Defects in the gene encoding Brutons tyrosine kinase (Btk) result in a disease called X-linked agammaglobulinemia, in which there is a profound decrease of mature B cells due to a block in B cell development. Recent studies have shown that Btk is tyrosine phosphorylated and activated upon B cell antigen receptor (BCR) stimulation. To elucidate the functions of this kinase, we examined BCR signaling of DT40 B cells deficient in Btk. Tyrosine phosphorylation of phospholipase C (PLC)-gamma 2 upon receptor stimulation was significantly reduced in the mutant cells, leading to the loss of both BCR-coupled phosphatidylinositol hydrolysis and calcium mobilization. Pleckstrin homology and Src-homology 2 domains of Btk were required for PLC-gamma 2 activation. Since Syk is also required for the BCR-induced PLC-gamma 2 activation, our findings indicate that PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions. ...
Autophagy is a major pathway for degradation of cytoplasmic components, and is induced by some apoptotic stimuli mostly in cancer cells under the condition in which apoptosis is blocked. Ligation of the B cell antigen receptor (BCR) induces apoptosis and plays a crucial role in self-tolerance. However, whether BCR ligation induces autophagy is not clear. Here, we demonstrate that autophagosomes are extensively formed in normal mouse B cells as well as the WEHI-231 B cell line upon induction of BCR ligation-induced apoptosis regardless of whether apoptosis is blocked by overexpression of Bcl-2. In contrast, autophagosomes were not formed during apoptosis of spleen B cells cultured with medium alone or in BCR-ligated BAL17 cells which do not undergo apoptosis. Moreover, autophagy is not induced when apoptotic BCR signaling is abrogated by CD40 signaling. These results indicate that autophagy is induced specifically by apoptotic BCR signaling even in unmanipulated normal B cells.
Clone REA1168 regognizes the cytoplamic domain of CD79a, which is also known as MB-1 and Igα. Along with CD79b (Igβ), CD79a is associated with surface Ig (sIg) to form the B cell antigen receptor complex. CD79a is a 47 kDa glycoprotein and comprises a single extracellular immunoglobulin domain, a transmembrane domain, and a signaling intracellular domain with immunoreceptor tyrosine-based activation motif (ITAM). CD79a/CD79b heterodimer facilitates differentiation of pre-B cells from pro-B cells, surface expression of sIg, signal transduction following antigen recognition, and enodocytosis of recognised antigens. Surface expression of CD79a dimishes in plasma cells, where it is mainly found as an intracellular molecule. CD79 is considered a B cell-specific marker and is often used to identify the B cell lineage of acute lymphoblastic leukemia. Recent reports however suggest expression of CD79a in T cell acute lymphoblastic leukemia. Individuals lacking CD79a have low/absent circulating pre-B cells and
Background Immature B lymphocytes and certain B cell lymphomas undergo apoptotic cell death following activation of the B cell antigen receptor (BCR) signal transduction pathway. for the three C-terminal tyrosines was expressed in a murine B cell Rabbit Polyclonal to FER (phospho-Tyr402) lymphoma cell line, BCL1.3B3 to interfere with regular Syk regulation as a way to examine the Syk activation part of BCR signaling. Intro of the kinase-inactive mutant resulted in the constitutive activation from the endogenous wildtype Syk enzyme in the lack of receptor engagement through a dominant-positive impact. Under these circumstances, Syk kinase activation happened in the lack of phosphorylation on Syk tyrosine residues. Although Syk is apparently necessary for BCR-induced apoptosis in a number of systems, no upsurge in spontaneous cell loss of life was seen in these cells. Remarkably, even though the endogenous Syk kinase was energetic enzymatically, no improvement in the phosphorylation of ...
Despite very similar gene expression profiles, the clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is heterogeneous. Immunoglobulin VH (IgVH) mutational status and expression of B-cell receptor (BCR) signaling mediators have been associated with disease progression. However, the consequences of BCR engagement on cell survival and evolution of the disease remain unclear. We show here that B-CLL cell survival is dependent on the threshold of BCR stimulation induced by immobilized antibody, in contrast to soluble anti-mu F(ab)2 antibody, which leads to apoptosis. Measurement of metabolic activity and apoptotic response discriminated two subgroups. Nonresponders showed low metabolic activity and unmodified apoptotic response upon BCR stimulation. In contrast, responders exhibited increased metabolic activity and inhibition of spontaneous apoptosis. This survival advantage was associated to a BCR-dependent activation profile leading to induction of cyclin D2/cyclin-dependent kinase 4
Ligation of membrane immunoglobulin M (mIgM) induces cell cycle arrest and apoptosis in the WEHI 231 B-lymphoma cell collection. show that resistance to apoptosis can arise as a result of mutations affecting discrete stages of the mIgM signalling pathway. The mutant lines reported here show defects that have not yet been recognized in previous studies and are likely to be useful tools in dissecting the signalling of cell death in W lymphocytes. Introduction Signals SKF 89976A HCl generated through membrane immunoglobulin on the surface of W lymphocytes can lead either to B-cell activation and proliferation or, alternatively, to programmed cell death or apoptosis, the greatest fate of the W cell depending on factors such as its developmental stage.1 Cross-linking of membrane immunoglobulin M (mIgM) generates a cascade of intracellular signals; in the beginning, quick tyrosine phosphorylation of non-receptor tyrosine kinases including SKF 89976A HCl syk, btk and users of the src-family, lyn, fyn, ...
Bolger-Munro, M., Choi, K., Cheung, F., Liu, Y. T., Dang-Lawson, M., Deretic, N., … Gold, M. R. (2021). The Wdr1-LIMK-Cofilin axis controls B cell antigen receptor-induced actin remodeling and signaling at the immune synapse. Frontiers in Cell and Developmental Biology. https://doi.org/10.3389/fcell.2021.649433 ...
Stimulation of immune cell receptors, such as the B cell receptor (BCR), can lead to multiple distinct cellular responses, making these cells excellent models for studying signal plasticity. Singh et al. found that inhibition of either release of calcium from the endoplasmic reticulum (with TMB-8) or uptake of calcium from the extracellular medium (with EGTA, a calcium chelator) produced a global dampening of BCR-dependent phosphorylation, including phosphorylation events that occurred within the first minute of BCR activation. Indeed, one of the events that was inhibited was the phosphorylation of Lyn, a Src family tyrosine kinase, which is believed to be the first enzyme activated in response to BCR ligand binding. This was surprising because calcium signals are downstream events; thus, this result suggested that calcium can feed back on the early signaling events. Formation of reactive oxygen species (ROS) in response to BCR activation occurred within seconds and was inhibited by ...
CD79b molecule, immunoglobulin-associated beta, also known as CD79B (Cluster of Differentiation 79B), is a human gene. It is associated with agammaglobulinemia-6. The B lymphocyte antigen receptor is a multimeric complex that includes the antigen-specific component, surface immunoglobulin (Ig). Surface Ig non-covalently associates with two other proteins, Ig-alpha and Ig-beta, which are necessary for expression and function of the B-cell antigen receptor. This gene encodes the Ig-beta protein of the B-cell antigen component. Alternatively spliced transcript variants encoding different isoforms have been described. Cluster of differentiation GRCh38: Ensembl release 89: ENSG00000007312 - Ensembl, May 2017 GRCm38: Ensembl release 89: ENSMUSG00000040592 - Ensembl, May 2017 Human PubMed Reference:. Mouse PubMed Reference:. Entrez Gene: CD79B CD79b molecule, immunoglobulin-associated beta. Reth M (1992). Antigen receptors on B lymphocytes. Annu. Rev. Immunol. 10: 97-121. ...
These collective observations support a model in which a CD22, EndoU, and c-Myc expression axis controls B cell fate after BCR ligation in B6 mice. EndoU levels remain low in WT[B6] B cells, allowing robust c-Myc expression and cell cycle progression after BCR engagement. In contrast, chronically high EndoU expression by CD22−/−[B6] B cells prevents c-Myc up-regulation after BCR ligation, resulting in AICD. EndoU was a major regulator of AICD in CD22−/−[B6] and IgTgsHEL mice, although additional unknown mechanisms undoubtedly also contribute to this complex regulatory process.. EndoU overexpression in vivo also occurred in response to BCR signals generated in IgTgsHEL mice, where B cells displayed a CD5highHSAhighIgMlow phenotype and failed to up-regulate c-Myc expression as was observed in CD22−/−[B6] mice. Genetic deletion of EndoU normalized this B cell phenotype in a substantial number of IgTgsHEL mice, which correlated with robust anti-HEL auto-Ab responses at an early age in ...
The quantity and quality of signals from the B cell antigen receptor (BCR) drives the positive and negative selection of B lymphocytes and establishes the balance of tolerance and immunity. Experiments using immunoglobulin transgenic mice and mutations in key BCR signalling components have given insight into how the antigen receptor is tuned and how thresholds for qualitatively different outcomes are established and maintained. This research also describes how genetic variants can shift the balance between autoimmunity and tolerance.
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The B lymphocyte antigen receptor is a multimeric complex that includes the antigen-specific component, surface immunoglobulin (Ig). Surface Ig non-covalently associates with two other proteins, Ig-alpha and Ig-beta, which are necessary for expression and function of the B-cell antigen receptor. This gene encodes the Ig-alpha protein of the B-cell antigen component. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008 ...
Capacitative Ca2+ entry (CCE) activated by release/depletion of Ca2+ from internal stores represents a major Ca2+ influx mechanism in lymphocytes and other nonexcitable cells. Despite the importance of CCE in antigen-mediated lymphocyte activation, molecular components constituting this mechanism remain elusive. Here we demonstrate that genetic disruption of transient receptor potential (TRP)1 significantly attenuates both Ca2+ release-activated Ca2+ currents and inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release from endoplasmic reticulum (ER) in DT40 B cells. As a consequence, B cell antigen receptor-mediated Ca2+ oscillations and NF-AT activation are reduced in TRP1-deficient cells. Thus, our results suggest that CCE channels, whose formation involves TRP1 as an important component, modulate IP3 receptor function, thereby enhancing functional coupling between the ER and plasma membrane in transduction of intracellular Ca2+ signaling in B lymphocytes ...
In this study, it was shown that IL-4-mediated signals were strikingly but transiently inhibited by TCR engagement of naive T cells. This inhibition involved triggering of both the PKC-MAPK and calcineurin pathways. It has recently been reported by Ivashkiv and colleagues that the IL-2 signal was inhibited by TCR engagement in preactivated T cells and the inhibition was mediated by the PKC-MAPK pathway (35). We have also checked the IL-4 signal in activated cells and observed results quite similar to those described above for naive T cells (data not shown). In addition, we found that the IL-2 signal was also inhibited by TCR engagement in naive T cells. McMahon and colleagues have shown that sustained activation of the Raf-MEK-ERK pathway elicited cytokine unresponsiveness in T cells (46). These results are consistent in indicating that MAPK plays an important role in the cross-talk between TCR and cytokine signals. Our data further show that although MAPK activation is necessary, it is not ...
V region of the variable domain of immunoglobulin heavy chains that participates in the antigen recognition (PubMed:24600447). Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic
V region of the variable domain of immunoglobulin heavy chains that participates in the antigen recognition. Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, ...
Measuring signaling kinetics allowed identification of two different ways the strength of BCR signaling is regulated in primary B cells. BCR-mediated signaling might be amplified by activating a greater number of the existing signaling molecules without changing activation and deactivation kinetics (i.e., more phosphorylated Syk per cell at a critical time). Alternatively, BCR signaling output might be altered by extending the time over which a given number of molecules in each cell were active, either by achieving maximal signaling more quickly or by extending the time at which maximum signaling is sustained. Our results show that B cells with an IgG BCR maintain ERK1/2 signaling over a significantly greater time than B cells with an IgM BCR (Fig. 2⇑). In contrast, our results in IgM isotype B cells show that PTPs were activated to remove phosphorylation of Syk and ERK1/2 within 4-8 min following BCR engagement (Figs. 2⇑ and 4⇑).. This contrast between weaker, transient signaling kinetics ...
Antigen receptor stimulation of mature alpha beta T lymphocytes can lead either to proliferation or death. Programmed cell death, termed apoptosis, leads to the clonal deletion of both thymocytes and mature T cells that establishes tolerance. How a mature T cell selects between proliferation and dea …
B cells are an important component of adaptive immunity. They produce and secrete millions of different antibody molecules, each of which recognizes a different (foreign) antigen. The B cell receptor (BCR) is an integral membrane protein complex that is composed of two immunoglobulin (Ig) heavy chains, two Ig light chains and two heterodimers of Ig-alpha and Ig-beta. After BCR ligation by antigen, three main protein tyrosine kinases (PTKs) -the SRC-family kinase LYN, SYK and the TEC-family kinase BTK- are activated. Phosphatidylinositol 3-kinase (PI3K) and phospholipase C-gamma 2 (PLC-gamma 2) are important downstream effectors of BCR signalling. This signalling ultimately results in the expression of immediate early genes that further activate the expression of other genes involved in B cell proliferation, differentiation and Ig production as well as other processes ...
B cells are an important component of adaptive immunity. They produce and secrete millions of different antibody molecules, each of which recognizes a different (foreign) antigen. The B cell receptor (BCR) is an integral membrane protein complex that is composed of two immunoglobulin (Ig) heavy chains, two Ig light chains and two heterodimers of Ig-alpha and Ig-beta. After BCR ligation by antigen, three main protein tyrosine kinases (PTKs) -the SRC-family kinase LYN, SYK and the TEC-family kinase BTK- are activated. Phosphatidylinositol 3-kinase (PI3K) and phospholipase C-gamma 2 (PLC-gamma 2) are important downstream effectors of BCR signalling. This signalling ultimately results in the expression of immediate early genes that further activate the expression of other genes involved in B cell proliferation, differentiation and Ig production as well as other processes ...
The advent of new live cell imaging techniques has provided both the temporal and spatial resolution over the time and length scales that are critical to decipher the earliest events in B cell activation. Although our understanding of these events is still incomplete, recent results from high resolution live cell imaging studies are providing the first glimpse into the process by which B cell signaling is initiated (9, 10, 38). Here we investigated the effect of colligating the FcγRIIB to the BCR through ICs on these early events, by imaging both the BCR and FcγRIIB during the first stages of B cell encounter of ICs incorporated into a planar lipid bilayer to mimic an APC surface. We conclude that the FcγRIIB blocks the earliest events in BCR activation including the formation of signaling active, immobile BCR oligomers and the transition of the cytoplasmic domains from a closed to a signaling active open conformation. The FcγRIIB accomplished this as it stably associated with raft ...
The CD79a molecule (MB-1, Igα) is part of the MB-1/B29 (CD79a/CD79b) disulfide-linked heterodimer which is non-covalently associated with membrane immunoglobulins (Igs) to build the B Cell antigen Receptor (BCR) complex.
We previously reported that B-cell receptor (BCR) signaling promoted a concomitant decrease of CXCR4 and CD62L membrane expression only in progressive cases of chronic lymphocytic leukemia (CLL). Recently, Quiroga and colleagues raised some challenging issues and pointed out discrepancies between the two reports.. In their letter, Quiroga and colleagues questioned our BCR stimulation protocol. Several studies, including ours, reported that soluble anti-immunoglobulin M (IgM) resulted in apoptosis, whereas immobilized anti-IgM or F(ab)2 fragment both sustained cell survival (1-3). Hence, the increased cell survival following soluble F(ab)2 exposure observed by Quiroga and colleagues is rather surprising.. We showed that downregulation of CXCR4 was associated with a reduced migration toward CXCL12. Our results are in agreement with numerous reports in various cell types including CLL cells (4). Quiroga and colleagues reported a similar CXCR4 decrease but associated to an unexplained increased ...
Figure 1. BCR development. The progenitor cell undergoes recombination of V, D, and J segments in the germline, which generates two identical heavy chains. Recombination of V and J segments generates two identical light chains. Random nucleotide additions or deletions at the junctions of the V, D, and J segments provide additional diversity. Furthermore, B cells activated by immune responses undergo somatic hypermutation (SHM), in which additional point mutations are introduced.. Understanding the profiles of BCRs, (i.e., sequencing the full-length CDR3 regions to determine the diversity of receptors and the clonotypes, defined by expression of specific H, K, and L gene segments) can not only aid in gaining insights into the adaptive immune response in healthy individuals, but also in those with a wide range of conditions, including infectious diseases, allergies, autoimmune disorders, cancers, and aging (Yaari & Kleinstein, 2015). Accurate determination of the clonotypes and isotypes expressed ...
Figure 1. BCR development. The progenitor cell undergoes recombination of V, D, and J segments in the germline, which generates two identical heavy chains. Recombination of V and J segments generates two identical light chains. Random nucleotide additions or deletions at the junctions of the V, D, and J segments provide additional diversity. Furthermore, B cells activated by immune responses undergo somatic hypermutation (SHM), in which additional point mutations are introduced.. Understanding the profiles of BCRs, (i.e., sequencing the full-length CDR3 regions to determine the diversity of receptors and the clonotypes, defined by expression of specific H, K, and L gene segments) can not only aid in gaining insights into the adaptive immune response in healthy individuals, but also in those with a wide range of conditions, including infectious diseases, allergies, autoimmune disorders, cancers, and aging (Yaari & Kleinstein, 2015). Accurate determination of the clonotypes and isotypes expressed ...
THE IgM B-CELL RECEPTOR a a THE IgM B-CELL RECEPTOR antigen binding mIg molecule H L V b a Ig-a/Ig-b heterodimer Signal transduction Lyn Kinases Syk Btk SHP-1 Phosphatases SLP-65/BLNK PLC HS1 Vav Adaptors + substrates
Chapter 6 Healthy humans have approximately 3x10 9 B-cells in the peripheral blood and this population encompasses the repertoire of distinct B-cells expressing different B- cell receptors (BCRs) necessary
Page details technical specifications, development, and operational history of the SIG SG 716 (Sturmgewehr Model 716) including pictures.
We investigated the role of the T cell antigen receptor (TcR) in control of T cell migration in an in vitro system. We used T cells from transgenic mice bearing a TcR for the lysozyme peptide 48-62 bound to I-A(k) (3A9). T cells from the 3A9 TcR transgenic mice crawled on purified intercellular adhesion molecule-1 substrates, but strikingly, stopped upon interaction with the physiological ligand, i.e., the mouse I-A(k) with covalently attached hen egg white lysozyme peptide residues 48-62 complex. TcR-triggered stopping was reversible by treatment with adhesion-strengthening phorbol esters. The microtubule organizing center of stopped cells was positioned adjacent to the site of stable cell anchorage. Direct conversion of lymphocyte function associated-1 to the high-affinity conformation with antibodies also stopped T cells in a similar manner to antigen. Thus, physiological TcR engagement triggers a stop signal through lymphocyte function associated-1. We propose that the stop signal is an early and
B cell Ag receptor (BCR) signaling changes dramatically during B cell development, resulting in activation in mature B cells and apoptosis, receptor editing, or anergy in immature B cells. BCR signaling in mature B cells was shown to be initiated by the translocation of the BCR into cholesterol- and sphingolipid-enriched membrane microdomains that include the Src family kinase Lyn and exclude the phosphatase CD45. Subsequently the BCR is rapidly internalized into the cell. Here we show that the BCR in the immature B cell line, WEHI-231, does not translocate into lipid rafts following cross-linking nor is the BCR rapidly internalized. The immature BCR initiates signaling from outside lipid rafts as evidenced by the immediate induction of an array of phosphoproteins and subsequent apoptosis. The failure of the BCR in immature B cells to enter lipid rafts may contribute to the dramatic difference in the outcome of signaling in mature and immature B cells.
B-cell receptor (BCR) signaling pathways and interactions with the tumor microenvironment account for mantle cell lymphoma (MCL) cells survival in lymphoid organs. In several MCL cases, the WNT/β-catenin canonical pathway is activated and β-catenin accumulates into the nucleus. As both BCR and β-catenin are important mediators of cell survival and interaction with the microenvironment, we investigated the crosstalk between BCR and WNT/β-catenin signaling and analyzed their impact on cellular homeostasis as well as their targeting by specific inhibitors. β-catenin was detected in all leukemic MCL samples and its level of expression rapidly increased upon BCR stimulation. This stabilization was hampered by the BCR-pathway inhibitor Ibrutinib, supporting β-catenin as an effector of the BCR signaling. In parallel, MCL cells as compared with normal B cells expressed elevated levels of WNT16, a NF-κB target gene. Its expression increased further upon BCR stimulation to participate to the stabilization
TY - JOUR. T1 - The relationship between surface immunoglobulin isotype and immune function of murine b lymphocytes. T2 - II. Surface immunoglobulin isotopes on unprimed b cells in the spleen*. AU - Zan Bar, I.. AU - Vitetta, E. S.. AU - Strober, S.. N1 - Copyright: Copyright 2017 Elsevier B.V., All rights reserved.. PY - 1977/5/1. Y1 - 1977/5/1. N2 - We investigated the ability of IgM-, IgD-, and IgG-bearing cells from the spleens of unprimed (BALB/c × C57BL/Ka)F1 mice to restore the adoptive primary anti-BSA and anti-DNP antibody responses. Purified populations of isotype-specific cells were prepared by immunofluorescent staining and sorting on the fluorescence activated cell sorter. Bright or dull cells were transferred to irradiated syngeneic recipients which were challenged with DNPoBSA in complete Freunds adjuvant. Unfractionated spleen cells as well as IgM- and IgDbearing cells restored the adoptive primary IgM and IgG antibody response. IgG-bearing cells restored a vigorous adoptive ...
Required in cooperation with CD79B for initiation of the signal transduction cascade activated by binding of antigen to the B-cell antigen receptor complex (BCR) which leads to internalization of the complex, trafficking to late endosomes and antigen presentation. Also required for BCR surface expression and for efficient differentiation of pro- and pre-B-cells. Stimulates SYK autophosphorylation and activation. Binds to BLNK, bringing BLNK into proximity with SYK and allowing SYK to phosphorylate BLNK. Also interacts with and increases activity of some Src-family tyrosine kinases. Represses BCR signaling during development of immature B-cells.
Hepatitis C virus (HCV) causes B-cell lymphoproliferative disorders (LPDs) expressing stereotyped B-cell receptors (BCRs) endowed with rheumatoid factor (RF) activity and putatively recognizing the HCV E2 protein. To further untangle the shaping and function of these BCRs, we analyzed immunoglobulin gene rearrangements of monoclonal B cells from 13 patients with HCV-associated LPDs and correlated their features with the clinical outcomes of antiviral therapy. While only two patients shared a stereotyped heavy-chain complementarity determining region 3 (CDR3) sequence, two kappa chain CDR3 stereotyped sequences accounted for 77% of BCRs. Light chains were enriched in sequences homologous to anti-HCV E2 antibodies compared with heavy chains (7/13 vs. 0/13; p = 0.005). Anti-HCV E2 homology was uniquely associated (7/7 vs. 0/6; p = 0.0006) with a stereotyped CDR3 sequence encoded by IGKV3-20/3D-20 gene(s) accounting for 54% of BCRs. An IGKV3-15/IGKJ1-encoded stereotyped sequence homologous to WA RF
T-cell antigen receptor-induced signaling requires both ZAP-70 and Lck protein-tyrosine kinases. One essential function of Lck in this process is to phosphorylate ZAP-70 and up-regulate its catalytic activity. We have previously shown that after T-cell antigen receptor stimulation, Lck binds to ZAP-70 via its Src homology 2 (SH2) domain (LckSH2) and, more recently, that Tyr319 of ZAP-70 is phosphorylated in vivo and plays a positive regulatory role. Here, we investigated the possibility that Tyr319 mediates the SH2-dependent interaction between Lck and ZAP-70. We show that a phosphopeptide encompassing the motif harboring Tyr319, YSDP, interacted with LckSH2, although with a lower affinity compared with a phosphopeptide containing the optimal binding motif, YEEI. Moreover, mutation of Tyr319 to phenylalanine prevented the interaction of ZAP-70 with LckSH2. Based on these results, a gain-of-function mutant of ZAP-70 was generated by changing the sequence Y319SDP into Y319EEI. As a result of its increased
Clone REA499 recognizes the human and mouse CD27 antigen, a single-pass type I membrane protein, also known as tumor necrosis factor receptor superfamily member 7 (TNFRSF7). CD27 is a member of the nerve growth factor receptor family and is exclusively expressed on cells of the lymphoid lineage, mostly in an activation-specific manner, and all enhance T cell receptor (TCR)-induced T cell expansion. CD27 and its ligand, CD70, have been defined at the protein, cDNA, and genomic level in both human and mouse. It is found on natural killer (NK), T, and B cell populations. In human and mice, the majority of CD4+ and CD8+ naive peripheral T cells express CD27 and expression is up-regulated upon TCR stimulation. Loss of CD27 expression is irreversible and seems to represent terminal effector T cell differentiation. In humans, naive B cells lack CD27 but antigen receptor stimulation induces expression. CD27+ B cells display all the functional and phenotypic characteristics of memory cells. Additional
TY - JOUR. T1 - Effects of IL-4 and Fcγ receptor II engagement on Egr-1 expression during stimulation of B lymphocytes by membrane immunoglobulin crosslinking. AU - Klaus, Stephen J.. AU - Phillips, Nancy E.. AU - Parker, David C.. PY - 1993/11. Y1 - 1993/11. N2 - Egr-1 is an immediate early gene that is rapidly upregulated in response to mitogenic signals induced by antigen receptor crosslinking on murine B lymphocytes. It has been shown that levels of Egr-1 expression are closely correlated with B cell proliferation in several models of B cell activation and tolerance. We compared the expression of Egr-1 during B cell stimulation with Fab′2 and IgG anti-immunoglobulin (anti-IG), since it is known that Fab′2 anti-Ig is mitogenic while IgG anti-Ig is not, owing to a dominant inhibitory effect of crosslinking the B cell Fcγ RII to membrane Ig. While mitogenic doses of Fab′2 anti-Ig induce large and rapid increases in Egr-1 expression, IgG anti-Ig results in smaller increases in Egr-1 ...
We show here that approximately 25% of the mature peripheral B cells can survive in the mouse for at least 2 months without Syk, in a manner that requires BAFF‐R and CD19 signaling. In contrast, deletion of the Syk gene in early B cells results in the appearance of a small number of immature IgM+ B cells, which, however, fail to give rise to any mature B cells in the periphery (Cheng et al, 1995). Thus, pre‐B and mature B cells have different requirements for Syk. Indeed, the pre‐BCR is an autonomously signaling receptor that continuously engages Syk, whereas the BCR forms an autoinhibited oligomer on mature B cells that is not in contact with Syk. This notion is supported by a proximity ligation analysis showing that Syk is localized near the BCR only after BCR activation (Infantino et al, 2010; Klasener et al, 2014).. The presence of large amounts of Syk‐negative mature B cells in the induced mb1‐CreERT2;Sykfl/fl mice allowed us to analyze the in vivo role of this kinase in the ...
We show here that approximately 25% of the mature peripheral B cells can survive in the mouse for at least 2 months without Syk, in a manner that requires BAFF‐R and CD19 signaling. In contrast, deletion of the Syk gene in early B cells results in the appearance of a small number of immature IgM+ B cells, which, however, fail to give rise to any mature B cells in the periphery (Cheng et al, 1995). Thus, pre‐B and mature B cells have different requirements for Syk. Indeed, the pre‐BCR is an autonomously signaling receptor that continuously engages Syk, whereas the BCR forms an autoinhibited oligomer on mature B cells that is not in contact with Syk. This notion is supported by a proximity ligation analysis showing that Syk is localized near the BCR only after BCR activation (Infantino et al, 2010; Klasener et al, 2014).. The presence of large amounts of Syk‐negative mature B cells in the induced mb1‐CreERT2;Sykfl/fl mice allowed us to analyze the in vivo role of this kinase in the ...
Primary immunodeficiency diseases are inherited disorders that affect human adaptive and innate immunity. In most cases, affected individuals experience recurrent infections, but they may also suffer from autoimmune diseases and malignancies. This chapter focuses on Signal Transduction by T and B Lymphocyte Antigen Receptors, including the historic and scientific background, clinical presentations, immunologic characteristics, and the molecular/genetic underpinnings. Where appropriate, diagnostic tools and therapeutic options are outlined -- from prophylactic anti-infective measures to hematopoietic stem cell transplantation and gene therapy.
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Purpose: B-cell receptor signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). However, blocking B-cell receptor signaling with dasatinib, an inhibitor of SRC kinase, produced variable results in preclinical and clinical studies. We aim to define the molecular mechanisms underlying the differential dasatinib sensitivity and to uncover more effective therapeutic targets in CLL.. Experimental Design: Fresh CLL B cells were treated with dasatinib, and cell viability was followed. The CLL cases were then divided into good and poor responders. The cellular response was correlated with the activities of B-cell receptor signaling molecules, as well as with molecular and cytogenetic prognostic factors.. Results: Among 50 CLL cases, dasatinib treatment reduced cell viability by 2% to 90%, with an average reduction of 47% on day 4 of culture. The drug induced CLL cell death through the intrinsic apoptotic pathway mediated by reactive oxygen species. Unexpectedly, ...
Fingerprint Dive into the research topics of Cell surface immunoglobulin. XI. The appearance of an IgD like molecule on murine lymphoid cells during ontogeny. Together they form a unique fingerprint. ...
The immune system plays a powerful and central role in human health. The adaptive arm of the immune system consists of B and T cells that recognize antigen using lymphocyte antigen receptors, whose functionality and specificity is derived from gene rearrangements that form the T cell receptor (TCR) and B cell receptor (BCR). Methods to profile the phenotype and repertoire of immune cells typically rely on expensive single-cell sorting based approaches and are difficult to apply to low-input clinical samples, where antigen-specific cells are scarce. Towards this end, we have developed technologies that enable the profiling of single-cell transcriptomes with high resolution and scalability as well as the recovery and sequencing of lymphocyte antigen receptors. This allows us the ability to profile large numbers of cells recovered from clinical samples, to analyze the phenotypes of T and B cells in the context of their clonal lineages, and infer the epitope specificities of individual T and B ...
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The two major classes of antigen receptors on murine B lymphocytes, mIgM and mIgD, are both contained in a complex with two additional molecules, Ig-alpha and Ig-beta, which permit signal transduction. Accordingly, early biochemical events after antigen binding to either receptor are similar; biolog …
Cumulative evidence indicates that the CD19 coreceptor can induce positive signals that could enhance B cell responses. By regulating Src kinases and PI3K activity, it lowers the threshold of BcR-mediated signaling. Strikingly, study of CD19-/- mice revealed an apparent tight regulation of CD19 cell surface density during B cell development (Saito et al., 2002). In contrast to mice that overexpress CD19, CD19-/- mice have a markedly elevated BcR signaling threshold compared with wild-type mice. Reversibly, transgenic expression of low levels of human CD19 with normal levels of mouse CD19 resulted in hyperactive B cells and loss of tolerance to nuclear Ags (Sato etal., 2000). Since the product of PI3K, phosphatidyl inositol 3,4,5 trisphosphate, activates protein kinase B (PKB), which in turn promotes B cell survival, CD19 participates positively in B cell activation. Its positive effect on PI3K activity also may result in survival of immature B cells with low-affinity-binding BcRs, a potential ...
Phospholipase C (PLC) cleaves phosphatidylinositol 4,5-bisphosphate to form the second messengers inositol 1,4,5-trisphosphate and diacylglycerol. Recently, PLC-L2, a PLC-like protein that lacks lipase activity, has been identified in skeletal muscle, as well as in B and T lymphocytes. Takenaka et al. generated PLC-2-deficient mice to investigate the possible role of PLC-2 signaling in B lymphocytes. PLC-L2-deficient mature B cells showed an enhanced proliferative response and increased expression of the activation marker CD69 after B cell receptor (BCR) stimulation in vitro, and mice displayed increased production of immunoglobulin M (IgM), IgG1, and IgG3 in response to antigen treatment in vivo. The authors used fura-2 imaging to show that Ca2+ influx after BCR stimulation was enhanced in PLC-2-deficient cells; moreover, translocation of nuclear factor of activated T cells (which is regulated by calcineurin, which is itself calcium-dependent) was enhanced. Finally, PLC-2-deficient cells showed ...
B-cell malignancies are heterogeneous diseases, and despite recent therapeutic advances, a high proportion of patients relapse or are refractory to treatment (1). Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and is characterized by the accumulation of clonal nonfunctional B lymphocytes in blood, bone marrow, lymph nodes, spleen, and liver (2). The clinical course of disease varies significantly; some patients have indolent disease and survive many years without therapy, whereas others experience rapidly fatal disease (3). The emergence of anti-CD20 antibody (rituximab)-based chemoimmunotherapy has led to significant progress in lymphoma and CLL therapy. However, because disease progression is inevitable, novel drugs are needed to improve long-term management (1, 4).. Agents targeting B-cell receptor (BCR) signaling through its downstream effectors phosphoinositide 3-kinase (PI3K) and Brutons tyrosine kinase (BTK) have emerged as promising treatment options ...
Anti-inflammatory cytokines are IL-4, IL-10, IL-11, IL-13, IL-16, transforming growth factor β, soluble TNF-receptor and soluble interleukin-1 receptor. » ... « The alveolar bone proper is 0.1 to 0.4 mm thick and is consisted of a Harversian system and lamellated and bundle bone. » ... « The immune response to infection is regulated by the balance between T helper (Th) 1 and Th2 cytokines. The differentiation of Th1 and Th2 T cell subsets is determined by a number of factors, including the antigen itself, antigen dose, route of administration, nature of the antigen-presenting cell and co-stimulatory molecules. » ... « Lymphocytes comprise 20-40% (1000 - 4000 cells/μl) of all leukocytes. » ... « Markers/Receptors on B cells are Surface Immunoglobulin (IgM and IgD), CD40, B7, ICAM-1, LFA-1, MHC II, CD32 (Ig Fc receptor), CD35 (Receptor for complement component). » ... « Genes for HLA are clustered in MHC located on Chromosome 6: 6p21. » ... « Most leukotoxin producing strains of A. ...
Anti-inflammatory cytokines are IL-4, IL-10, IL-11, IL-13, IL-16, transforming growth factor β, soluble TNF-receptor and soluble interleukin-1 receptor. » ... « The alveolar bone proper is 0.1 to 0.4 mm thick and is consisted of a Harversian system and lamellated and bundle bone. » ... « The immune response to infection is regulated by the balance between T helper (Th) 1 and Th2 cytokines. The differentiation of Th1 and Th2 T cell subsets is determined by a number of factors, including the antigen itself, antigen dose, route of administration, nature of the antigen-presenting cell and co-stimulatory molecules. » ... « Lymphocytes comprise 20-40% (1000 - 4000 cells/μl) of all leukocytes. » ... « Markers/Receptors on B cells are Surface Immunoglobulin (IgM and IgD), CD40, B7, ICAM-1, LFA-1, MHC II, CD32 (Ig Fc receptor), CD35 (Receptor for complement component). » ... « Genes for HLA are clustered in MHC located on Chromosome 6: 6p21. » ... « Most leukotoxin producing strains of A. ...
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Brown, L D.; Shen, F W.; Uhr, J W.; and Vitetta, E S., The expression of lyb-2.1 On murine b lymphocytes. Abstr. (1978). Subject Strain Bibliography 1978. 1222 ...
mouse Dbnl protein: a 55 kDa actin-binding cytoskeleton adapter protein that is coupled to signal transduction from lymphocyte antigen receptors; a substrate for Src & Syk kinases; isolated from mouse; RefSeq NM_013810
The B-cell Antigen receptor constitutes a disulphide linked heterodimer, consisting of CD79a (mb1) and CD79b / B29 polypeptides which are
Depletion of XIAP restores caspase-3 processing and activity. Cytosolic extracts of L1236 and KMH2 cells and of control B cell L1309 were prepared, and equal am
Comparison of TLR4 ligand-exposed or nonexposed B cells in the iLN by intravital TP-LSM. (A) Imaging. Labeled LPS-activated and control B cells were transferr
Complete information for BCAP31 gene (Protein Coding), B-Cell Receptor Associated Protein 31, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
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Somatic assembly of T cell receptor and B cell receptor (BCR) genes produces a vast diversity of lymphocyte antigen recognition capacity. The advent of ...
The Enzyme Collection contains over 550 mAbs that recognize catalytic domains or associated regulatory subunits in enyme complexes
LYN-1604 is a potential ULK1 agonist with IC50 of 1.66 μM against MDA-MB-231 cells and it binds to wild-type ULK1 with a binding affinity in the nanom... Quality confirmed by NMR & HPLC. See customer reviews, validations & product citations.