen-experienced precursors to antibody-secreting cells. In this review, we explore the cellular and molecular processes involved in Bmem development, Bmem phenotypes, and effector functions. We then examine how these concepts may be applied to the potential role(s) of Bmem in MS pathogenesis. We investigate Bmem both within the periphery and inside the CNS compartment, focusing on Bmem phenotypes and proposed functions in MS and its animal models. Finally, we review how current immunomodulatory therapies, including B cell-directed therapies and other immunomodulatory therapies, modify Bmem and how this knowledge may be harnessed to direct therapeutic strategies in MS.

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