scholarly journals Characterization of Definitive Regulatory B Cell Subsets by Cell Surface Phenotype, Function and Context

2021 ◽  
Vol 12 ◽  
Author(s):  
Savannah D. Neu ◽  
Bonnie N. Dittel
Keyword(s):  
B Cells ◽  
B Cell ◽  
Clinical Settings ◽  
Autoimmune Encephalomyelitis ◽  
Regulatory B Cell ◽  
Broad Term ◽  
B Cell Subsets ◽  
Experimental Autoimmune ◽  
Identification Strategy

Regulatory B cell or “Breg” is a broad term that represents the anti-inflammatory activity of B cells, but does not describe their individual phenotypes, specific mechanisms of regulation or relevant disease contexts. Thus, given the variety of B cell regulatory mechanisms reported in human disease and their animal models, a more thorough and comprehensive identification strategy is needed for tracking and comparing B cell subsets between research groups and in clinical settings. This review summarizes the discovery process and mechanism of action for well-defined regulatory B cell subsets with an emphasis on the mouse model of multiple sclerosis experimental autoimmune encephalomyelitis. We discuss the importance of conducting thorough B cell phenotyping along with mechanistic studies prior to defining a particular subset of B cells as Breg. Since virtually all B cell subsets can exert regulatory activity, it is timely for their definitive identification across studies.

scholarly journals Multiple Functions of B Cells in the Pathogenesis of Systemic Lupus Erythematosus

2019 ◽  
Vol 20 (23) ◽  
pp. 6021 ◽  
Author(s):  
Kongyang Ma ◽  
Wenhan Du ◽  
Xiaohui Wang ◽  
Shiwen Yuan ◽  
Xiaoyan Cai ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Therapeutic Interventions ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Regulatory B Cell ◽  
Functional Features ◽  
B Cell Subsets

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by excessive autoantibody production and multi-organ involvement. Although the etiology of SLE still remains unclear, recent studies have characterized several pathogenic B cell subsets and regulatory B cell subsets involved in the pathogenesis of SLE. Among pathogenic B cell subsets, age-associated B cells (ABCs) are a newly identified subset of autoreactive B cells with T-bet-dependent transcriptional programs and unique functional features in SLE. Accumulation of T-bet+ CD11c+ ABCs has been observed in SLE patients and lupus mouse models. In addition, innate-like B cells with the autoreactive B cell receptor (BCR) expression and long-lived plasma cells with persistent autoantibody production contribute to the development of SLE. Moreover, several regulatory B cell subsets with immune suppressive functions have been identified, while the impaired inhibitory effects of regulatory B cells have been indicated in SLE. Thus, further elucidation on the functional features of B cell subsets will provide new insights in understanding lupus pathogenesis and lead to novel therapeutic interventions in the treatment of SLE.

scholarly journals Experimental Autoimmune Encephalomyelitis Induction in Genetically B Cell–deficient Mice

1996 ◽  
Vol 184 (6) ◽  
pp. 2271-2278 ◽  
Author(s):  
Susan D. Wolf ◽  
Bonnie N. Dittel ◽  
Fridrika Hardardottir ◽  
Charles A. Janeway
Keyword(s):  
T Cells ◽  
B Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
B Cell ◽  
Immune Modulation ◽  
Disease Onset ◽  
Central Nervous System Disease ◽  
Autoimmune Encephalomyelitis ◽  
Deficient Mice ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is an animal model for autoimmune central nervous system disease mediated by CD4 T cells. To examine the role of B cells in the induction of EAE, we used B10.PL (I-Au) mice rendered deficient in B cells by deletion of their μ chain transmembrane region (B10.PLμMT). By immunizing B10.PL and B10.PLμMT mice with the NH-terminal myelin basic protein encephalitogenic peptide Ac1-11, we observed no difference in the onset or severity of disease in the absence of mature B cells. There was, however, a greater variation in disease onset, severity, and especially of recovery in the B cell–deficient mice compared to controls. B10.PLμMT mice rarely returned to normal in the absence of B cells. Taken together, our data suggest that B cells do not play a role in the activation of encephalitogenic T cells, but may contribute to the immune modulation of acute EAE. The mechanisms to explain these effects are discussed.

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 B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells

2012 ◽  
Vol 209 (5) ◽  
pp. 1001-1010 ◽  
Author(s):  
Tom A. Barr ◽  
Ping Shen ◽  
Sheila Brown ◽  
Vicky Lampropoulou ◽  
Toralf Roch ◽  
...  
Keyword(s):  
B Cells ◽  
Autoimmune Disease ◽  
B Cell ◽  
Severe Disease ◽  
Cell Depletion ◽  
Protective Effects ◽  
B Cell Depletion ◽  
Autoimmune Encephalomyelitis ◽  
Major Mechanism ◽  
Experimental Autoimmune

B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6–secreting pathogenic B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell–specific IL-6 deficiency showed less severe disease than mice with wild-type B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6–sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6–producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell–driven pathogenesis in T cell–mediated autoimmune disease such as EAE and MS.

scholarly journals B cell-mediated immunomodulation by S-nitrosoglutathione (GSNO) in experimental autoimmune encephalomyelitis

2020 ◽  
Author(s):  
Judong Kim ◽  
S.M. Touhidul Islam ◽  
Jeseong Won ◽  
Avtar K. Singh ◽  
Inderjit Singh
Keyword(s):  
B Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
B Cell ◽  
Cell Function ◽  
Autoimmune Encephalomyelitis ◽  
Immune Balance ◽  
Eae Model ◽  
Experimental Autoimmune

Abstract Background Experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal model for human multiple sclerosis (MS), a demyelinating autoimmune disease mediated by T and B lymphocytes. The aim of the present study was to investigate the role of S-nitrosoglutathione (GSNO), a physiological nitric oxide carrier molecule, in regulation of effector or regulatory B cell function as IL-6 and IL-10 expressions and thus the potential role of GSNO in targeting B cell-mediated immunopathogenesis in MS using EAE model. Methods To this purpose, the in vivo EAE mouse model, generated by immunization with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide, or in vitro model of cultured B cells stimulated with lipopolysaccharide or anti-IgM antibody were treated with exogenous GSNO or N6022, an inhibitor of GSNO reductase (GSNOR; GSNO degrading enzyme) to increase endogenous GSNO, and then analyzed for B cell specific IL-6 and IL-10 expression. Results In EAE model, administration of exogenous GSNO or inhibition of endogenous GSNO catabolism by N6022 treatment ameliorated the clinical disease with decreased CNS infiltration of B cells. In addition, GSNO/N6022 treatments increased the number of IL-10+ B cells but decreased the number of IL-6+ B cells in the CNS and spleen. Accordingly, GSNO/N6022 treatments increased the expression of IL-10 while reducing the IL-6 expression in the blood. Similar observations were also made in in vitro B cell culture model where GSNO treatment increased the IL-10+ B cells but decreased the IL-6+ B cells under BCR or TLR4 stimulatory conditions and under CD40 and BAFF co-stimulatory conditions. Accordingly, GSNO treatment increased the B cell production of IL-10 but reduced the IL-6 production under both stimulatory and co-stimulatory conditions. In vitro stimulation and co-stimulation of cultured naïve B cells increased two major distinct B cell populations; CD1dlow CD5high and CD1dhigh CD5high. In both populations, GSNO treatment increased the number of IL-10+ cells but decreased the IL-6+ cells. Conclusion These data document, for the first time, that cellular GSNO homeostasis is a critical target for the regulation of IL-10+ B cells vs. IL-6+ B cells mediated immune balance under auto-immune disease conditions.

scholarly journals Cnp Promoter-Driven Sustained ERK1/2 Activation Increases B-Cell Activation and Suppresses Experimental Autoimmune Encephalomyelitis

ASN NEURO ◽  
2020 ◽  
Vol 12 ◽  
pp. 175909142097191
Author(s):  
Marisa A. Jeffries ◽  
Alison E. Obr ◽  
Kelly Urbanek ◽  
Sharyl L. Fyffe-Maricich ◽  
Teresa L. Wood
Keyword(s):  
T Cells ◽  
B Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
B Cell ◽  
Active Form ◽  
Fold Increase ◽  
Clinical Severity ◽  
Autoimmune Encephalomyelitis ◽  
Immune Mediated ◽  
Experimental Autoimmune

The ERK1/2 signaling pathway promotes myelin wrapping during development and remyelination, and sustained ERK1/2 activation in the oligodendrocyte (OL) lineage results in hypermyelination of the CNS. We therefore hypothesized that increased ERK1/2 signaling in the OL lineage would 1) protect against immune-mediated demyelination due to increased baseline myelin thickness and/or 2) promote enhanced remyelination and thus functional recovery after experimental autoimmune encephalomyelitis (EAE) induction. Cnp-Cre;Mek1DD-eGFP/+ mice that express a constitutively active form of MEK1 (the upstream activator of ERK1/2) in the OL lineage, exhibited a significant decrease in EAE clinical severity compared to controls. However, experiments using tamoxifen-inducible Plp-CreERT;Mek1DD-eGFP/+ or Pdgfrα-CreERT;Mek1DD-eGFP mice revealed this was not solely due to a protective or reparative effect resulting from MEK1DD expression specifically in the OL lineage. Because EAE is an immune-mediated disease, we examined Cnp-Cre; Mek1DD-eGFP/+ splenic immune cells for recombination. Surprisingly, GFP+ recombined CD19+ B-cells, CD11b+ monocytes, and CD3+ T-cells were noted when Cre expression was driven by the Cnp promoter. While ERK1/2 signaling in monocytes and T-cells is associated with proinflammatory activation, fewer studies have examined ERK1/2 signaling in B-cell populations. After in vitro stimulation, MEK1DD-expressing B-cells exhibited a 3-fold increase in CD138+ plasmablasts and a 5-fold increase in CD5+CD1dhi B-cells compared to controls. Stimulated MEK1DD-expressing B-cells also exhibited an upregulation of IL-10, known to suppress the initiation of EAE when produced by CD5+CD1dhi regulatory B-cells. Taken together, our data support the conclusion that sustained ERK1/2 activation in B-cells suppresses immune-mediated demyelination via increasing activation of regulatory B10 cells.

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

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lihi Radomir ◽  
Matthias P. Kramer ◽  
Michal Perpinial ◽  
Nofar Schottlender ◽  
Stav Rabani ◽  
...  
Keyword(s):  
B Cells ◽  
Autoimmune Encephalomyelitis ◽  
Regulatory B Cell ◽  
The Central Nervous System ◽  
Factor C ◽  
And Function ◽  
Human And Mouse ◽  
Experimental Autoimmune

AbstractB cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10+ Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10+ Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10+ Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10+ Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases.

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