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Frontiers in Immunology 2021B cells are central to the pathogenesis of multiple autoimmune diseases, through antigen presentation, cytokine secretion, and the production of autoantibodies. During... (Review)
Review
B cells are central to the pathogenesis of multiple autoimmune diseases, through antigen presentation, cytokine secretion, and the production of autoantibodies. During development and differentiation, B cells undergo drastic changes in their physiology. It is emerging that these are accompanied by equally significant shifts in metabolic phenotype, which may themselves also drive and enforce the functional properties of the cell. The dysfunction of B cells during autoimmunity is characterised by the breaching of tolerogenic checkpoints, and there is developing evidence that the metabolic state of B cells may contribute to this. Determining the metabolic phenotype of B cells in autoimmunity is an area of active study, and is important because intervention by metabolism-altering therapeutic approaches may represent an attractive treatment target.
Topics: Autoimmune Diseases; Autoimmunity; Autophagy; B-Lymphocytes; Biomarkers; Disease Susceptibility; Energy Metabolism; Humans; Lymphocyte Activation; Lymphopoiesis; Molecular Targeted Therapy
PubMed: 34163480
DOI: 10.3389/fimmu.2021.681105 -
Frontiers in Immunology 2018The BAFF-receptor (BAFFR) is encoded by the TNFRSF13C gene and is one of the main pro-survival receptors in B cells. Its function is impressively documented in humans by... (Review)
Review
The BAFF-receptor (BAFFR) is encoded by the TNFRSF13C gene and is one of the main pro-survival receptors in B cells. Its function is impressively documented in humans by a homozygous deletion within exon 2, which leads to an almost complete block of B cell development at the stage of immature/transitional B cells. The resulting immunodeficiency is characterized by B-lymphopenia, agammaglobulinemia, and impaired humoral immune responses. However, different from mutations affecting pathway components coupled to B cell antigen receptor (BCR) signaling, BAFFR-deficient B cells can still develop into IgA-secreting plasma cells. Therefore, BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels.
Topics: Animals; Autoimmunity; B-Cell Activating Factor; B-Cell Activation Factor Receptor; B-Lymphocytes; Cell Survival; Gene Expression Regulation; Humans; Lymphopoiesis; Mice; Signal Transduction
PubMed: 30349534
DOI: 10.3389/fimmu.2018.02285 -
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 -
Nature Communications Nov 2021Integration of external signals and B-lymphoid transcription factor activities organise B cell lineage commitment through alternating cycles of proliferation and...
Integration of external signals and B-lymphoid transcription factor activities organise B cell lineage commitment through alternating cycles of proliferation and differentiation, producing a diverse repertoire of mature B cells. We use single-cell transcriptomics/proteomics to identify differentially expressed gene networks across B cell development and correlate these networks with subtypes of B cell leukemia. Here we show unique transcriptional signatures that refine the pre-B cell expansion stages into pre-BCR-dependent and pre-BCR-independent proliferative phases. These changes correlate with reciprocal changes in expression of the transcription factor EBF1 and the RNA binding protein YBX3, that are defining features of the pre-BCR-dependent stage. Using pseudotime analysis, we further characterize the expression kinetics of different biological modalities across B cell development, including transcription factors, cytokines, chemokines, and their associated receptors. Our findings demonstrate the underlying heterogeneity of developing B cells and characterise developmental nodes linked to B cell transformation.
Topics: B-Lymphocytes; CCAAT-Enhancer-Binding Proteins; Cell Proliferation; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Heat-Shock Proteins; Humans; Leukopoiesis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cells, B-Lymphoid; Prognosis; Proteomics; Single-Cell Analysis; Trans-Activators
PubMed: 34824268
DOI: 10.1038/s41467-021-27232-5 -
Journal of Immunology (Baltimore, Md. :... Nov 2016The ability to culture and expand B cells in vitro has become a useful tool for studying human immunity. A limitation of current methods for human B cell culture is the...
The ability to culture and expand B cells in vitro has become a useful tool for studying human immunity. A limitation of current methods for human B cell culture is the capacity to support mature B cell proliferation. We developed a culture method to support the efficient activation and proliferation of naive and memory human B cells. This culture supports extensive B cell proliferation, with ∼10-fold increases following 8 d in culture and 10-fold increases when cultures are split and cultured for 8 more days. In culture, a significant fraction of naive B cells undergo isotype switching and differentiate into plasmacytes. Culture-derived (CD) B cells are readily cryopreserved and, when recovered, retain their ability to proliferate and differentiate. Significantly, proliferating CD B cells express high levels of MHC class II, CD80, and CD86. CD B cells act as APCs and present alloantigens and microbial Ags to T cells. We are able to activate and expand Ag-specific memory B cells; these cultured cells are highly effective in presenting Ag to T cells. We characterized the TCR repertoire of rare Ag-specific CD4 T cells that proliferated in response to tetanus toxoid (TT) presented by autologous CD B cells. TCR Vβ usage by TT-activated CD4 T cells differs from resting and unspecifically activated CD4 T cells. Moreover, we found that TT-specific TCR Vβ usage by CD4 T cells was substantially different between donors. This culture method provides a platform for studying the BCR and TCR repertoires within a single individual.
Topics: Antigen-Presenting Cells; B-Lymphocytes; CD4 Antigens; CD4-Positive T-Lymphocytes; Cell Culture Techniques; Cell Line; Cell Proliferation; Cells, Cultured; Humans; Immunologic Memory; Lymphocyte Activation; Receptors, Antigen, T-Cell; Tetanus Toxoid
PubMed: 27815447
DOI: 10.4049/jimmunol.1502193 -
The Journal of Nutritional Biochemistry Feb 2019Zinc ions serve as second messengers in major cellular pathways, including the regulation pathways of proliferation and their proper regulation is necessary for...
Zinc ions serve as second messengers in major cellular pathways, including the regulation pathways of proliferation and their proper regulation is necessary for homeostasis and a healthy organism. Accordingly, expression of zinc transporters can be altered in various cancer cell lines and is often involved in producing elevated intracellular zinc levels. In this study, human B cells were infected with Epstein-Barr virus (EBV) to generate immortalized cells, which revealed traits of tumor cells, such as high proliferation rates and an extended lifespan. These cells showed differentially altered zinc transporter expression with ZIP7 RNA and protein expression being especially increased as well as a corresponding increased phosphorylation of ZIP7 in EBV-transformed B cells. Accordingly, free zinc levels were elevated within these cells. To prove whether the observed changes resulted from immortalization or rather high proliferation, free zinc levels in in vitro activated B cells and in freshly isolated B cells expressing the activation marker CD69 were determined. Here, comparatively increased zinc levels were found, suggesting that activation and proliferation, but not immortalization, act as crucial factors for the elevation of intracellular free zinc.
Topics: Adult; Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; B-Lymphocytes; Cation Transport Proteins; Cell Proliferation; Cells, Cultured; Herpesvirus 4, Human; Humans; Lectins, C-Type; Lymphocyte Activation; Mice; NIH 3T3 Cells; Phosphorylation; Zinc
PubMed: 30448545
DOI: 10.1016/j.jnutbio.2018.10.008 -
Journal of Virology Aug 2013Replication-deficient rabies viruses (RABV) are promising rabies postexposure vaccines due to their prompt and potent stimulation of protective virus neutralizing...
Replication-deficient rabies viruses (RABV) are promising rabies postexposure vaccines due to their prompt and potent stimulation of protective virus neutralizing antibody titers, which are produced in mice by both T-dependent and T-independent mechanisms. To promote such early and robust B cell stimulation, we hypothesized that live RABV-based vaccines directly infect B cells, thereby activating a large pool of antigen-presenting cells (APCs) capable of providing early priming and costimulation to CD4(+) T cells. In this report, we show that live RABV-based vaccine vectors efficiently infect naive primary murine and human B cells ex vivo. Infection of B cells resulted in the significant upregulation of early markers of B cell activation and antigen presentation, including CD69, major histocompatibility complex class II (MHC-II), and CD40 in murine B cells or HLA-DR and CD40 in human B cells compared to mock-infected cells or cells treated with an inactivated RABV-based vaccine. Furthermore, primary B cells infected with a live RABV expressing ovalbumin were able to prime and stimulate naive CD4(+) OT-II T cells to proliferate and to secrete interleukin-2 (IL-2), demonstrating a functional consequence of B cell infection and activation by live RABV-based vaccine vectors. We propose that this direct B cell stimulation by live RABV-based vaccines is a potential mechanism underlying their induction of early protective T cell-dependent B cell responses, and that designing live RABV-based vaccines to infect and activate B cells represents a promising strategy to develop a single-dose postexposure rabies vaccine where the generation of early protective antibody titers is critical.
Topics: Adult; Animals; B-Lymphocytes; CD4-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; Female; Humans; Interleukin-2; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Rabies Vaccines; Rabies virus; Vaccines, Attenuated
PubMed: 23760241
DOI: 10.1128/JVI.00800-13 -
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 -
Clinical and Experimental Immunology Dec 2017Analysis of B cell activating factor (BAFF) receptors before and after B cell depletion therapy (BCDT) might offer a clue to the understanding of whether some B cell... (Review)
Review
Analysis of B cell activating factor (BAFF) receptors before and after B cell depletion therapy (BCDT) might offer a clue to the understanding of whether some B cell subsets may represent useful biomarkers of biological and clinical responses. Among the BAFF receptors in a cohort of rheumatoid arthritis (RA) patients, the AA have shown, by fluorescence activated cell sorter (FACS) analysis of median fluorescence intensity (MFI), that transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) do not change, whereas the most important, BAFF receptor 3 (BR3), appears to be decreased before as well as after BCDT in all B cell subsets but not in plasmablasts, the most important subset, depleted by BCDT.
Topics: Animals; Arthritis, Rheumatoid; B-Cell Activating Factor; B-Cell Activation Factor Receptor; B-Lymphocytes; Flow Cytometry; Humans; Lymphocyte Depletion; Transmembrane Activator and CAML Interactor Protein
PubMed: 28834574
DOI: 10.1111/cei.13039 -
Clinical and Experimental Immunology Nov 2014The biologically active form of vitamin D3 , 1, 25-dihydroxyvitamin D3 (calcitriol), is a potent modulator of the immune response. We have shown previously that...
The biologically active form of vitamin D3 , 1, 25-dihydroxyvitamin D3 (calcitriol), is a potent modulator of the immune response. We have shown previously that calcitriol modulates the immunoglobulin response in vitro and in vivo in mice and humans. To analyse the underlying molecular mechanisms we studied whether calcitriol-primed B cells modulate T cell activation and function. Human B cells were stimulated with anti-CD40 and interleukin (IL)-4 in the presence of increasing concentrations of calcitriol. After removal of calcitriol, primed B cells were co-cultured with autologous CD4(+) T cells; the B cell phenotype T cell activation and their consecutive cytokine production were also assessed. Naive T cells co-cultured with calcitriol-primed naive B cells showed a reduced expansion, nuclear factor of activated T cells, cytoplasmic 2 (NFATc2) expression and cytokine production upon restimulation. CD86 expression on B cells after calcitriol priming was identified as an underlying mechanism, as T cell activation and expansion was rescued by activating anti-CD28 antibodies. Our data indicate that calcitriol-primed B cells display an impaired capacity to activate T cells. Taken together, we identified a novel B cell-dependent vitamin D immune regulatory mechanism, namely by decreased co-stimulation of calcitriol-primed B cells.
Topics: Antibodies, Monoclonal; B-Lymphocytes; CD28 Antigens; Calcitriol; Cells, Cultured; Cytokines; Gene Expression; Humans; Immunophenotyping; Lymphocyte Activation; T-Lymphocytes
PubMed: 24965738
DOI: 10.1111/cei.12406