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.

Intercellular adhesion molecule (ICAM) 1/CD54 plays an important role in T cell dependent B cell activation and for function of B lymphocytes as antigen-presenting cells. ICAM-1 expression is upregulated as a consequence of B lymphocyte antigen receptor (BCR) signaling, thereby serving to render antigen-stimulated B cells more receptive to T cell-mediated costimulatory signals. We have investigated BCR-induced expression of the Icam-1 gene in primary B cells and B cell lines and have found it to be dependent on BCR-induced expression of the transcription factor EGR1. Icam-1 transcription, induced by BCR cross-linking or bypassing the BCR with phorbol ester, is absent in a B cell line in which the EGR1-encoding gene (egr-1) is methylated and not expressed. A potential EGR1-binding site was located at -701 bp upstream of the murine Icam-1 gene transcription start site and shown by electrophoretic mobility shift assay to bind to murine EGR1. Mutation of this site in the context of 1.1 kb of the ...

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

The findings here demonstrate that selectively restoring B7.2 expression on otherwise self-tolerant B cells is sufficient to switch their fate from peripheral deletion to large-scale proliferation and autoantibody secretion during interactions with specific CD4+ T cells. Of the many early signals and responses to BCR engagement that are repressed or altered in tolerant B cells ((12)-(14)), the data here single out repression of the B7.2 response as being necessary to allow peripheral tolerance by FasL/Fas-mediated clonal abortion. The findings raise interesting questions about how B7.2 switches the outcome of interactions between tolerant B and T cells, and highlight the regulation of B7.2 in B cells as a key process that may be dysregulated by inherited or acquired triggers to systemic autoimmune disease.. Three possible mechanisms may in principle explain how dysregulated expression of B7.2 on tolerant B cells switches the outcome of interactions with autoantigen-specific T cells from deletion ...

Constant region of immunoglobulin heavy chains. 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, after exposure to antigen and selection, allow affinity maturation for

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 ...

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 ...

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. ...

The B cell receptor (BCR) consists of an antigen-binding membrane immunoglobulin (mIg) associated with the CD79α and CD79β heterodimer. Naïve B cells express the IgM and IgD isotypes, which have very short cytoplasmic tails and therefore depend on CD79α and CD79β for signal transduction. After antigenic stimulation, B cells undergo isotype switching to yield IgG, IgE, or IgA. Recent research suggests that the ability of the B cell coreceptor CD22 to regulate BCR signaling depends on the isotype of the mIg cytoplasmic tail. Cell lines that express a BCR with the cytoplasmic tail from IgG, the isotype found in memory B cells, are not subject to CD22 regulation, whereas cell lines that express BCRs with IgM cytoplasmic tails are subject to CD22 regulation. Moreover, stimulation through BCRs containing an IgG cytoplasmic tail causes increased numbers of antigen-specific clones to accumulate. These observations are a valuable step toward understanding the difference in B cell signaling between ...

Merck & Co., Inc., Kenilworth, NJ, USA is a global healthcare leader working to help the world be well. From developing new therapies that treat and prevent disease to helping people in need, we are committed to improving health and well-being around the world. The Merck Manual was first published in 1899 as a service to the community. The legacy of this great resource continues as the Merck Manual in the US and Canada and the MSD Manual in the remainder of the world. Learn more about our commitment to Global Medical Knowledge.. ...

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.

The role of BAFF in B cell self tolerance was examined by tracking the fate of anti-HEL self-reactive B cells in BAFF transgenic mice using four different models of self-reactive B cell deletion. BAFF overexpression did not affect the development of self-reactive B cells normally deleted in the bone marrow or during the early stages of peripheral development. By contrast, self-reactive B cells normally deleted around the late T2 stage of peripheral development were rescued from deletion, matured, and colonized the splenic follicle. Furthermore, self-reactive B cells normally selectively deleted from the marginal zone repopulated this compartment when excess BAFF was present. Self-reactive B cells rescued by excess BAFF were not anergic. BAFF overexpression therefore rescued only self-reactive B cells normally deleted with relatively low stringency and facilitated their migration into otherwise forbidden microenvironments. This partial subversion of B cell self tolerance is likely to underlie the

It is generally assumed that chronic lymphocytic leukemia of B cell origin (B-CLL) is characterized by the presence of surface membrane immunoglobulins (SmIg) and by the absence of cytoplasmic immunoglobulins (CyIg). In a variable number of cases SmI

Based on genetic studies that establish the role of spleen tyrosine kinase (Syk) in immune function, inhibitors of this kinase are being investigated as therapeutic agents for inflammatory diseases. Because genetic studies eliminate both adapter functions and kinase activity of Syk, it is difficult to delineate the effect of kinase inhibition alone as would be the goal with small-molecule kinase inhibitors. We tested the hypothesis that specific pharmacological inhibition of Syk activity retains the immunomodulatory potential of Syk genetic deficiency. We report here on the discovery of (4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino) pyrimidine-5-carboxamide acetate (P505-15), a highly specific and potent inhibitor of purified Syk (IC50 1-2 nM). In human whole blood, P505-15 potently inhibited B cell antigen receptor-mediated B cell signaling and activation (IC50 0.27 and 0.28 μM, respectively) and Fcε receptor 1-mediated basophil degranulation (IC50 0.15 μM). ...

Cluster of differentiation CD79A also known as B-cell antigen receptor complex-associated protein alpha chain and MB-1 membrane glycoprotein, is a protein that in humans is encoded by the CD79A gene. The CD79a protein together with the related CD79b protein, forms a dimer associated with membrane-bound immunoglobulin in B-cells, thus forming the B-cell antigen receptor (BCR). This occurs in a similar manner to the association of CD3 with the T-cell receptor, and enables the cell to respond to the presence of antigens on its surface. It is associated with agammaglobulinemia-3. The mouse CD79A gene, then called mb-1, was cloned in the late 1980s, followed by the discovery of human CD79A in the early 1990s. It is a short gene, 4.3 kb in length, with 5 exons encoding for 2 splice variants resulting in 2 isoforms. CD79A is conserved and abundant among ray-finned fish (actinopterygii) but not in the evolutionarily more ancient chondrichthyes such as shark. The occurrence of CD79A thus coincides with ...

Recently, neurabin-I and SAMD14 have been described as the autoantigenic target of approximately 66% of B-cell receptors (BCRs) of primary central nervous system lymphomas (PCNSL). Neurabin-I and SAMD14 share a highly homologous SAM domain that becomes immunogenic after atypical hyper-N-glycosylation (SAMD14 at ASN339 and neurabin-I at ASN1277). This post-translational modification of neurabin-I and SAMD14 seems to lead to a chronic immune reaction with B-cell receptor activation contributing to lymphoma genesis of PCNSLs. The selective tropism of PCNSL to the CNS corresponds well to the neurabin-I and SAMD14 protein expression pattern. When conjugated to Pseudomonas Exotoxin A (ETA´), the PCNSL reactive epitope exerts cytotoxic effects on lymphoma cells expressing a SAMD14/neurabin-I reactive BCR. Thus, the reactive epitopes of SAMD14/neurabin-I might be useful to establish additional therapeutic strategies against PCNSL. To test this possibility, we integrated the PCNSL-reactive epitope of SAMD14

Follicular B cell survival requires signaling from BAFFR, a receptor for BAFF and the B cell antigen receptor (BCR). This tonic BCR survival signal is distinct from that induced by antigen binding and may be ligand-independent. We show that inducible inactivation of the Syk tyrosine kinase, a key signal transducer from the BCR following antigen binding, resulted in the death of most follicular B cells because Syk-deficient cells were unable to survive in response to BAFF. Genetic rescue studies demonstrated that Syk transduces BAFFR survival signals via ERK and PI3 kinase. Surprisingly, BAFFR signaling directly induced phosphorylation of both Syk and the BCR-associated Igα signaling subunit, and this Syk phosphorylation required the BCR. We conclude that the BCR and Igα may be required for B cell survival because they function as adaptor proteins in a BAFFR signaling pathway leading to activation of Syk, demonstrating previously unrecognized crosstalk between the two receptors. ...

Dendritic cells (DCs) are the only APCs capable of initiating adaptive immune responses. The initiation of immune responses requires that DCs 1) internalize

Development of therapies for diffuse large B-cell lymphomas (DLBCL) requires a precise knowledge of signaling aberrations essential for tumor development. In normal B cells, the B cell receptor (BCR) initiates intracellular signals crucial for the survival and proliferation and may contribute to pathogenesis. Previous studies identified PKCbII, PKD1 and PKD3 as key DAG regulated downstream targets of BCR induced signaling and many refractory DLBCL tumors exhibit elevated expression of PKCbII. This correlates with activation of the PKCbII-NF-kB signaling cascade; and inhibition of PKCbII blocks the survival of these tumors in vitro. In this study, we show PKD2 is the predominant PKD family protein that is expressed and activated in response to BCR engagement in normal and malignant human B cells. Following BCR engagement in naïve B lymphocytes, activated PKD2 initially co-localizes with the BCR and then shuttles from the cytoplasm to the nucleus. We show using immunohistochemistry that ...

V region of the variable domain of immunoglobulin light 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:20176268, PubMed:22158414). 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, ...

miRs (microRNAs) post-transcriptionally regulate gene expression mainly by repressing translation or by inducing mRNA degradation. Dicer, an enzyme responsible for miR biogenesis, is required for T-cell function, suggesting regulatory roles for miRs in lymphocytes. However, specific roles for individual miRs are only just beginning to emerge. miR-155 is encoded within an exon of the non-coding RNA known as bic (B-cell integration cluster) and high levels of bic expression are induced upon antigen receptor stimulation of B- and T-cells, as well as TLR (Toll-like receptor) stimulation of macrophages and dendritic cells. High levels of bic/miR-155 are found in B-cell lymphomas and solid tumours, indicating that this locus may also be linked to cancer. Indeed, transgenic mice overexpressing miR-155 develop B-cell malignancies. To define the in vivo role of bic/miR-155 (bic), we have studied bic-deficient mice. These mice are immunodeficient and fail to generate high levels of class-switched antibody upon

Background About 30% of cases of chronic lymphocytic leukaemia (CLL) carry quasi-identical B-cell receptor immunoglobulins and can be assigned to distinct stereotyped subsets. Although preliminary evidence suggests that B-cell receptor immunoglobulin stereotypy is relevant from a clinical viewpoint, this aspect has never been explored in a systematic manner or in a cohort of adequate size that would enable clinical conclusions to be drawn. Methods For this retrospective, multicentre study, we analysed 8593 patients with CLL for whom immunogenetic data were available. These patients were followed up in 15 academic institutions throughout Europe (in Czech Republic, Denmark, France, Greece, Italy, Netherlands, Sweden, and the UK) and the USA, and data were collected between June 1, 2012, and June 7, 2013. We retrospectively assessed the clinical implications of CLL B-cell receptor immunoglobulin stereotypy, with a particular focus on 14 major stereotyped subsets comprising cases expressing ...

Subbarao, B and Mosier, D E., Lyb antigens and their role in b lymphocyte activation. (1982). Subject Strain Bibliography 1982. 1201 ...

BLNK: a central linker protein in B cell activation, 1998), activating its interaction sites and binding itself to BLNK. This protein lacks of catalytic activity; its task is to facilitate the protein-protein and protein-cytoplasmic membrane interaction among those elements involved in the initial phase of this signaling pathway (Adapter proteins in lymphocyte antigen-receptor signaling, 2000). BLNK can anchors itself to the cytoplasmic membrane thank to a leucine motif located on its N-terminal. When the B Cell Receptor (BCR) is activated, occurs a chain of events that actives the phosphatidylinositol-3 kinase (PI 3 K) which generates PIP 3 (Signalling of Brutons tyrosine kinase, Btk, 1999). It binds Btk, through the PH domain (A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains, 1997), causing its transfer from the cytosol to the cytoplasmic membrane; this process is facilitated by BLNK through its SH2 domain. Furthermore BLNK recruits the PLCγ2 ...

Antibody (Ab) affinity maturation enables an individual to maintain immunity to an increasing number of pathogens within the limits of a total Ig production threshold. A better understanding of this process is critical for designing vaccines that generate optimal Ab responses to pathogens. Our study describes a simple flow-cytometric method that enumerates virus-specific germinal center (GC) B cells as well as their AC50, a measure of Ab avidity, defined as the antigen concentration required to detect 50% of specific B cells. Using a model of mouse Ab responses to the influenza A virus hemagglutinin (IAV HA), we obtained data indicating that AC50 decreases with time postinfection in an affinity maturation-dependent process. As proof of principle of the utility of the method, our data clearly show that relative to intranasal IAV infection, intramuscular immunization against inactivated IAV in adjuvant results in a diminished GC HA B cell response, with increased AC50 correlating with an increased ...

TY - JOUR. T1 - Targeting B-cell anergy in chronic lymphocytic leukemia.. AU - Apollonio, Benedetta. AU - Scielzo, Cristina. AU - Bertilaccio, Maria Teresa Sabrina. AU - Ten Hacken, Elisa. AU - Scarfò, Lydia. AU - Ranghetti, Pamela. AU - Stevenson, Freda. AU - Packham, Graham. AU - Ghia, Paolo. AU - Muzio, Marta. AU - Caligaris-Cappio, Federico. PY - 2013/5/9. Y1 - 2013/5/9. N2 - B-cell receptor (BCR) triggering and responsiveness have a crucial role in the survival and expansion of chronic lymphocytic leukemia (CLL) clones. Analysis of in vitro response of CLL cells to BCR triggering allowed the definition of 2 main subsets of patients and lack of signaling capacity was associated with constitutive activation of extracellular-regulated kinases 1/2 (ERK1/2) and nuclear factor of activated T cells c1 (NF-ATc1), consistent with the idea that at least one group of CLL patients derives from the abnormal expansion of anergic B cells. In the present work, we further investigated the anergic subset of ...

B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1. Gene expression profiling identified two major subtypes of DLBCL, known as germinal centre B cell-like and activated B cell-like (ABC)2,3, that show poor outcomes after immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase signalling cascade of SYK, BTK and PKCß to promote the assembly of the CARD11-BCL10-MALT1 adaptor complex, which recruits and activates IκB kinase4-6. Genome sequencing revealed gain-of-function mutations that target the CD79A and CD79B BCR subunits and the Toll-like receptor signalling adaptor MYD885,7, with MYD88(L265P) being the most prevalent isoform. In a clinical trial, the BTK inhibitor ibrutinib produced responses in 37% of cases of ABC1. The most striking response rate (80%) was observed in tumours with both ...

This raised the question as to whether SpA might act as a superantigen, triggering activation of the BCR signaling pathway in a substantial proportion of MCL patients.. Therefore, we explored the interaction of SpA with lymphoma BCR-derived immunoglobulins harboring the SpA binding motif. Since SpA has a high affinity to the Fc domain of human IgG, representative MCL Igs were expressed as Fab fragments. Six different MCL- (with and without SpA binding motif), two CLL- and one FL-derived Fab fragments were produced and tested for SpA reactivity using an ELISA with coated SpA. In fact, all Fab fragments exhibiting the SpA binding motif bound to SpA in this assay, whereas Fab fragments without SpA binding motif were non-reactive (Figure 1B).. Having established that SpA binds to a substantial proportion of MCL-derived immunoglobulins in vitro, we next investigated whether this interaction is sufficient to activate the BCR signaling pathway in human B-cells expressing SpA-reactive MCL BCR. We ...

B cell receptor (BCR) signaling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1. Gene expression profiling identified two major DLBCL subtypes, known as germinal center (GC) B cell-like (GCB) and activated B cell-like (ABC)2,3, with inferior outcomes following immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase cascade of SYK, BTK and PKCβ to promote the assembly of the CARD11-BCL10-MALT1 (CBM) adapter complex that recruits and activates IκB kinase (IKK)4-6. Genome sequencing revealed gain-of-function mutations targeting the CD79A and CD79B BCR subunits and the Toll-like receptor (TLR) signaling adapter MYD885,7, with MYD88L265P being the most prevalent isoform. In a clinical trial, the BTK inhibitor, ibrutinib, produced responses in 37% of ABC cases1. The most striking response rate (80%) was observed in tumors with ...

SLP76 (SH2 domain-containing leukocyte protein of 76 kDa) is a cytosolic adaptor protein which translocates to the plasma mambrane and is involved in multiple signaling pathways in T cells, mast cells, neutrophils and platelets; B cells express its analog SLP65/BLNK (B cell linker protein). SLP76 is phosphorylated by Syk-family and Tec-family tyrosine kinases and couples them to the phosphorylation and activation of PLC-gamma. Via Gads or Grb2, SLP76 also associates with LAT adaptor by involvement of SLP76 proline-rich region. The SH2 domain of SLP76 has been identified as the region involved in binding the serine/threonine kinase HPK1. HPK1 may act as both a positive and a negative regulator by promoting the Jnk-mitogen activated protein kinase (MAPK) pathway and inhibiting the pathway leading to AP-1 activation ...

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Toll-like receptors (TLRs) play an important role in immune responses to pathogens by transducing signals in innate immune cells in response to microbial products. TLRs are also expressed on B cells, and TLR signaling in B cells contributes to antibody-mediated immunity and autoimmunity. The SYK tyrosine kinase is essential for signaling from the B cell antigen receptor (BCR), and thus for antibody responses. Surprisingly, we find that it is also required for B cell survival, proliferation, and cytokine secretion in response to signaling through several TLRs. We show that treatment of B cells with lipopolysaccharide, the ligand for TLR4, results in SYK activation and that this is dependent on the BCR. Furthermore, we show that B cells lacking the BCR are also defective in TLR-induced B cell activation. Our results demonstrate that TLR4 signals through two distinct pathways, one via the BCR leading to activation of SYK, ERK, and AKT and the other through MYD88 leading to activation of NF-κB ...

CD19 is a transmembrane glycoprotein of Ig superfamily expressed by B cells from the time of heavy chain rearrangement until plasma cell differentiation. It forms a tetrameric complex with CD21 (complement receptor type 2), CD81 (TAPA-1) and Leu13. Together with BCR (B cell antigen receptor), this complex signals to decrease B cell treshold for activation by the antigen. Besides being signal-amplifying coreceptor for BCR, CD19 can also signal independently of BCR coligation and it turns out to be a central regulatory component upon which multiple signaling pathways converge. Mutation of the CD19 gene results in hypogammaglobulinemia, whereas CD19 overexpression causes B cell hyperactivity ...

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a cytoplasmic linker or adaptor protein that plays a critical role in B cell development. This protein bridges B cell receptor-associated kinase activation with downstream signaling pathways, thereby affecting various biological functions. The phosphorylation of five tyrosine residues is necessary for this protein to nucleate distinct signaling effectors following B cell receptor activation. Mutations in this gene cause hypoglobulinemia and absent B cells, a disease in which the pro- to pre-B-cell transition is developmentally blocked. Deficiency in this protein has also been shown in some cases of pre-B acute lymphoblastic leukemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012 ...

Human B cells are currently not known to produce the proapoptotic protease granzyme B (GrB) in physiological settings. We have discovered that BCR stimulation with either viral Ags or activating Abs in the context of the acute phase cytokine IL-21 can induce the secretion of substantial amounts of GrB by human B cells. Importantly, GrB response to viral Ags was significantly stronger in B cells from subjects recently vaccinated against the corresponding viruses as compared with unvaccinated subjects. GrB-secreting B cells featured a homogeneous CD19+CD20+CD27−CD38−IgD− phenotype, improved survival, and enhanced expression of costimulatory, Ag-presenting and cell-adhesion molecules. B cell-derived GrB was enzymatically active and its induction required the activation of similar signaling pathways as those in CTLs. Our findings suggest that GrB-secreting B cells support the early antiviral immune response against viruses with endosomal entry pathways, thereby counteracting overwhelming viral ...

Immunoglobulin M (IgM)- Structure and Functions. IgM is an antigen receptor on B cells and the first antibody produced in an immune response.

Antigenic Determinants recognized and bound by the B-Cell receptor. Epitopes recognized by the B-Cell receptor are located on the surface of the Antigen ...

Dive into the research topics of p21(ras) function is important for T cell antigen receptor and protein kinase C regulation of nuclear factor of activated T cells. Together they form a unique fingerprint. ...

Induction and maintenance of unresponsiveness of B cells that recognize low valency autoantigens presents a challenging biological problem. Such antigens, even if they have high affinity for the BCR, are likely to induce relative weak signals because they do not aggregate receptors efficiently. Available evidence suggests that when autoantigen avidity and, consequently, ability to induce signaling is not sufficient to induce editing or clonal deletion, autoreactive B cells may be rendered anergic. Chronic stimulation by such antigens leads to changes in intracellular signaling circuitry that makes the cell unresponsive to a variety of signals, including aggregation of previously unoccupied BCR. This unresponsiveness is not durable, as would be expected if it were mediated by genetic reprogramming. Removal of autoantigen from BCR can lead to restoration of responsiveness within minutes, suggesting maintenance by activation of labile regulatory signaling pathways (Gauld et al., 2005). Definitive ...

Tirabrutinib HCl, also known as ONO-4059 HCl, is a potent and orally active Bruton agammaglobulinemia tyrosine kinase (BTK) in hibitor. Upon administration, ONO-4059 covalently binds to BTK within B cells, thereby preventing B-cell receptor signaling and impeding B-cell development. As a result, this agent may inhibit the proliferation of B-cell malignancies. BTK, a cytoplasmic tyrosine kinase and member of the Tec family of kinases, plays an important role in B lymphocyte development, activation, signaling, proliferation and survival.

The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. J Immunol. 1985 Aug; 135(2):973-9 ...

The immunoglobulin E (IgE) B cell receptor promotes plasma cell differentiation in the absence of cognate antigen and limits the competitive fitness of IgE+ B cells in germinal centers.

5. Oh H, Ozkirimli E, Shah K, Harrison ML, Geahlen RL. Generation of an analog-sensitive Syk tyrosine kinase for the study of signaling dynamics from the B cell antigen receptor. J Biol Chem. 2007 Nov 16;282(46):33760-8. Epub 2007 Oct 3. PubMed PMID: 17913708 ...

|p|Brutons tyrosine kinase (BTK) is a Tec family kinase that plays a critical role in B cell development. Upon B cell receptor engagement, BTK translocates to the plasma membrane, where it is transphosphorylated by LYN and SYK kinases at Tyr 551. This initial phosphorylation event is followed by au

Cambier JC, Morrison DC, Chien MM, Lehmann KR. Modeling of T cell contact-dependent B cell activation. IL-4 and antigen receptor ligation primes quiescent B cells to mobilize calcium in response to Ia cross-linking. J Immunol. 1991 Apr 01; 146(7):2075-82 ...

Function: Positive effector of BCR-stimulated responses. Couples the B-cell antigen receptor (BCR) to the mobilization of calcium ion either through a phosphoinositide 3-kinase-dependent pathway, when not phosphorylated on tyrosines of the linker region, or through a phospholipase C-gamma-dependent pathway, when phosphorylated on Tyr-348 and Tyr-352. Thus the differential phosphorylation of Syk can determine the pathway by which BCR is coupled to the regulation of intracellular calcium ion (By similarity ...

Abstract. The adaptive immune system uses several strategies to generate a repertoire of T- and B-cell antigen receptors with sufficient diversity to recognize

Neither the CD8 a or p chain gene rearranges during differentiation. Considering the high level of identity between the CD8 J-like sequence and those involved in rearrangement, this lack of rearrangement in CD8 raises interesting evolutionary possibilities that will be discussed later. The CD8 a! and p genes are single copy, are located within a few kilobases of each other, and are closely linked to the x light chain locus (J. Parnes, personal communication). , 1986). Even though CD4 and CD8 molecules appear to perform analogous functions with homologous ligands, class I1 and class I MHC molecules, respectively, they do not appear to share a recent common origin. The differential expression of alternately spliced products such as secreted versus membrane Ig and the developmentally expressed variants of N-CAM indicate that alternate RNA splicing provides a further level of functional diversity to the IgGSF. In fact, nearly all members examined to date generate alternate splicing products. Also, ...

Patients with chronic lymphocytic leukemia (CLL) assigned to stereotyped subset #4 express highly homologous B-cell receptor immunoglobulin (BcR IG) sequences with intense intraclonal diversification (ID) in the context ...

The protein encoded by this gene is a transcriptional repressor capable of binding an E-box element either as a homodimer or as a heterodimer with E2A in vitro. The encoded protein also forms heterodimers with E2A proteins in vivo. This protein is capable of inhibiting the transactivation capability of E47, an E2A protein, in mammalian cells. This gene is a downstream target of the B-cell receptor signal transduction pathway. [provided by RefSeq, Jul 2008 ...

In summary: After a point with (probably multiple) κ rearrangement failures, both κ loci (usually) get deleted, leaving only λ. So if a B cell expressing a BCR with λ is self-reactive, it wont have the chance to rearrange its κ.. However, theres a lot more involved. For one, its possible to get a functional and non-self-reactive λ chain BCR without repeated κ rearrangement failures.. Since the quoted passage might be confusing out of context, Id like to mention briefly that your questions description of light chain recombination is very simplified. In reality, there are many additional mechanisms involved and many different paths to get a functional κ rearrangement, a functional λ rearrangement, neither, or even both. Moreover, theres a lot we dont know, since we learn one experiment at a time, and we cant always directly measure what wed like to.. First, rearrangement has been observed to occur simultaneously in κ and λ. This fact might explain why its possible to get a ...

The Microbe collection is a diverse group of mAbs that recognize primarily surface components of prokaryotes including bacteria and viruses

If you want to install a new completion file, for example django_bash_completion, then simply add the script to /etc/bash_completion.d/. The rest is taken care of.

マウス・モノクローナル抗体 ab1890 交差種: Ms,Rat,Hu 適用: WB,IP,ICC,Flow Cyt,ICC/IF…Lyn抗体一覧…画像、プロトコール、文献などWeb上の情報が満載のアブカムの Antibody 製品。国内在庫と品質保証制度も充実。