CD22 antigen: biosynthesis, glycosyiation and surface expression of a B lymphocyte protein involved in B cell activation and adhesion

1991 ◽  
Vol 3 (7) ◽  
pp. 623-633 ◽  
Author(s):  
Reinhard Schwartz-Albiez ◽  
Bernd Dörken ◽  
Davidv A. Monner ◽  
Gerhard Moldenhauer
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
B Lymphocyte ◽  
Surface Expression ◽  
B Cell Activation

scholarly journals AB0024 IN VITRO CHARACTERIZATION OF CENERIMOD, A POTENT AND SELECTIVE SPHINGOSINE 1-PHOSPHATE RECEPTOR 1 (S1P1) MODULATOR IN PREVENTING MIGRATION OF NON-ACTIVATED AND ACTIVATED PRIMARY HUMAN B CELLS IN THE PRESENCE OR ABSENCE OF GLUCOCORTICOIDS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1046.1-1046
Author(s):  
L. Schlicher ◽  
P. Kulig ◽  
M. Murphy ◽  
M. Keller
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
B Cell Activation ◽  
Human B Cells ◽  
Circulating Lymphocytes

Background:Cenerimod is a potent, selective, and orally active sphingosine 1-phosphate receptor 1 (S1P1) modulator that is currently being evaluated in a Phase 2b study in patients with systemic lupus erythematosus (SLE) (NCT03742037). S1P1 receptor modulators sequester circulating lymphocytes within lymph nodes, thereby reducing pathogenic autoimmune cells (including B lymphocytes) in the blood stream and in inflamed tissues. Extensive clinical experience has become available for the nonselective S1P receptor modulator fingolimod in relapsing forms of multiple sclerosis, supporting this therapeutic concept for the treatment of autoimmune disorders.Objectives:Although the effect of S1P-receptor modulators in reducing peripheral B cells is well documented1,2, the role of the S1P1 receptor on this cell type is only incompletely understood. In this study, the mode of action of cenerimod on primary human B cells was investigated in a series of in vitro experiments, including S1P1 receptor cell surface expression and chemotaxis towards S1P. Moreover, S1P1 expression following B cell activation in vitro was studied. As glucocorticoids (GC) are frequently used in the treatment of patients with autoimmune disorders including SLE, the potential influence of GC on the mode of action of cenerimod was evaluated.Methods:Primary human B lymphocytes from healthy donors were isolated from whole blood. In one set of experiments, cells were treated with different concentrations of cenerimod to measure S1P1 receptor internalization by flow cytometry. In a second set of experiments, isolated B cells were activated using different stimuli or left untreated. Cells were then analysed for S1P1 and CD69 cell surface expression and tested in a novel real-time S1P-mediated migration assay. In addition, the effect of physiological concentrations of GCs (prednisolone and prednisone) on cenerimod activity in preventing S1P mediated migration was tested.Results:In vitro, cenerimod led to a dose-dependent internalization of the S1P1 receptor on primary human B lymphocytes. Cenerimod also blocked migration of nonactivated and activated B lymphocytes towards S1P in a concentration-dependent manner, which is in line with the retention of lymphocytes in the lymph node and the reduction of circulating lymphocytes observed in the clinical setting. Upon B cell activation, which was monitored by CD69 upregulation, a simultaneous downregulation of S1P1 expression was detected, leading to less efficient S1P-directed cell migration. Importantly, physiological concentrations of GC did not affect the inhibitory activity of cenerimod on B cell migration.Conclusion:These results show that cenerimod, by modulating S1P1, blocks B lymphocyte migration towards its natural chemoattractant S1P and demonstrate compatibility of cenerimod with GC. These results are consistent with results of comparable experiments done previously using primary human T lymphocytes.References:[1]Nakamura M et al., Mult Scler. 2014 Sep; 20(10):1371-80.[2]Strasser DS et al., RMD Open 2020;6:e001261.Disclosure of Interests:None declared

scholarly journals Carbohydrate-dependent B cell activation by fucose-binding bacterial lectins

2019 ◽  
Vol 12 (571) ◽  
pp. eaao7194 ◽  
Author(s):  
Isabel Wilhelm ◽  
Ella Levit-Zerdoun ◽  
Johanna Jakob ◽  
Sarah Villringer ◽  
Marco Frensch ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Surface ◽  
B Cell ◽  
Cell Activation ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
B Cell Activation ◽  
Intracellular Ca ◽  
Bacterial Lectins

Bacterial lectins are typically multivalent and bind noncovalently to specific carbohydrates on host tissues to facilitate bacterial adhesion. Here, we analyzed the effects of two fucose-binding lectins, BambL fromBurkholderia ambifariaand LecB fromPseudomonas aeruginosa, on specific signaling pathways in B cells. We found that these bacterial lectins induced B cell activation, which, in vitro, was dependent on the cell surface expression of the B cell antigen receptor (BCR) and its co-receptor CD19, as well as on spleen tyrosine kinase (Syk) activity. The resulting release of intracellular Ca2+was followed by an increase in the cell surface abundance of the activation marker CD86, augmented cytokine secretion, and subsequent cell death, replicating all of the events that are observed in vitro upon canonical and antigen-mediated B cell activation. Moreover, injection of BambL in mice resulted in a substantial, BCR-independent loss of B cells in the bone marrow with simultaneous, transient enlargement of the spleen (splenomegaly), as well as an increase in the numbers of splenic B cells and myeloid cells. Together, these data suggest that bacterial lectins can initiate polyclonal activation of B cells through their sole capacity to bind to fucose.

Expression of XBP1s in B lymphocytes is critical for pristane-induced lupus nephritis in mice

2020 ◽  
Vol 318 (5) ◽  
pp. F1258-F1270 ◽  
Author(s):  
Li Xiang ◽  
An Liu ◽  
Guoshuang Xu
Keyword(s):  
B Cells ◽  
Lupus Nephritis ◽  
Mouse Model ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
B Lymphocyte ◽  
B Cell Activation ◽  
Protein Levels ◽  
Almost All

B lymphocyte hyperactivity plays a pathogenic role in systemic lupus erythematosus (SLE), and spliced X box-binding protein 1 (XBP1s) has been implicated in B cell maturation and differentiation. We hypothesized that blockade of the XBP1s pathway inhibits the B cell hyperactivity underlying SLE and lupus nephritis (LN) development. In the present study, we systematically evaluated the changes in B cell activation induced by the Xbp1 splicing inhibitor STF083010 in a pristane-induced lupus mouse model. The lupus mouse model was successfully established, as indicated by the presence of LN with markedly increased urine protein levels, renal deposition of Ig, and mesangial cell proliferation. In lupus mice, B cell hyperactivity was confirmed by increased CD40 and B cell-activating factor levels. B cell activation and plasma cell overproduction were determined by increases in CD40-positive and CD138-positive cells in the spleens of lupus mice by flow cytometry and further confirmed by CD45R and Ig light chain staining in the splenic tissues of lupus mice. mRNA and protein expression of XBP1s in B cells was assessed by real-time PCR, Western blot analysis, and immunofluorescence analysis and was increased in lupus mice. In addition, almost all changes were reversed by STF083010 treatment. However, the expression of XBP1s in the kidneys did not change when mice were exposed to pristane and STF083010. Taken together, these findings suggest that expression of XBP1s in B cells plays key roles in SLE and LN development. Blockade of the XBP1s pathway may be a potential strategy for SLE and LN treatment.

scholarly journals Constitutive BR3 receptor signaling in diffuse, large B-cell lymphomas stabilizes nuclear factor-κB–inducing kinase while activating both canonical and alternative nuclear factor-κB pathways

Blood ◽  
2011 ◽  
Vol 117 (1) ◽  
pp. 200-210 ◽  
Author(s):  
Lan V. Pham ◽  
Lingchen Fu ◽  
Archito T. Tamayo ◽  
Carlos Bueso-Ramos ◽  
Elias Drakos ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
B Lymphocyte ◽  
Tumor Necrosis Factor Receptor ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
Genetically Engineered ◽  
Nuclear Factor ◽  
B Cell Activation ◽  
Large B Cell

Abstract Aberrant nuclear factor κB (NF-κB) signaling has been found to be of particular importance in diffuse, large B-cell lymphoma (DLBCL) cell survival and proliferation. Although the canonical NF-κB signaling pathway has been studied in some detail, activation of the alternative NF-κB pathway in DLBCL is not well characterized. Important insights into the regulation of the alternative NF-κB pathway in B lymphocytes has recently revealed the regulatory importance of the survival kinase NIK (NF-κB–inducing kinase) in genetically engineered murine models. Our studies demonstrate that both the canonical and alternative NF-κB pathways are constitutively activated in DLBCL. We also demonstrate that NIK kinase aberrantly accumulates in DLBCL cells due to constitutive activation of B-cell activation factor (BAFF)–R (BR3) through interaction with autochthonous B-lymphocyte stimulator (BLyS) ligand in DLBCL cells. Activation of BR3 in DLBCL induces recruitment and degradation of tumor necrosis factor receptor-associated factor 3, which results in NIK kinase accumulation, IκBα phosphorylation, and NF-κB p100 processing, thereby resulting in continuous activation of both NF-κB pathways in DLBCL cells, leading to autonomous lymphoma cell growth and survival. These results further elucidate mechanisms involved in abnormal NF-κB activation in DLBCL, and should contribute to better future therapeutic approaches for patients with DLBCL.

scholarly journals LPS stimulates IgM production in vivo without help from non-B cells

2016 ◽  
Vol 22 (5) ◽  
pp. 307-315 ◽  
Author(s):  
Mingfang Lu ◽  
Robert Munford
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Surface Expression ◽  
B Cell Activation ◽  
Direct Stimulation ◽  
Activation Markers ◽  
Necessary And Sufficient ◽  
Lps Signaling

Gram-negative bacterial LPS induce murine B-cell activation and innate (polyclonal) Ab production. Mouse B cells express the LPS signaling receptor (TLR4), yet how LPS activates B-cell responses in vivo is not known. Can LPS directly stimulate B cells to induce innate Ab production? Is activation of non-B cells also required? To address these questions, we transfused LPS-responsive ( Tlr4+/+) or non-responsive ( Tlr4−/−) B cells into LPS-responsive or non-responsive mice. Increased expression of the early activation markers CD69 and CD86 could be induced on transfused Tlr4−/− B cells by injecting LPS subcutaneously into Tlr4+/+ mice, demonstrating indirect activation of B cells by TLR4-responsive non-B cells in vivo, but the Tlr4−/− B cells did not increase serum IgM levels. In contrast, when Tlr4−/− recipients were transfused with Tlr4+/+ B cells, LPS induced large amounts of serum IgM and LPS could also enhance specific Ab production to a protein that was co-injected with it (adjuvant response). Thus, LPS-exposed non-B cells mediated increased surface expression of early B-cell activation markers, but this response did not predict innate Ab responses or LPS adjuvanticity in vivo. Direct stimulation of B cells by LPS via TLR4 was necessary and sufficient to induce B cells to produce Ab in vivo.

RP105 Is Associated With MD-1 and Transmits an Activation Signal in Human B Cells

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2815-2822 ◽  
Author(s):  
Yoshihiro Miura ◽  
Rintaro Shimazu ◽  
Kensuke Miyake ◽  
Sachiko Akashi ◽  
Hirotaka Ogata ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Surface ◽  
B Cell ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
B Cell Activation ◽  
Cell Surface Molecule ◽  
Induced Apoptosis

Abstract RP105 was originally discovered as a mouse B-cell surface molecule that transmits an activation signal. The signal leads to resistance against irradiation-induced apoptosis and massive B-cell proliferation. Recently, we found that mouse RP105 is associated with another molecule, MD-1. We have isolated here the human MD-1 cDNA. We show that human MD-1 is also associated with human RP105 and has an important role in cell surface expression of RP105. We also describe a monoclonal antibody (MoAb) that recognizes human RP105. Expression of RP105 is restricted to CD19+ B cells. Histological studies showed that RP105 is expressed mainly on mature B cells in mantle zones. Germinal center cells are either dull or negative. RP105 is thus a novel human B-cell marker that is preferentially expressed on mature B cells. Moreover, the anti-RP105 MoAb activates B cells, leading to increases in cell size, expression of a costimulatory molecule CD80, and DNA synthesis. The B-cell activation pathway using RP105 is conserved in humans. © 1998 by The American Society of Hematology.

scholarly journals Crosslinkage of B lymphocyte surface immunoglobulin by anti-Ig or antigen induces prolonged oscillation of intracellular ionized calcium.

1987 ◽  
Vol 166 (2) ◽  
pp. 601-606 ◽  
Author(s):  
H A Wilson ◽  
D Greenblatt ◽  
M Poenie ◽  
F D Finkelman ◽  
R Y Tsien
Keyword(s):  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
B Lymphocyte ◽  
Accessory Cell ◽  
Base Line ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Technical Approach ◽  
Indicator Dyes

Our results indicate that B lymphocytes stimulated with anti-Ig or antigen exhibit repetitive [Ca2+]i transients which persist for hours. The magnitude of these transients favors an important and ongoing role for [Ca2+]i elevation in antigen driven B cell activation. Repetitive Ca2+ transients may prove to be a prevalent mechanism of Ca2+ signaling. In preliminary experiments (with L. E. Samelson and R. D. Klausner), we have observed Ca2+ transients in cloned T cells stimulated with antigen. Woods et al. have described repetitive free Ca2+ transients in hepatocytes stimulated with extracellular ligands promoting glycogenolysis, and suggest that the intervals of base-line [Ca2+]i levels explain the absence of mitochondrial overload in chronically stimulated cells. These considerations apply equally to B lymphocytes and recommend caution in delineating the range of Ca2+-mediated functions by prolonged coculture of cells with Ca2+ ionophores. Our experiments were done in a simple recording chamber with one cell type. No cell interactions were observed. Given the variety of indicator dyes now available, the technical approach we present, augmented by a more sophisticated recording chamber, is a potentially powerful tool for examining the intrinsic, and T- or accessory cell-dependent, physiology of B cell differentiation.

scholarly journals Regulation of B-lymphocyte clonal proliferation by stimulatory and inhibitory macrophage-derived factors

1977 ◽  
Vol 146 (5) ◽  
pp. 1420-1435 ◽  
Author(s):  
JI Kurland ◽  
PW Kincade ◽  
MAS Moore
Keyword(s):  
Lymph Node ◽  
B Cell ◽  
Colony Formation ◽  
Cell Activation ◽  
B Lymphocyte ◽  
Optimal Number ◽  
B Cell Activation ◽  
Agar Culture ◽  
Sheep Erythrocytes ◽  
Clonal Proliferation

A functional subpopulation of murine B lymphocytes proliferate in semisolid agar culture in the presence of 2-mercaptoethanol to form colonies. The effects of diffusible macrophage-derived factors on this focal proliferation was investigated using a two-layer culture system which prevented macrophage-lymphocyte contact and permitted B-cell activation to be critically assessed under conditions of extremely low cell densities. Adherent peritoneal macrophages incorporated within underlayers of spleen or lymph node cell cultures potentiated both the number and size of developing B-cell colonies. These effects were most striking when low numbers of spleen or lymph node cells, or macrophage- depleted lymphoid cell suspensions were used. Thus, macrophage-depleted lymph node ceils gave rise to virtually no colonies, but colony-forming ability was restored by the presence of an optimal number of macrophages. When the number of macrophages exceeded that required for optimal stimulation, colony formation was suppressed; an effect which was largely prevented by indomethacin, an inhibitor of prostaglandin synthesis. Under these conditions, stimulation and inhibition of B-cell activation by macrophages could be dissociated, indicating that each signal is selectively controlled by individual molecules elaborated by the macrophage. With an appropriate number of macrophages required for B-cell activation, and sufficient indomethacin to inhibit the accumulation of macrophage-derived prostaglandin, B-lymphocyte clonal proliferation was a linear function of the number of B cells placed in culture. In the absence of macrophages, B-cell colony formation was potentiated by both lipopolysaccharide and intact sheep erythrocytes through a mechanism different from that of the macrophage-derived stimulatory factor. In addition to their direct stimulatory effect on B-cell proliferation, lipopolysaccharide and sheep erythrocytes were each capable of modulating the production and/or release of B-cell stimulatory and inhibitory factors by the macrophage. Parallel studies of conventional mitogen- stimulated lymphocyte cultures did not show a requirement for macrophages and confirm that the semisolid assay is uniquely suited to studies on the regulatory role of the macrophage in B-cell activation.

scholarly journals Bacterial lectin BambL acts as a B cell superantigen

2021 ◽  
Author(s):  
Marco Frensch ◽  
Christina Jäger ◽  
Peter F. Müller ◽  
Annamaria Tadić ◽  
Isabel Wilhelm ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Cell Activation ◽  
Human Peripheral Blood ◽  
Adaptive Immune Response ◽  
Surface Expression ◽  
B Cell Activation ◽  
Activation Induced Cell Death ◽  
Model Cell

AbstractB cell superantigens crosslink conserved domains of B cell receptors (BCRs) and cause dysregulated, polyclonal B cell activation irrespective of normal BCR-antigen complementarity. The cells typically succumb to activation-induced cell death, which can impede the adaptive immune response and favor infection. In the present study, we demonstrate that the fucose-binding lectin of Burkholderia ambifaria, BambL, bears functional resemblance to B cell superantigens. By engaging surface glycans, the bacterial lectin activated human peripheral blood B cells, which manifested in the surface expression of CD69, CD54 and CD86 but became increasingly cytotoxic at higher concentrations. The effects were sensitive to BCR pathway inhibitors and excess fucose, which corroborates a glycan-driven mode of action. Interactome analyses in a model cell line suggest BambL binds directly to glycans of the BCR and regulatory coreceptors. In vitro, BambL triggered BCR signaling and induced CD19 internalization and degradation. Owing to the lectin’s six binding sites, we propose a BCR activation model in which BambL functions as a clustering hub for receptor glycans, modulates normal BCR regulation, and induces cell death through exhaustive activation.

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