scholarly journals Lipid raft–dependent plasma membrane repair interferes with the activation of B lymphocytes

2015 ◽  
Vol 211 (6) ◽  
pp. 1193-1205 ◽  
Author(s):  
Heather Miller ◽  
Thiago Castro-Gomes ◽  
Matthias Corrotte ◽  
Christina Tam ◽  
Timothy K. Maugel ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
B Cell ◽  
B Lymphocytes ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Cell Activation ◽  
Dependent Manner ◽  
B Cell Activation ◽  
Membrane Repair ◽  
Membrane Injury

Cells rapidly repair plasma membrane (PM) damage by a process requiring Ca2+-dependent lysosome exocytosis. Acid sphingomyelinase (ASM) released from lysosomes induces endocytosis of injured membrane through caveolae, membrane invaginations from lipid rafts. How B lymphocytes, lacking any known form of caveolin, repair membrane injury is unknown. Here we show that B lymphocytes repair PM wounds in a Ca2+-dependent manner. Wounding induces lysosome exocytosis and endocytosis of dextran and the raft-binding cholera toxin subunit B (CTB). Resealing is reduced by ASM inhibitors and ASM deficiency and enhanced or restored by extracellular exposure to sphingomyelinase. B cell activation via B cell receptors (BCRs), a process requiring lipid rafts, interferes with PM repair. Conversely, wounding inhibits BCR signaling and internalization by disrupting BCR–lipid raft coclustering and by inducing the endocytosis of raft-bound CTB separately from BCR into tubular invaginations. Thus, PM repair and B cell activation interfere with one another because of competition for lipid rafts, revealing how frequent membrane injury and repair can impair B lymphocyte–mediated immune responses.

scholarly journals Actin Depolymerization Transduces the Strength of B-Cell Receptor Stimulation

2005 ◽  
Vol 16 (5) ◽  
pp. 2275-2284 ◽  
Author(s):  
Shengli Hao ◽  
Avery August
Keyword(s):  
B Cell ◽  
Lipid Raft ◽  
Cell Activation ◽  
Cell Receptor ◽  
Dependent Manner ◽  
B Cell Activation ◽  
Erk Activation ◽  
Actin Depolymerization ◽  
Transcription Factor Activation ◽  
Raft Clustering

Polymerization of the actin cytoskeleton has been found to be essential for B-cell activation. We show here, however, that stimulation of BCR induces a rapid global actin depolymerization in a BCR signal strength-dependent manner, followed by polarized actin repolymerization. Depolymerization of actin enhances and blocking actin depolymerization inhibits BCR signaling, leading to altered BCR and lipid raft clustering, ERK activation, and transcription factor activation. Furthermore actin depolymerization by itself induces altered lipid raft clustering and ERK activation, suggesting that F-actin may play a role in separating lipid rafts and in setting the threshold for cellular 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 Tumor-Derived Autophagosomes (DRibbles) Induce B Cell Activation in a TLR2-MyD88 Dependent Manner

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e53564 ◽  
Author(s):  
Weixia Li ◽  
Meng Zhou ◽  
Hongyan Ren ◽  
Hong-Ming Hu ◽  
Liwei Lu ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Dependent Manner ◽  
B Cell Activation

scholarly journals Complement Receptor Type 1 Suppresses Human B Cell Functions in SLE Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Mariann Kremlitzka ◽  
Bernadett Mácsik-Valent ◽  
Anna Polgár ◽  
Emese Kiss ◽  
Gyula Poór ◽  
...  
Keyword(s):  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Receptor Type ◽  
Complement Receptor ◽  
B Cell Activation ◽  
Complement Receptor Type ◽  
Cell Functions ◽  
Inhibitory Capacity

Complement receptors (CRs) play an integral role in innate immunity and also function to initiate and shape the adaptive immune response. Our earlier results showed that complement receptor type 1 (CR1, CD35) is a potent inhibitor of the B cell receptor- (BCR-) induced functions of human B lymphocytes. Here we show that this inhibition occurs already at the initial steps of B cell activation since ligation of CR1 reduces the BCR-induced phosphorylation of key signaling molecules such as Syk and mitogen activated protein kinases (MAPKs). Furthermore, our data give evidence that although B lymphocytes of active systemic lupus erythematosus (SLE) patients express lower level of CR1, the inhibitory capacity of this complement receptor is still maintained and its ligand-induced clustering results in significant inhibition of the main B cell functions, similar to that found in the case of healthy individuals. Since we have found that reduced CR1 expression of SLE patients does not affect the inhibitory capacity of the receptor, our results further support the therapeutical potential of CD35 targeting the decrease of B cell activation and autoantibody production in autoimmune patients.

scholarly journals A nonsense mutation in IKBKB causes combined immunodeficiency

Blood ◽  
2014 ◽  
Vol 124 (13) ◽  
pp. 2046-2050 ◽  
Author(s):  
Talal Mousallem ◽  
Jialong Yang ◽  
Thomas J. Urban ◽  
Hongxia Wang ◽  
Mehdi Adeli ◽  
...  
Keyword(s):  
B Cell ◽  
Nk Cells ◽  
B Lymphocytes ◽  
Nonsense Mutation ◽  
Cell Activation ◽  
B Cell Activation ◽  
Combined Immunodeficiency ◽  
Antigen Receptors ◽  
Key Points

Key PointsA nonsense mutation in IKBKB caused the absence of IKKβ and a lack of T- and B-cell activation through their antigen receptors. IKKβ is not necessary for development of T or B lymphocytes but is important for their activation and for the development/function of NK cells.

scholarly journals Molecular interactions of complement receptors on B lymphocytes: a CR1/CR2 complex distinct from the CR2/CD19 complex.

1991 ◽  
Vol 173 (5) ◽  
pp. 1083-1089 ◽  
Author(s):  
D A Tuveson ◽  
J M Ahearn ◽  
A K Matsumoto ◽  
D T Fearon
Keyword(s):  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Complement Receptors ◽  
B Cell Activation ◽  
Humoral Immune ◽  
Membrane Immunoglobulin ◽  
Erythroleukemia Cells ◽  
Low Concentrations ◽  
The Complement System

The complement system augments the humoral immune response to low concentrations of antigen. This effect may be partly mediated by complement receptors on the surface of B lymphocytes that bind immunogenic complexes bearing fragments of C3 and C4. We have shown by immunoprecipitation analysis that the two complement receptors expressed by B lymphocytes, complement receptor 1 (CR1) and CR2, form a detergent-sensitive complex on the surface of tonsillar B lymphocytes and on K562 erythroleukemia cells that were co-transfected with cDNAs encoding CR1 and CR2. The CR1/CR2 complex is distinct from the CR2/CD19 complex and may assist B cell activation by efficiently capturing C3b-containing immunogens and maintaining such immunogens on the B cell after CR1 and factor I-mediated cleavage to iC3b and C3dg. The complement activating immunogen may then trigger signal transduction by the CR1/CR2 complex, the CR2/CD19 complex, or membrane immunoglobulin.

Cluster formation among small resting B lymphocytes leading to B cell activation

1989 ◽  
Vol 1 (1) ◽  
pp. 36-42 ◽  
Author(s):  
Yousuke Takahama ◽  
Shlro Ono ◽  
Katsuhlko Ishlhara ◽  
Toshlyuki Hamaoka
Keyword(s):  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Cluster Formation ◽  
B Cell Activation

Abatacept Reduces Levels of Switched Memory B Cells, Autoantibodies, and Immunoglobulins in Patients with Rheumatoid Arthritis

2014 ◽  
Vol 41 (4) ◽  
pp. 666-672 ◽  
Author(s):  
Mirko Scarsi ◽  
Lucia Paolini ◽  
Doris Ricotta ◽  
Antonio Pedrini ◽  
Silvia Piantoni ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Serum Levels ◽  
Memory B Cells ◽  
Cell Phenotype ◽  
B Cell Activation ◽  
Switch Memory

Objective.Abatacept (ABA) is a chimeric molecule, able to block the CD28-mediated costimulatory pathway. To evaluate the hypothesis that, through this mechanism of action, ABA may down-modulate the immune responses of B lymphocytes in rheumatoid arthritis (RA), we investigated the serum levels of immunoglobulins (Ig), free light chains (FLC), anticitrullinated protein antibodies (ACPA), and rheumatoid factor (RF), as well as the number of B lymphocytes differentiated into post-switch memory cells in patients treated with ABA.Methods.The serum levels of Ig, FLC, different ACPA, RF isotypes, and the B cell phenotype were longitudinally evaluated in 30 patients with RA treated with ABA.Results.At baseline, the proportion of total and post-switch memory B cells was lower in RA than in healthy individuals. After 6 months of ABA treatment we observed significant reductions of serum levels of IgG, IgA, and IgM, as well as FLC, with a normalization in many patients who had initially abnormal values. A significant reduction of the titers of IgG- and IgA-ACPA, as well as of IgM-, IgA-, and IgG-RF was also observed. A decrease of autoantibodies below the upper limits of normal values was found in 2 of 26 patients (8%) initially seropositive for IgG-ACPA, 1 of 14 (7%) for IgA-ACPA, 5 of 22 (23%) for IgM-RF, 7 of 22 (30%) for IgA-RF, and 5 of 16 (31%) for IgG-RF. After treatment, the proportion of circulating post-switch memory B cells was also further significantly decreased.Conclusion.ABA treatment in patients with RA can reduce signs of polyclonal B cell activation, inducing a trend toward normalization of serum levels of different classes of Ig and of FLC, decreasing titers of ACPA and RF, and percentages of post-switch memory B cells.

scholarly journals Role of interleukin 1 in anti-immunoglobulin-induced B cell proliferation.

1983 ◽  
Vol 157 (5) ◽  
pp. 1529-1543 ◽  
Author(s):  
M Howard ◽  
S B Mizel ◽  
L Lachman ◽  
J Ansel ◽  
B Johnson ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Interleukin 1 ◽  
Accessory Cell ◽  
B Cell Activation ◽  
B Cell Growth Factor ◽  
Absolute Dependence

In this report we describe conditions for polyclonal activation of small numbers of highly purified mouse B lymphocytes. Three signals are required for induction of DNA synthesis by the particular subset of small B lymphocytes investigated: a signal delivered by antibodies specific for the IgM receptor expressed on the B cell membrane; a signal delivered by a T cell-derived factor (B cell growth factor [BCGF]); and a signal delivered by the macrophage-derived factor interleukin 1 (IL-1). The conclusion that IL-1 has B cell co-stimulator activity is based on the findings that highly purified preparations of mouse and human IL-1 have the capacity to cause proliferation in B cells treated with anti-IgM and BCGF. Such cultures show an absolute dependence on exogenously added IL-1 when 2-mercaptoethanol is omitted from the medium. BCGF and IL-1 each act in a non-antigen-specific, non-H-2-restricted, synergistic manner. Their requirement is not observed when B cells are cultured at high density, presumably reflecting accessory cell contamination and endogenous factor production under these conditions. The B cell activation induced by these three signals is restricted to proliferation without the production of antibody-forming cells.

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