scholarly journals M-CSF-Stimulated CD11b+ Myeloid Cells Induce Alopecia Areata in C3H/HeJ Mice

2021 ◽  
Author(s):  
Yunyuan Li ◽  
Ruhangiz T. Kilani ◽  
Rana Alamdaran ◽  
Arveen Shokravi ◽  
Aziz Ghahary
Keyword(s):  
Conditioned Medium ◽  
B Lymphocytes ◽  
Alopecia Areata ◽  
Cell Activation ◽  
Myeloid Cells ◽  
Skin Inflammation ◽  
Splenocyte Proliferation ◽  
B Cell Activation ◽  
Macrophage Colony ◽  
Dermal Injection

Abstract Alopecia areata (AA) is a T cell-mediated autoimmune skin disease with clinical features of hair loss and skin inflammation. It is unclear whether other immune cells except T lymphocytes are also involved in the development of AA. Here, our results reveal that dermal injection of either CD11b+ myeloid cells isolated from AA-affected skin or non-AA splenocyte-derived CD11b+ cells treated with macrophage colony-stimulating factor (M-CSF) induces AA in C3H/HeJ mice. The functional similarity of these cells in induction of AA seems to be due to a higher expression of M-CSF in AA affected skin. To explore the mechanism by which dermal injection of CD11b+ cells induce AA, we co-culture either AA derived skin cells or M-CSF-stimulated CD11b+ cells with naïve splenocytes. The results of splenocyte proliferation assay and immunoglobulin release in conditioned medium show a significant increase of splenocyte proliferation and IgG level in conditioned medium under both conditions as compared to controls. Most activated splenocytes induced by M-CSF-stimulated myeloid cells are B lymphocytes. B cell activation are further confirmed in AA-affected skin and skin draining lymph nodes of AA mice. In conclusion, in this study, we have provided evidence that M-CSF stimulated CD11b+ cells are able to induce AA in C3H/HeJ mice through a possible mechanism by activating B lymphocytes. This finding may provide insight for understanding the pathogenesis of AA.

Polyclonal activation of B lymphocytes during experimental infection with Schistosoma mansoni

Parasitology ◽  
1990 ◽  
Vol 100 (1) ◽  
pp. 83-91 ◽  
Author(s):  
L. M. Lopes ◽  
M. A. C. Pereira ◽  
S. E. Gerken ◽  
N. Vaz
Keyword(s):  
Schistosoma Mansoni ◽  
B Lymphocytes ◽  
Experimental Infection ◽  
Adoptive Transfer ◽  
Cell Activation ◽  
Protein A ◽  
B Cell Activation ◽  
Spleen Cells ◽  
Polyclonal Activation ◽  
Immunoglobulin Isotypes

SummaryA significant polyclonal activation of B lymphocytes was observed during experimental infection of C57BL/10J mice with Schistosoma mansoni. The isotypic pattern of this expansion, assessed by the Protein-A plaque-forming cell method, was compared with and found to differ from those occurring after infection by Trypanosoma cruzi or injection of bacterial LPS. In the infection of S. mansoni an early expansion of most immunoglobulin isotypes occurs together with a late, sustained expansion of IgG1-secreting cells. High levels of polyclonal B cell activation were observed after adoptive transfer of spleen cells from infected mice to isogenic recipients pre-treated with hydroxyurea.

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 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 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 Activation of the p21ras pathway couples antigen receptor stimulation to induction of the primary response gene egr-1 in B lymphocytes.

1995 ◽  
Vol 181 (1) ◽  
pp. 417-422 ◽  
Author(s):  
S B McMahon ◽  
J G Monroe
Keyword(s):  
B Lymphocytes ◽  
Cell Activation ◽  
Antigen Receptor ◽  
Primary Response ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Cross Linking ◽  
B Cell Activation ◽  
Response Gene ◽  
Primary Response Gene

The primary response gene egr-1 encodes a sequence-specific transcription factor whose expression is necessary for antigen receptor-stimulated activation of B lymphocytes. The molecular processes involved in linking egr-1 induction to antigen receptor signaling have not been defined. The present study demonstrates that expression of an activated form of p21ras results in egr-1 induction similar to that previously shown after antigen receptor cross-linking. In addition, both antigen receptor cross-linking and p21ras use the same element in the egr-1 promoter to exert their effects. Using dominant-negative mutants of p21ras and raf-1, we demonstrate that induction of egr-1 after antigen receptor cross-linking is mediated by activation of the p21ras/mitogen-activated protein kinase signaling pathway. While regulation of the p21ras pathway during B cell activation has been intensively studied, this report represents the first description of a biologically relevant event associated with its activation.

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 Crosslinking of surface immunoglobulin and Fc receptors on B lymphocytes inhibits stimulation of inositol phospholipid breakdown via the antigen receptors.

1985 ◽  
Vol 162 (6) ◽  
pp. 1825-1836 ◽  
Author(s):  
M K Bijsterbosch ◽  
G G Klaus
Keyword(s):  
B Cells ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Fc Receptors ◽  
Inhibitory Effect ◽  
Prolonged Release ◽  
B Cell Activation ◽  
Antigen Receptors ◽  
Inositol Phospholipid ◽  
Inositol Phospholipid Breakdown

F(ab')2 fragments of rabbit anti-mouse Ig induce proliferation of murine B lymphocytes, whereas the intact antibodies are not mitogenic. F(ab')2 anti-Ig stimulates the rapid breakdown of inositol phospholipids in B cells, resulting in the prolonged release of inositol (poly)phosphates and diacylglycerol. In marked contrast, intact anti-Ig initially induces a comparable response, which is abrogated after some 30 s. Blocking either the Fc receptors on the B cells or the Fc portion of the antibodies significantly reversed the inhibitory effect. On the other hand, both forms of anti-Ig elicited comparable increases in free cytoplasmic Ca2+ levels in B cells. These results therefore indicate that crosslinkage of Fc and surface Ig receptors on B cells inhibits inositol phospholipid breakdown (but not Ca2+ flux) resulting from ligation of the antigen receptors. Since there is evidence implicating inositol phospholipid breakdown in the induction of cell growth, this effect could provide a biochemical explanation for the known capacity of antigen-antibody complexes to inhibit B cell activation.

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.

Antigen stored in dendritic cells after macropinocytosis is released unprocessed from late endosomes to target B cells

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 95-105 ◽  
Author(s):  
Delphine Le Roux ◽  
Agnès Le Bon ◽  
Audrey Dumas ◽  
Kahina Taleb ◽  
Martin Sachse ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Cells ◽  
Lymph Nodes ◽  
B Lymphocytes ◽  
Cell Activation ◽  
B Cell Activation ◽  
Extracellular Medium ◽  
Native Form ◽  
Active Processes ◽  
Endocytic Compartments

Abstract B lymphocytes can be triggered in lymph nodes by nonopsonized antigens (Ag), potentially in their native form. However, the mechanisms that promote encounter of B lymphocytes with unprocessed antigens in lymph nodes are still elusive. We show here that antigens are detected in B cells in the draining lymph nodes of mice injected with live, but not fixed, dendritic cells (DCs) loaded with antigens. This highlights active processes in DCs to promote Ag transfer to B lymphocytes. In addition, antigen-loaded DCs found in the draining lymph node were CD103+. Using 3 different model Ag, we then show that immature DCs efficiently take up Ag by macropinocytosis and store the internalized material in late endocytic compartments. We find that DCs have a unique ability to release antigens from these compartments in the extracellular medium, which is controlled by Rab27. B cells take up the regurgitated Ag and the chemokine CXCL13, essential to attract B cells in lymph nodes, enhances this transfer. Our results reveal a unique property of DCs to regurgitate unprocessed Ag that could play an important role in B-cell activation.

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