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Blood Sep 2008The discovery that lymphocyte subpopulations participate in distinct components of the immune response focused attention onto the origins and function of lymphocytes... (Review)
Review
The discovery that lymphocyte subpopulations participate in distinct components of the immune response focused attention onto the origins and function of lymphocytes more than 40 years ago. Studies in the 1960s and 1970s demonstrated that B and T lymphocytes were responsible primarily for the basic functions of antibody production and cell-mediated immune responses, respectively. The decades that followed have witnessed a continuum of unfolding complexities in B-cell development, subsets, and function that could not have been predicted. Some of the landmark discoveries that led to our current understanding of B lymphocytes as the source of protective innate and adaptive antibodies are highlighted in this essay. The phenotypic and functional diversity of B lymphocytes, their regulatory roles independent of antibody production, and the molecular events that make this lineage unique are also considered. Finally, perturbations in B-cell development that give rise to certain types of congenital immunodeficiency, leukemia/lymphoma, and autoimmune disease are discussed in the context of normal B-cell development and selection. Despite the significant advances that have been made at the cellular and molecular levels, there is much more to learn, and cross-disciplinary studies in hematology and immunology will continue to pave the way for new discoveries.
Topics: Animals; Antigens, Differentiation, B-Lymphocyte; Autoimmune Diseases; B-Lymphocyte Subsets; B-Lymphocytes; Cell Differentiation; Cell Membrane; History, 20th Century; History, 21st Century; Humans; Immunologic Deficiency Syndromes; Leukemia; Lymphoma; Mice; Models, Immunological
PubMed: 18725575
DOI: 10.1182/blood-2008-02-078071 -
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 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 -
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 -
The Journal of Experimental Medicine Jul 2023B cells develop from hematopoietic stem cells in the bone marrow. Once generated, they serve multiple roles in immune regulation and host defense. However, their most... (Review)
Review
B cells develop from hematopoietic stem cells in the bone marrow. Once generated, they serve multiple roles in immune regulation and host defense. However, their most important function is producing antibodies (Ab) that efficiently clear invading pathogens. This is achieved by generating memory B cells that rapidly respond to subsequent Ag exposure, and plasma cells (PCs) that continually secrete Ab. These B cell subsets maintain humoral immunity and host protection against recurrent infections for extended periods of time. Thus, the generation of antigen (Ag)-specific memory cells and PCs underlies long-lived serological immunity, contributing to the success of most vaccines. Our understanding of immunity is often derived from animal models. However, analysis of individuals with monogenic defects that disrupt immune cell function are unprecedented models to link genotypes to clinical phenotypes, establish mechanisms of disease pathogenesis, and elucidate critical pathways for immune cell development and differentiation. Here, we review fundamental breakthroughs in unraveling the complexities of humoral immunity in humans that have come from the discovery of inborn errors disrupting B cell function.
Topics: Animals; Humans; B-Lymphocytes; Plasma Cells; Cell Differentiation; Immunity, Humoral; B-Lymphocyte Subsets; Antibodies
PubMed: 37273190
DOI: 10.1084/jem.20221105 -
Annals of the Rheumatic Diseases Nov 2020Primary Sjögren's syndrome (pSS) is characterised by chronic hyperactivation of B lymphocytes. Salivary gland epithelial cells (SGECs) could play a role in promoting...
OBJECTIVE
Primary Sjögren's syndrome (pSS) is characterised by chronic hyperactivation of B lymphocytes. Salivary gland epithelial cells (SGECs) could play a role in promoting B-lymphocyte activation within the target tissue. We aimed to study the interactions between SGECs from patients with pSS or controls and B lymphocytes.
METHODS
Patients had pSS according to 2016 European League Against Rheumatism/American College of Rheumatology criteria. Gene expression analysis of SGECs and B lymphocytes from pSS and controls isolated from salivary gland biopsies and blood was performed by RNA-seq. SGECs from pSS and controls were cocultured with B-lymphocytes sorted from healthy donor blood and were stimulated. Transwell and inhibition experiments were performed.
RESULTS
Gene expression analysis of SGECs identified an upregulation of interferon signalling pathway and genes involved in immune responses (, and ) in pSS. Activation genes and were upregulated in salivary gland sorted B lymphocytes from patients with pSS. SGECs induced an increase in B-lymphocyte survival, which was higher for SGECs from patients with pSS than controls. Moreover, when stimulated with poly(I:C), SGECs from patients with pSS induced higher activation of B-lymphocytes than those from controls. This effect depended on soluble factors. Inhibition with anti-B-cell activating factor, anti-A proliferation-inducing ligand, anti-interleukin-6-R antibodies, JAK1/3 inhibitor or hydroxychloroquine had no effect, conversely to leflunomide, Bruton's tyrosine kinase (BTK) or phosphatidyl-inositol 3-kinase (PI3K) inhibitors.
CONCLUSIONS
SGECs from patients with pSS had better ability than those from controls to induce survival and activation of B lymphocytes. Targeting a single cytokine did not inhibit this effect, whereas leflunomide, BTK or PI3K inhibitors partially decreased B-lymphocyte viability in this model. This gives indications for future therapeutic options in pSS.
Topics: Aged; B-Lymphocytes; Cell Survival; Cells, Cultured; Coculture Techniques; Epithelial Cells; Female; Humans; Lymphocyte Activation; Male; Middle Aged; Salivary Glands; Sjogren's Syndrome; Transcriptome
PubMed: 32843324
DOI: 10.1136/annrheumdis-2019-216588 -
Immunity Jan 2016There is little insight into or agreement about the signals that control differentiation of memory B cells (MBCs) and long-lived plasma cells (LLPCs). By performing BrdU...
There is little insight into or agreement about the signals that control differentiation of memory B cells (MBCs) and long-lived plasma cells (LLPCs). By performing BrdU pulse-labeling studies, we found that MBC formation preceded the formation of LLPCs in an adoptive transfer immunization system, which allowed for a synchronized Ag-specific response with homogeneous Ag-receptor, yet at natural precursor frequencies. We confirmed these observations in wild-type (WT) mice and extended them with germinal center (GC) disruption experiments and variable region gene sequencing. We thus show that the GC response undergoes a temporal switch in its output as it matures, revealing that the reaction engenders both MBC subsets with different immune effector function and, ultimately, LLPCs at largely separate points in time. These data demonstrate the kinetics of the formation of the cells that provide stable humoral immunity and therefore have implications for autoimmunity, for vaccine development, and for understanding long-term pathogen resistance.
Topics: Adoptive Transfer; Animals; B-Lymphocyte Subsets; B-Lymphocytes; Cell Differentiation; Cell Separation; Enzyme-Linked Immunospot Assay; Flow Cytometry; Germinal Center; Immunity, Humoral; Immunohistochemistry; Immunologic Memory; Mice; Mice, Inbred BALB C; Mice, Transgenic; Plasma Cells; Time Factors
PubMed: 26795247
DOI: 10.1016/j.immuni.2015.12.004 -
Clinical Reviews in Allergy & Immunology Oct 2017B lymphocytes are critical for effective immunity; they produce antibodies and cytokines, present antigens to T lymphocytes and regulate immune responses. However,... (Review)
Review
B lymphocytes are critical for effective immunity; they produce antibodies and cytokines, present antigens to T lymphocytes and regulate immune responses. However, because of the inherent randomness in the process of generating their vast repertoire of antigen-specific receptors, B cells can also cause diseases through recognizing and reacting to self. Therefore, B lymphocyte selection and responses require tight regulation at multiple levels and at all stages of their development and activation to avoid diseases. Indeed, newly generated B lymphocytes undergo rigorous tolerance mechanisms in the bone marrow and, subsequently, in the periphery after their migration. Furthermore, activation of mature B cells is regulated through controlled expression of co-stimulatory receptors and intracellular signalling thresholds. All these regulatory events determine whether and how B lymphocytes respond to antigens, by undergoing apoptosis or proliferation. However, defects that alter regulated co-stimulatory receptor expression or intracellular signalling thresholds can lead to diseases. For example, autoimmune diseases can result from altered regulation of B cell responses leading to the emergence of high-affinity autoreactive B cells, autoantibody production and tissue damage. The exact cause(s) of defective B cell responses in autoimmune diseases remains unknown. However, there is evidence that defects or mutations in genes that encode individual intracellular signalling proteins lead to autoimmune diseases, thus confirming that defects in intracellular pathways mediate autoimmune diseases. This review provides a synopsis of current knowledge of signalling proteins and pathways that regulate B lymphocyte responses and how defects in these could promote autoimmune diseases. Most of the evidence comes from studies of mouse models of disease and from genetically engineered mice. Some, however, also come from studying B lymphocytes from patients and from genome-wide association studies. Defining proteins and signalling pathways that underpin atypical B cell response in diseases will help in understanding disease mechanisms and provide new therapeutic avenues for precision therapy.
Topics: Animals; Autoimmunity; B-Lymphocytes; Humans; Immunity, Humoral; Immunomodulation; Intracellular Signaling Peptides and Proteins; Signal Transduction
PubMed: 28456914
DOI: 10.1007/s12016-017-8609-4 -
Clinical and Experimental Immunology Dec 2022Our understanding of the B-cell subsets found in human blood and their functional significance has advanced greatly in the past decade. This has been aided by the... (Review)
Review
Our understanding of the B-cell subsets found in human blood and their functional significance has advanced greatly in the past decade. This has been aided by the evolution of high dimensional phenotypic tools such as mass cytometry and single-cell RNA sequencing which have revealed heterogeneity in populations that were previously considered homogenous. Despite this, there is still uncertainty and variation between studies as to how B-cell subsets are identified and named. This review will focus on the most commonly encountered subsets of B cells in human blood and will describe gating strategies for their identification by flow and mass cytometry. Important changes to population frequencies and function in common inflammatory and autoimmune diseases will also be described.
Topics: Humans; B-Lymphocyte Subsets; B-Lymphocytes; Autoimmune Diseases; Lupus Erythematosus, Systemic; Flow Cytometry
PubMed: 36617261
DOI: 10.1093/cei/uxac104 -
Frontiers in Immunology 2023To date, studies of tissue-resident immunity have mainly focused on innate immune cells and T cells, with limited data on B cells. B-1 B cells are a unique subset of B... (Review)
Review
To date, studies of tissue-resident immunity have mainly focused on innate immune cells and T cells, with limited data on B cells. B-1 B cells are a unique subset of B cells with innate-like properties, enriched in murine pleural and peritoneal cavities and distinct from conventional B-2 cells in their ontogeny, phenotype and function. Here we discuss how B-1 cells represent exemplar tissue-resident immune cells, summarizing the evidence for their long-term persistence & self-renewal within tissues, differential transcriptional programming shaped by organ-specific environmental cues, as well as their tissue-homeostatic functions. Finally, we review the emerging data supporting the presence and homeostatic role of B-1 cells across non-lymphoid organs (NLOs) both in mouse and human.
Topics: Humans; Animals; Mice; B-Lymphocyte Subsets; B-Lymphocytes; Cues; Homeostasis; Peritoneal Cavity
PubMed: 37744333
DOI: 10.3389/fimmu.2023.1106294