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Cell Apr 2019B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are... (Review)
Review
B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short- and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease.
Topics: Animals; Antibodies, Neutralizing; Antigens; B-Lymphocytes; Germinal Center; Humans; Immunologic Memory; Plasma Cells; T-Lymphocytes; Vaccines
PubMed: 31002794
DOI: 10.1016/j.cell.2019.03.016 -
Frontiers in Immunology 2021Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting... (Review)
Review
Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.
Topics: Animals; B-Lymphocyte Subsets; B-Lymphocytes, Regulatory; Biomarkers; Cell Differentiation; Cytokines; Gene Expression Regulation; Humans; Immunomodulation; T-Lymphocyte Subsets
PubMed: 33995344
DOI: 10.3389/fimmu.2021.611795 -
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 -
Immunity Dec 2020Activated B cells participate in either extrafollicular (EF) or germinal center (GC) responses. Canonical responses are composed of a short wave of plasmablasts (PBs)... (Review)
Review
Activated B cells participate in either extrafollicular (EF) or germinal center (GC) responses. Canonical responses are composed of a short wave of plasmablasts (PBs) arising from EF sites, followed by GC producing somatically mutated memory B cells (MBC) and long-lived plasma cells. However, somatic hypermutation (SHM) and affinity maturation can take place at both sites, and a substantial fraction of MBC are produced prior to GC formation. Infection responses range from GC responses that persist for months to persistent EF responses with dominant suppression of GCs. Here, we review the current understanding of the functional output of EF and GC responses and the molecular switches promoting them. We discuss the signals that regulate the magnitude and duration of these responses, and outline gaps in knowledge and important areas of inquiry. Understanding such molecular switches will be critical for vaccine development, interpretation of vaccine efficacy and the treatment for autoimmune diseases.
Topics: Animals; Autoimmune Diseases; B-Lymphocyte Subsets; B-Lymphocytes; Germinal Center; Humans; Immunity; Immunoglobulin Class Switching; Infections; Lymphocyte Activation; Plasma Cells; Vaccines
PubMed: 33326765
DOI: 10.1016/j.immuni.2020.11.006 -
Nature Reviews. Immunology Jul 2017Recent work has provided new insights into how altered B cell-intrinsic signals - through the B cell receptor (BCR) and key co-receptors - function together to promote... (Review)
Review
Recent work has provided new insights into how altered B cell-intrinsic signals - through the B cell receptor (BCR) and key co-receptors - function together to promote the pathogenesis of autoimmunity. These combined signals affect B cells at two distinct stages: first, in the selection of the naive repertoire; and second, during extrafollicular or germinal centre activation responses. Thus, dysregulated signalling can lead to both an altered naive BCR repertoire and the generation of autoantibody-producing B cells. Strikingly, high-affinity autoantibodies predate and predict disease in several autoimmune disorders, including type 1 diabetes and systemic lupus erythematosus. This Review summarizes how, rather than being a downstream consequence of autoreactive T cell activation, dysregulated B cell signalling can function as a primary driver of many human autoimmune diseases.
Topics: Animals; Autoimmunity; B-Lymphocytes; Humans; Receptors, Antigen, B-Cell; Signal Transduction
PubMed: 28393923
DOI: 10.1038/nri.2017.24 -
Frontiers in Immunology 2019Antibodies against foreign antigens are a critical component of the overall immune response and can facilitate pathogen clearance during a primary infection and also... (Review)
Review
Antibodies against foreign antigens are a critical component of the overall immune response and can facilitate pathogen clearance during a primary infection and also protect against subsequent infections. Dysregulation of the antibody response can lead to an autoimmune disease, malignancy, or enhanced infection. Since the experimental delineation of a distinct B cell lineage in 1965, various methods have been developed to understand antigen-specific B cell responses in the context of autoimmune diseases, primary immunodeficiencies, infection, and vaccination. In this review, we summarize the established techniques and discuss new and emerging technologies for probing the B cell response and by taking advantage of the specificity of B cell receptor (BCR)-associated and secreted antibodies. These include ELISPOT, flow cytometry, mass cytometry, and fluorescence microscopy to identify and/or isolate primary antigen-specific B cells. We also present our approach to identify rare antigen-specific B cells using magnetic enrichment followed by flow cytometry. Once these cells are isolated, proliferation assays and adoptive transfer experiments in mice can be used to further characterize antigen-specific B cell activation, function, and fate. Transgenic mouse models of B cells targeting model antigens and of B cell signaling have also significantly advanced our understanding of antigen-specific B cell responses .
Topics: Animals; B-Lymphocytes; Enzyme-Linked Immunospot Assay; Flow Cytometry; Humans; Immunomagnetic Separation; Lymphocyte Activation; Mice; Microscopy, Fluorescence; Receptors, Antigen, B-Cell
PubMed: 31396218
DOI: 10.3389/fimmu.2019.01694 -
Immunity Oct 2018Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5...
Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5 CD11c cells (DN2) representing pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased Toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naive cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells, and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naive B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B cell activation in SLE, and identifies therapeutic targets.
Topics: Adult; Aged; Aged, 80 and over; B-Lymphocyte Subsets; B-Lymphocytes; Female; Gene Regulatory Networks; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Plasma Cells; Toll-Like Receptor 7; Transcriptome; Young Adult
PubMed: 30314758
DOI: 10.1016/j.immuni.2018.08.015 -
Science (New York, N.Y.) Jul 2021The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic...
The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial-meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells, which may help maintain immune privilege within the CNS.
Topics: Aging; Animals; B-Lymphocyte Subsets; B-Lymphocytes; Bone Marrow Cells; Cell Movement; Central Nervous System; Dura Mater; Fibroblasts; Homeostasis; Immune Privilege; Lymphopoiesis; Meninges; Mice; Plasma Cells; Single-Cell Analysis; Skull
PubMed: 34083450
DOI: 10.1126/science.abf9277 -
Nature Aug 2022The lymphocyte genome is prone to many threats, including programmed mutation during differentiation, antigen-driven proliferation and residency in diverse...
The lymphocyte genome is prone to many threats, including programmed mutation during differentiation, antigen-driven proliferation and residency in diverse microenvironments. Here, after developing protocols for expansion of single-cell lymphocyte cultures, we sequenced whole genomes from 717 normal naive and memory B and T cells and haematopoietic stem cells. All lymphocyte subsets carried more point mutations and structural variants than haematopoietic stem cells, with higher burdens in memory cells than in naive cells, and with T cells accumulating mutations at a higher rate throughout life. Off-target effects of immunological diversification accounted for approximately half of the additional differentiation-associated mutations in lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every on-target IGHV mutation during the germinal centre reaction. Structural variation was 16-fold higher in lymphocytes than in stem cells, with around 15% of deletions being attributable to off-target recombinase-activating gene activity. DNA damage from ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory cells. The mutation burden and signatures of normal B cells were broadly similar to those seen in many B-cell cancers, suggesting that malignant transformation of lymphocytes arises from the same mutational processes that are active across normal ontogeny. The mutational landscape of normal lymphocytes chronicles the off-target effects of programmed genome engineering during immunological diversification and the consequences of differentiation, proliferation and residency in diverse microenvironments.
Topics: B-Lymphocytes; Cell Differentiation; Cell Proliferation; Cellular Microenvironment; DNA Damage; Germinal Center; Humans; Immunologic Memory; Lymphocytes; Mutation; Neoplasms
PubMed: 35948631
DOI: 10.1038/s41586-022-05072-7 -
Nature Reviews. Immunology Apr 2021Memory B cells (MBCs) are critical for the rapid development of protective immunity following re-infection. MBCs capable of neutralizing distinct subclasses of... (Review)
Review
Memory B cells (MBCs) are critical for the rapid development of protective immunity following re-infection. MBCs capable of neutralizing distinct subclasses of pathogens, such as influenza and HIV, have been identified in humans. However, efforts to develop vaccines that induce broadly protective MBCs to rapidly mutating pathogens have not yet been successful. Better understanding of the signals regulating MBC development and function are essential to overcome current challenges hindering successful vaccine development. Here, we discuss recent advancements regarding the signals and transcription factors regulating germinal centre-derived MBC development and function.
Topics: B-Lymphocyte Subsets; B-Lymphocytes; CD40 Antigens; Cell Differentiation; Gene Expression Regulation; Germinal Center; Humans; Immunologic Memory; Precursor Cells, B-Lymphoid; Proto-Oncogene Proteins c-bcl-6; Proto-Oncogene Proteins c-myc; Receptors, Antigen, B-Cell; STAT3 Transcription Factor; STAT6 Transcription Factor; Signal Transduction; Toll-Like Receptors
PubMed: 33024284
DOI: 10.1038/s41577-020-00446-2