B cell antigen receptor signaling 101

Porto, Joseph M. Dal; Gauld, Stephen B.; Merrell, Kevin; Mills, David; Pugh‐Bernard, Aimee E.; Cambier, John C.

doi:10.1016/j.molimm.2004.04.008

Cited by 491 publications

(515 citation statements)

References 191 publications

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“…Inhibition of Lyn showed suppression of microglial activation in an Alzheimer's disease model 80. Phosphorylation at tyrosine 397 (p‐Tyr397‐Lyn) is required for Lyn to perform its functional kinase activity81 to effect downstream proinflammatory pathways 79. Hence our observation of downregulation of p‐Tyr397‐Lyn suggests a possible mechanism by which CN‐105 reduces microglial activation.…”

Section: Discussionmentioning

confidence: 69%

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Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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ObjectiveAt present, the absence of a pharmacological neuroprotectant represents an important unmet clinical need in the treatment of ischemic and traumatic brain injury. Recent evidence suggests that administration of apolipoprotein E mimetic therapies represent a viable therapeutic strategy in this setting. We investigate the neuroprotective and anti‐inflammatory properties of the apolipoprotein E mimetic pentapeptide, CN‐105, in a microglial cell line and murine model of ischemic stroke.MethodsTen to 13‐week‐old male C57/BL6 mice underwent transient middle cerebral artery occlusion and were randomly selected to receive CN‐105 (0.1 mg/kg) in 100 μL volume or vehicle via tail vein injection at various time points. Survival, motor‐sensory functional outcomes using rotarod test and 4‐limb wire hanging test, infarct volume assessment using 2,3,5‐Triphenyltetrazolium chloride staining method, and microglial activation in the contralateral hippocampus using F4/80 immunostaining were assessed at various time points. In vitro assessment of tumor necrosis factor‐alpha secretion in a microglial cell line was performed, and phosphoproteomic analysis conducted to explore early mechanistic pathways of CN‐105 in ischemic stroke.ResultsMice receiving CN‐105 demonstrated improved survival, improved functional outcomes, reduced infarct volume, and reduced microglial activation. CN‐105 also suppressed inflammatory cytokines secretion in microglial cells in vitro. Phosphoproteomic signals suggest that CN‐105 reduces proinflammatory pathways and lower oxidative stress.Interpretation CN‐105 improves functional and histological outcomes in a murine model of ischemic stroke via modulation of neuroinflammatory pathways. Recent clinical trial of this compound has demonstrated favorable pharmacokinetic and safety profile, suggesting that CN‐105 represents an attractive candidate for clinical translation.

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Section: Discussionmentioning

confidence: 69%

“…For example, CN‐105 may suppress microglial activation through the deactivation of Lyn. Lyn belongs to the Src family of tyrosine kinases predominantly expressed in granulocytes78 and involved in early B‐cell signaling pathway 79. Inhibition of Lyn showed suppression of microglial activation in an Alzheimer's disease model 80.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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“…The 2R.50 T cells express MHC class II (I-A d )-restricted TCR specific for rabbit IgG and were maintained and used as previously described (34,35). The LK35.2 B cell transfectant (HyHEL10), which expresses a hen egg lysozyme (HEL)-specific IgM BCR, and 2G7 T cells, which express a MHC class II (I-E k )-restricted TCR specific for HEL [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] , were gifts from F. Batista (Medical Research Laboratory of Molecular Biology, Cambridge, U.K.) and were maintained and used as previously described (36).…”

Section: Cellsmentioning

confidence: 99%

“…This process is initiated by triggering the BCRs, which dictate the specificity of response and regulate B cell survival, activation, and differentiation. Crosslinking of the BCRs by Ag triggers a cascade of signaling events initiated by ITAM phosphorylation at the Ig␣ and Ig␤ subunits of the BCR by Src family kinases (1,2). BCR-Ag complexes are internalized into early endosomes and subsequently traffic into the late endocytic compartments, where they are degraded into peptides, loaded onto MHC class II, and displayed on the surface of B cells (3).…”

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confidence: 99%

Requirement for Phosphoinositide 3-Kinase p110δ Signaling in B Cell Antigen Receptor-Mediated Antigen Presentation

Al‐Alwan

Okkenhaug

Vanhaesebroeck

et al. 2007

The Journal of Immunology

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The BCR serves to both signal cellular activation and enhance uptake and presentation of Ags by B cells; however, the intracellular signaling mechanisms linking the BCR to Ag presentation functions have been controversial. PI3Ks are critical signaling enzymes controlling many cellular processes, with the p110δ isoform playing a critical role in BCR signaling. In this study, we used pharmacological and genetic approaches to evaluate the role of p110δ signaling in Ag presentation by primary B lymphocytes. It was found that activation of allogeneic T cells is significantly reduced when B cells are pretreated with global PI3K inhibitors, but was intact when p110δ signaling was specifically inactivated. In contrast, inactivation of p110δ significantly impaired the ability of B cells to activate T cells in a BCR-mediated Ag uptake and presentation model. Prestimulation of p110δ-inactivated B cells with anti-CD40 or LPS could not rescue their BCR-mediated Ag presentation ability to normal levels. p110δ signaling was required for efficient presentation of either anti-Ig or protein Ag via a lysozyme-specific BCR. p110δ-inactivated B cells were able to internalize Ag normally, and no defects in association of Ag with lysosome-associated membrane protein 1+ late endosomes were observed; however, these cells were less effective in forming polarized conjugates with Ag-specific T cells. Our data demonstrate a role for p110δ signaling in B cell Ag presentation function, implicating 3-phosphoinositides and their targets in the latter stages of this process.

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“…BCR stimulation induces either B cell proliferation or activationinduced cell death (AICD) through various BCR-mediated signaling pathways, including levels of intracellular Ca 2+ mobilization and activation of MAPKs and NF-kB, which are regulated by the phosphorylation status of various signaling molecules (9)(10)(11)(12). In BCR-mediated MAPK signaling, ERK is involved in cell proliferation (13,14), and JNK and p38 are involved in stress response and cell death (15)(16)(17).…”

mentioning

confidence: 99%

Transgenic Overexpression of G5PR That Is Normally Augmented in Centrocytes Impairs the Enrichment of High-Affinity Antigen-Specific B Cells, Increases Peritoneal B-1a Cells, and Induces Autoimmunity in Aged Female Mice

Kitabatake

Toda

Kuwahara

et al. 2012

The Journal of Immunology

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To investigate signals that control B cell selection, we examined expression of G5PR, a regulatory subunit of the serine/threonine protein phosphatase 2A, which suppresses JNK phosphorylation. G5PR is upregulated in activated B cells, in Ki67-negative centrocytes at germinal centers (GCs), and in purified B220+Fas+GL7+ mature GC B cells following Ag immunization. G5PR rescues transformed B cells from BCR-mediated activation-induced cell death by suppression of late-phase JNK activation. In G5PR-transgenic (G5PRTg) mice, G5PR overexpression leads to an augmented generation of GC B cells via an increase in non-Ag–specific B cells and a consequent reduction in the proportion of Ag-specific B cells and high-affinity Ab production after immunization with nitrophenyl-conjugated chicken γ-globulin. G5PR overexpression impaired the affinity–maturation of Ag-specific B cells, presumably by diluting the numbers of high-affinity B cells. However, aged nonimmunized female G5PRTg mice showed an increase in the numbers of peritoneal B-1a cells and the generation of autoantibodies. G5PR overexpression did not affect the proliferation of B-1a and B-2 cells but rescued B-1a cells from activation-induced cell death in vitro. G5PR might play a pivotal role in B cell selection not only for B-2 cells but also for B-1 cells in peripheral lymphoid organs.

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B cell antigen receptor signaling 101

Cited by 491 publications

References 191 publications

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Requirement for Phosphoinositide 3-Kinase p110δ Signaling in B Cell Antigen Receptor-Mediated Antigen Presentation

Transgenic Overexpression of G5PR That Is Normally Augmented in Centrocytes Impairs the Enrichment of High-Affinity Antigen-Specific B Cells, Increases Peritoneal B-1a Cells, and Induces Autoimmunity in Aged Female Mice

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