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Immunology May 2012B-cell activation is triggered by the binding of antigen to the B-cell receptor (BCR). The early molecular events triggered by BCR binding of ligand have been... (Review)
Review
B-cell activation is triggered by the binding of antigen to the B-cell receptor (BCR). The early molecular events triggered by BCR binding of ligand have been well-characterized both biochemically and using optical microscopy techniques to visualize B-cell activation as it happens. However, we understand much less about the BCR before activation. For this reason, this review will address recent advances in our view of the structure, organization and dynamics of the resting, unstimulated BCR. These parameters have important implications for our understanding of the initiation of B-cell activation and will be discussed in the context of current models for BCR activation. These models include the conformation-induced oligomerization model, in which binding of antigen to monomeric BCR induces a pulling or twisting force causing conformational unmasking of a clustering interface in the Cμ4 domain. Conversely, the dissociation activation model proposes that BCRs exist in auto-inhibitory oligomers on the resting B-cell surface and binding of antigen promotes the dissociation of the BCR oligomer exposing phosphorylation residues within Igα/Igβ. Finally, the collision coupling model suggests that BCR are segregated from activating co-receptors or kinases and activation is associated with changes in BCR mobility on the cell surface, which allows for the functional interaction of these elements.
Topics: B-Lymphocytes; Cell Polarity; Humans; Ligands; Lymphocyte Activation; Protein Transport; Receptors, Antigen, B-Cell
PubMed: 22269039
DOI: 10.1111/j.1365-2567.2012.03564.x -
Journal of Periodontal Research Jul 1989The evidence that periodontitis-associated bacteria contain potent PBA factors is very strong. Clearly, antibodies directed against non-oral antigens are produced in the... (Review)
Review
The evidence that periodontitis-associated bacteria contain potent PBA factors is very strong. Clearly, antibodies directed against non-oral antigens are produced in the inflamed periodontal lesion, and PBA appears to contribute to that production. It is also clear that B cells and plasma cells are the major cell types in the periodontal lesion. Furthermore, alterations in the regulation of B-cell responses to PBA factors are associated with severe periodontal disease. However, evidence demonstrating that activated B cells and plasma cells are directly involved in the pathogenic mechanisms leading to destruction of the periodontal support is still circumstantial. Polyclonal B-cell activation and potential pathways by which PBA-stimulated cells could be involved in periodontal destruction remain largely hypothetical. It appears that IL-1 is an important osteoclast-activating agent, and that LPS, which is a potent PBA factor in many systems, can elicit IL-1 production by B cells as well as by the monocyte/macrophage lineage. Recent data indicating that IL-1 is produced by numerous malignant B-cell lines lend support for the idea that B-cell IL-1 could be important in bone resorption. It is also likely that polyclonal activation may lead to production of autoantibody such as anti-type I and anti-type III collagens, and the destruction of self tissues through ADCC reactions, immune complex formation, and complement activation. Further research is needed to determine how the B cell/plasma cell may participate in tissue injury in periodontitis, and how the B-cell response to PBA factors is regulated.
Topics: Animals; B-Lymphocytes; Bacterial Physiological Phenomena; Humans; Lymphocyte Activation; Periodontitis; Plasma Cells
PubMed: 2528622
DOI: 10.1111/j.1600-0765.1989.tb01787.x -
Current Topics in Microbiology and... 2005The developmental program that commits a hematopoietic stem cell to the B lymphocyte lineage employs transcriptional regulators to enable the assembly of an antigen... (Review)
Review
The developmental program that commits a hematopoietic stem cell to the B lymphocyte lineage employs transcriptional regulators to enable the assembly of an antigen receptor complex with a useful specificity and with signalling competence. Once a naive IgM+ B cell is generated, it must correctly integrate signals from the antigen receptor with those from cytokine receptors and co-receptors delivering T cell help. The B cell responds through the regulated expression of genes that implement specific cell expansion and differentiation, secretion of high levels of high-affinity antibody, and generation of long-term memory. The transcriptional regulators highlighted in this chapter are those for which genetic evidence of function in IgM+ B cells in vivo has been provided, often in the form of mutant mice generated by conventional or conditional gene targeting. A critical developmental step is the maturation of bone marrow emigrant "transitional" B cells into the mature, long-lived cells of the periphery, and a number of the transcription factors discussed here impact on this process, yielding B cells with poor mitogenic responses in vitro. For mature B cells, it is clear that not only the nature, but the duration and amplitude of an activating signal are major determinants of the transcription factor activities enlisted, and so the ultimate outcome. The current challenge is the identification of the target genes that are activated to implement the correct response, so that we may more precisely and safely manipulate B cell behavior to predictably and positively influence humoral immune responses.
Topics: Animals; B-Lymphocytes; Humans; Lymphocyte Activation; Mice; Signal Transduction; Trans-Activators; Transcription Factors; Transcription, Genetic
PubMed: 16480041
DOI: 10.1007/3-540-26363-2_6 -
Immunological Reviews Aug 2000Signal transduction through the B-cell antigen receptor (BCR) determines the fate of B lymphocytes during their development and during immune responses. A multitude of... (Review)
Review
Signal transduction through the B-cell antigen receptor (BCR) determines the fate of B lymphocytes during their development and during immune responses. A multitude of signal transduction events are known to be activated by ligation of the BCR; however, the critical parameters determining the biological outcome of the signal transduction cascade are only just beginning to be understood. Two enzymes which act on plasma membrane phospholipids, phosphatidylinositol 3-kinase (PI3K) and phospholipase Cgamma (PLCgamma), have been implicated as critical mediators of B-cell activation and differentiation signals. Activation of these ubiquitous enzymes is regulated by B-lymphocyte-specific signal transduction proteins, such as CD 19 and B-cell linker protein. These enzymes function by generating both membrane-anchored and soluble second messenger molecules which regulate the activity of downstream signal transduction proteins. Active PI3K produces phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) and phosphatidylinositol-3,4-trisphosphate (PI(3,4,5)P3) which can bind to signaling proteins such as Btk or Akt via their pleckstrin homology domains, resulting in their membrane recruitment and activation. The lipid phosphatases SHIP and PTEN negatively regulate production of PI(3,4)P2 and PI(3,4,S)P3 and therefore function to put a "brake" on the PI3K pathway. Active PLCgamma produces inositol-1,4,5-trisphosphate, which regulates Ca2+ mobilization, and diacylglycerol, which binds to a subset of protein kinase C enzymes leading to their membrane localization and activation. Recent evidence has indicated that PLCgamma activation is partially dependent on the PI(3,4,5)P3 production by activated PI3K. Since PI3K and PLCgamma also share common downstream targets such as the NF-AT and NF-kappaB transcription factors, it is becoming clear that these two pathways are interconnected at several levels. Studies of mice deficient in components of the PI3K and PLCgamma pathways demonstrate that these pathways play critical roles in both pre-BCR and BCR-dependent selection events during B-cell differentiation. Taken together, the present data clearly indicate that PI3K and PLCgamma play critical and indispensable roles in the signal transduction cascades leading to multiple biological responses downstream of the BCR.
Topics: Animals; B-Lymphocytes; Cell Differentiation; Humans; Isoenzymes; Lymphocyte Activation; Mice; Models, Biological; Phosphatidylinositol 3-Kinases; Phospholipase C gamma; Receptors, Antigen, B-Cell; Second Messenger Systems; Signal Transduction; Type C Phospholipases
PubMed: 11043766
DOI: 10.1034/j.1600-065x.2000.00611.x -
International Immunopharmacology Jul 2021B-cell activating factor (BAFF) is an essential cytokine for B-cell maturation, differentiation and survival, and excess BAFF induces aggressive or neoplastic B-cell...
B-cell activating factor (BAFF) is an essential cytokine for B-cell maturation, differentiation and survival, and excess BAFF induces aggressive or neoplastic B-cell disorders and contributes to development of autoimmune diseases. Metformin, an anti-diabetic drug, has recently garnered a great attention due to its anti-proliferative and immune-modulatory features. However, little is known regarding the effect of metformin on BAFF-stimulated B cells. Here, we show that metformin attenuated human soluble BAFF (hsBAFF)-induced cell proliferation and survival by blocking the Erk1/2 pathway in normal and B-lymphoid (Raji) cells. Pretreatment with U0126, knockdown of Erk1/2, or expression of dominant negative MKK1 strengthened metformin's inhibition of hsBAFF-activated Erk1/2 and B-cell proliferation/viability, whereas expression of constitutively active MKK1 rendered high resistance to metformin. Further investigation found that overexpression of wild type PTEN or ectopic expression of dominant negative Akt potentiated metformin's suppression of hsBAFF-induced Erk1/2 activation and proliferation/viability in Raji cells, implying a PTEN/Akt-dependent mechanism involved. Furthermore, we noticed that metformin hindered hsBAFF-activated mTOR pathway in B cells. Inhibition of mTOR with rapamycin or knockdown of mTOR enhanced metformin's suppression of hsBAFF-induced phosphorylation of S6K1, PTEN, Akt, and Erk1/2, as well as B-cell proliferation/viability. These results indicate that metformin prevents BAFF activation of Erk1/2 from cell proliferation and survival by impeding mTOR-PTEN/Akt signaling pathway in normal and neoplastic B-lymphoid cells. Our findings support that metformin has a great potential for prevention of excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases.
Topics: Animals; B-Cell Activating Factor; B-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Hypoglycemic Agents; Lymphocyte Activation; Metformin; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; PTEN Phosphohydrolase; Primary Cell Culture; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 34004440
DOI: 10.1016/j.intimp.2021.107771 -
Frontiers in Immunology 2020Common variable immunodeficiency (CVID) is the most frequently diagnosed primary antibody deficiency. About half of CVID patients develop chronic non-infectious... (Review)
Review
Common variable immunodeficiency (CVID) is the most frequently diagnosed primary antibody deficiency. About half of CVID patients develop chronic non-infectious complications thought to be due to intrinsic immune dysregulation, including autoimmunity, gastrointestinal disease, and interstitial lung disease (ILD). Multiple studies have found ILD to be a significant cause of morbidity and mortality in CVID. Yet, the precise mechanisms underlying this complication in CVID are poorly understood. CVID ILD is marked by profound pulmonary infiltration of both T and B cells as well as granulomatous inflammation in many cases. B cell depletive therapy, whether done as a monotherapy or in combination with another immunosuppressive agent, has become a standard of therapy for CVID ILD. However, CVID is a heterogeneous disorder, as is its lung pathology, and the precise patients that would benefit from B cell depletive therapy, when it should administered, and how long it should be repeated all remain gaps in our knowledge. Moreover, some have ILD recurrence after B cell depletive therapy and the relative importance of B cell biology remains incompletely defined. Developmental and functional abnormalities of B cell compartments observed in CVID ILD and related conditions suggest that imbalance of B cell signaling networks may promote lung disease. Included within these potential mechanisms of disease is B cell activating factor (BAFF), a cytokine that is upregulated by the interferon gamma (IFN-γ):STAT1 signaling axis to potently influence B cell activation and survival. B cell responses to BAFF are shaped by the divergent effects and expression patterns of its three receptors: BAFF receptor (BAFF-R), transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA). Moreover, soluble forms of BAFF-R, TACI, and BCMA exist and may further influence the pathogenesis of ILD. Continued efforts to understand how dysregulated B cell biology promotes ILD development and progression will help close the gap in our understanding of how to best diagnose, define, and manage ILD in CVID.
Topics: B-Lymphocytes; Common Variable Immunodeficiency; Humans; Lung; Lung Diseases, Interstitial
PubMed: 33613556
DOI: 10.3389/fimmu.2020.622114 -
Frontiers in Immunology 2020Adjuvants enhance magnitude and duration of immune responses induced by vaccines. In this study we assessed in neonatal mice if and how the adjuvant LT-K63 given with a...
Adjuvants enhance magnitude and duration of immune responses induced by vaccines. In this study we assessed in neonatal mice if and how the adjuvant LT-K63 given with a pneumococcal conjugate vaccine, Pnc1-TT, could affect the expression of tumor necrosis factor receptor (TNF-R) superfamily members, known to be involved in the initiation and maintenance of antibody responses; B cell activating factor receptor (BAFF-R) and B cell maturation antigen (BCMA) and their ligands, BAFF, and a proliferation inducing ligand (APRIL). Initially we assessed the maturation status of different B cell populations and their expression of BAFF-R and BCMA. Neonatal mice had dramatically fewer B cells than adult mice and the composition of different subsets within the B cell pool differed greatly. Proportionally newly formed B cells were most abundant, but they had diminished BAFF-R expression which could explain low proportions of marginal zone and follicular B cells observed. Limited BCMA expression was also detected in neonatal pre-plasmablasts/plasmablasts. LT-K63 enhanced vaccine-induced BAFF-R expression in splenic marginal zone, follicular and newly formed B cells, leading to increased plasmablast/plasma cells, and their enhanced expression of BCMA in spleen and bone marrow. Additionally, the induction of BAFF and APRIL expression occurred early in neonatal mice immunized with Pnc1-TT either with or without LT-K63. However, BAFF and APRIL cells in spleens were maintained at a higher level in mice that received the adjuvant. Furthermore, the early increase of APRIL cells in bone marrow was more profound in mice immunized with vaccine and adjuvant. Finally, we assessed, for the first time in neonatal mice, accessory cells of the plasma cell niche in bone marrow and their secretion of APRIL. We found that LT-K63 enhanced the frequency and APRIL expression of eosinophils, macrophages, and megakaryocytes, which likely contributed to plasma cell survival, even though APRIL cells showed a fast decline. All this was associated with enhanced, sustained vaccine-specific antibody-secreting cells in bone marrow and persisting vaccine-specific serum antibodies. Our study sheds light on the mechanisms behind the adjuvanticity of LT-K63 and identifies molecular pathways that should be triggered by vaccine adjuvants to induce sustained humoral immunity in early life.
Topics: Animals; Animals, Newborn; B-Lymphocytes; Bacterial Toxins; Enterotoxins; Escherichia coli Proteins; Immunity, Humoral; Lymphocyte Activation; Mice
PubMed: 33193301
DOI: 10.3389/fimmu.2020.527310 -
Journal of Virology Aug 2017Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and...
Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block B cell receptor (BCR) signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction. Further investigation shows that mammalian target of rapamycin complex 2 (mTORC2) contributes to BCR-mediated lytic induction and that FK506-binding protein 12 (FKBP12) binding alone is not adequate to block activation. Finally, we show that BCR signaling can activate EBV lytic induction in freshly isolated B cells from peripheral blood mononuclear cells (PBMCs) and that activation can be inhibited by ibrutinib or idelalisib. EBV establishes viral latency in B cells. Activation of the B cell receptor pathway activates lytic viral expression in cell lines. Here we show that drugs that inhibit important kinases in the BCR signaling pathway inhibit activation of lytic viral expression but do not inhibit several other lytic activation pathways. Immunosuppressant drugs such as cyclosporine and tacrolimus but not rapamycin also inhibit BCR-mediated EBV activation. Finally, we show that BCR activation of lytic infection occurs not only in tumor cell lines but also in freshly isolated B cells from patients and that this activation can be blocked by BCR inhibitors.
Topics: B-Lymphocytes; Herpesvirus 4, Human; Humans; Immunologic Factors; Receptors, Antigen, B-Cell; Signal Transduction; Virus Activation
PubMed: 28566383
DOI: 10.1128/JVI.00747-17 -
Cold Spring Harbor Symposia on... 1977The evidence for the one, nonspecific signal hypothesis, which states that the B lymphocytes are activated by nonclonally distributed receptors which are not the Ig... (Review)
Review
The evidence for the one, nonspecific signal hypothesis, which states that the B lymphocytes are activated by nonclonally distributed receptors which are not the Ig receptors, has been summarized. Even though protein A is a polyclonal B-cell activator, it does not exert its effect by interacting with the Fc part of Ig receptors. One consequence of the one, nonspecific signal concept is that thymus-dependent antigens cannot activate or tolerize B cells. It was shown that B cells from animals tolerant to a thymus-dependent protein antigen could be activated by polyclonal B-cell activators to produce antibodies against the tolerogen. Experimentally induced tolerance did not differ from tolerance to self antigens, since LPS and PPD induced autoantibodies capable of lysing autologous red cells and isotope-labeled autologous and syngenic spleen cells. Thus B cells cannot discriminate self from non-self, whereas T cells have been shown to possess this ability.
Topics: Animals; Antibody Formation; Antigens; Autoantigens; B-Lymphocytes; Bacterial Proteins; Binding Sites; Binding Sites, Antibody; Clone Cells; DNA; Haptens; Immune Tolerance; Immunoglobulin Fc Fragments; Lymphocyte Activation; Lymphocytes; Polysaccharides, Bacterial; Receptors, Antigen, B-Cell; T-Lymphocytes
PubMed: 330090
DOI: 10.1101/sqb.1977.041.01.027 -
Genes & Development Jan 2018Earlier studies have identified transcription factors that specify B-cell fate, but the underlying mechanisms remain to be revealed. Two new studies by Miyai and... (Review)
Review
Earlier studies have identified transcription factors that specify B-cell fate, but the underlying mechanisms remain to be revealed. Two new studies by Miyai and colleagues (pp. 112-126) and Li and colleagues (pp. 96-111) in this issue of provide new and unprecedented insights into the genetic and epigenetic mechanisms that establish B-cell identity.
Topics: B-Lymphocytes; Cell Differentiation; Lymphocyte Activation; Trans-Activators; Transcription Factors
PubMed: 29449365
DOI: 10.1101/gad.311357.118