The B cell surface molecule CD19 is also a therapeutic target. This theory has been modified over the years but still serves as a guiding principle of adaptive immunity. B cell life span: a review Debate has surrounded the subject of B cell life span since it was first measured in mice in the early 1970s. Here, we review recent findings related to B cells and to the humoral immune response in cancer and their translational significance. Fillatreau S et al. CD23+ IgM+ IgD+ naïve B cells., found in PB, primary follicle, and follicular mantle zone. (1984). B cell progenitors progress through sequential and mutually exclusive states of proliferation and recombination, coordinated by cytokines and chemokines. (. The increased understanding of B cell biology established over the past 20 years has led to the development of therapeutic agents for treating autoimmune diseases and lymphomas driven by aberrant B cell function. Finally, we highlight the application of B cell biology in the development of novel therapeutics for the treatment of B cell mediated diseases. Early B cell development and commitment to the B cell lineage occurs in the foetal liver prenatally, before continuing in the bone marrow throughout life. The advent of functional and structural genomics has greatly accelerated our understanding of oncogenic mechanisms in lymphomagenesis. TFs, transcription factors; Pax5, paired box gene 5; EBF, early B cell factor 1; OCT2, octamer transcription factor 2; BCL6, B cell lymphoma 6 protein; IRF4, interferon regulatory factor 4; XBP1, X-box binding protein 1;TACI, transmembrane activator and cyclophilin ligand interactor; BCMA, B cell maturation antigen; BR3, B lymphocyte stimulator receptor 3; Ig, immunoglobulin. A developmental link between B cells and antibody production was established with studies showing that surface immunoglobulin (Ig) expression could be used as a marker of normal and leukemic B cells (Froland et al. This is mediated through somatic mutations in Ig genes followed by selective survival of B cells producing antibodies of the highest affinity. (1980). Video transcript. Signals through the B-cell receptor (BCR) guide and are required for B-cell maturation, survival, and fate decision. Naïve B cells are located in the secondary lymphoid organs. Komori T et al. B cell activation is initiated when the IgD and monomeric IgM surface receptors of B cells bind to specific antigens. Once activated, the T cells then express CD40L which binds to CD40 on the B cell surface. (1965). The architecture and dynamics of responding cell populations. 2013). It is here that their antigen receptors (surface immunoglobulin) are assembled. We … Early production of intracellular IgM by B-lymphocyte precursors in mouse. 1993; Tonegawa 1983; Alt et al. Here, we review the role of the BCR during B-cell development, leading to the emergence of B1, marginal zone, and peripheral follicular B cells. However, several of these antibodies such as ruplizumab and toralizumab demonstrate platelet dependent adverse effects in patients (Blüml et al. B lymphocytes: how they develop and function. This leads to the transcription of immunoglobulin genes, the release of cytokines from T cells and B cell proliferation. T cell mediated activation of B cells is initiated when antigen specific B cells bind antigens via Ig receptors, thereby enhancing the expression of co-stimulatory molecules on the B cell surface. Transitional B cell maturation occurs primarily in the spleen, with T1 B cells present in the red pulp and outer periarterial lymphatic sheath (PALS) and T2 cells in the follicles (Chung et al. Bortezomib is a proteasome inhibitor that was originally developed for treating multiple myeloma. Eventually, large pre-B cells stop proliferating and RAG1/2 proteins are re-expressed to induce light chain rearrangement, marking the small pre-B cell stage. This therapeutic protein is called Atacicept (TACI-Ig), and it binds and blocks both BLyS and APRIL to inhibit B cell maturation (Gross et al. Abnormal B lymphocyte development, activation and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Rituximab was originally developed for the treatment of B cell malignancies but is also used to treat moderate to severe RA as well as other autoimmune diseases such as Wegener’s granulomatosis and microscopic polyangiitis (Blüml et al. 2020 Mar 16;12:1959-1967. doi: 10.2147/CMAR.S248034. Epub 2020 Sep 16. Epub 2020 Dec 7. In addition to producing antibodies, they perform critical immune functions such as generating immunological memory, antigen presentation and regulatory cytokine production. Fig. These stimuli induce B cell activation through toll-like receptors. Consequently, several blocking monoclonal antibodies targeting CD40L have been developed and tested in clinical trials. B cells constitute approximately 15% of peripheral blood leukocytes and arise from hemopoietic stem cells in the bone marrow. They represent a distinct lineage, with separate and unique functions from T cells. Tonegawa S (1983). The progenitor cells that are committed to the B cell lineage are selected at random. Inflammatory response. Characterization of a human B lymphocyte-specific antigen. Experimental evidence supporting the clonal theory demonstrated that each antibody producing cell makes one type of antibody, and is stimulated by its cognate antigen to produce and secrete more of the same kind of antibody (Nossal and Lederberg 1958). In Drugs targeting B-cells in autoimmune diseases, Milestones in drug therapy, X. Bosch et al., eds. 2005). However, they are incapable of inducing efficient isotype switching or affinity maturation, which requires T cell help. This finding defined separate B and T cell lineages in adaptive immunity. These are called GCs, which are temporary structures in which the functional features of TD responses emerge, particularly affinity maturation and formation of memory B cells and long lived plasma cells. 2002). 1993 Jul;5(7):735-41. doi: 10.1093/intimm/5.7.735. Inhibiting the effects of the B cell survival factor BLyS on B cells is also an advanced therapeutic strategy for addressing B cell mediated diseases. SARS-CoV-2 primary infection fosters polyclonal B cell responses (IgG 1,2,3 and IgA 1,2 subclasses), with preferential use of IgHV3-30 and IgHV3-9 (which is enriched in IgG B cells). Figure 2 shows the various stages that are developed after activation of B cells. An Overview of B Cells – from Discovery to Therapy mini-review. Delineation of the thymic and bursal lymphoid systems in the chicken. Whereas TI type I antigens can activate both immature and mature B cells, TI type II antigens only activate mature B cells (Janeway et al. In the late phase, affinity maturation and B cell memory formation occurs, and this takes place in GCs within lymphoid follicles. B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. Signaling through the pre-BCR is crucial for continued B cell development, and leads to reduced RAG1/2 protein levels and an increase in proliferation to form large pre-B cells (Kitamura et al. This mini-review provides a brief history of the discovery of B cells, as well as describes the characteristics of each B cell lineage and the processes of B cell development, maturation and activation. The first B cell targeting therapeutic antibody approved by the US Food and Drug Administration was Rituximab, a mouse/human chimeric IgG1 monoclonal antibody. These critical immune cells remain an active area of research particularly because disruption of B cell development or function results in a number of autoimmune diseases and malignancies. Similar to the anti-CD19 antibody MEDI-551, epratuzimab exerts modest ADCC. … Fierabracci A (2012). The phenotypic nature of B regulatory cells in mouse is currently being debated and there appears to be two regulatory B cell lineages in mice. Fagraeus A (1948). 1971; Le Bien and Tedder 2008). Memory B cells were shown to be induced by T cell-independent type II polysaccharide antigens; however, these memory B cells show very low levels of … Br J Clin Pharmacol. 2013). B cells produce antibody, molecules, however, these antibodies are not secreted. However, recent advances in B cell biology have capitalized on old findings and demonstrated that B cells also release a broad variety of cytokines. The mechanism of isotype switching is referred to as switch recombination in which the VDJ gene segment recombines with a downstream C region gene, and deleting the intervening section. It occurs at all ages but is more prevalent among children than adults and, importantly, accounts for a much higher proportion of cancers in that age group. Ueber das zutandekommen der diphtheria-immunitat und der tetanus-immunitat bei thieren. Engel P et al. B cells regulate autoimmunity by provision of IL-10. (1992). (1976). Elenitoba-Johnson and Megan S. Lim Annual Review of Pathology: Mechanisms of Disease Immune Regulatory Function of B Cells Claudia Mauri and Anneleen Bosma Annual Review of Immunology. Figure 1 summarizes the process of early B cell development and Figure 2 provides an overview of the characteristics of early B cell subsets in human and mouse. 2001). Quick review of B Cells and B Cell development in humans.Download this and other presentations for FREE from Examville's Study Aids section. It develops when B-cells (also called B-lymphocytes) become abnormal. Partial Cell Functions- Nobel Lecture December 11, 1908. A further role pairs naïve B cells with naïve T cells to stop the latter from proliferating. Some plasma cells migrate to the bone marrow, where they persist for several years and continue to produce antibodies even in the absence of antigen. Inflammation. Privacy, Help Overview of T cell dependent B cell activation in germinal centers. The natural-selection theory of antibody formation. In 1974, B cells were shown to originate from the fetal liver and bone marrow in mice (Cooper 2015), and their precursors, pre-B cells, were later identified in the fetal liver and bone marrow of mice (Raff et al. Eur J Nucl Med Mol Imaging 2014;41:565-74. 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. This surface marker also regulates the threshold for B cell activation. •Cases that show V region mutations may correspond to a subset of PB CD5+ IgM+ B cells that appear to be memory B cells. (2001). 2 , 3 Why this may be, and why this may soon change, is the topic of this review. Obukhanych and Nussenzweigh (2006). (2005). The first B cell specific molecule described was termed B1 and is now known as CD20 (Stashenko et al. 2010). Somatic generation of antibody diversity. 1980). Short lived plasma cell in secondary lymphoid organs, Circulating in both BM and lymphoid locations, IgMhi IgDlo CD1d+ CD9+ CD21+ CD22+ CD35+ CD45R+ CD23+, IgD- CD45Rlo Review of B cells, CD4+ T cells and CD8+ T cells. (2013). Cytokines mediate isotype switching following CD40-CD40L interaction. Wei B et al. Kinetics of B cell subpopulations in peripheral lymphoid tissues: evidence for the presence of phenotypically distinct short-lived and long-lived B cell subsets. Studies show that MEDI-551 successfully depletes B cells from blood and lymphoid organs at lower doses than Rituximab (Blüml et al. These cells have also been shown to directly inhibit T cell proliferation in murine models (Wei et al. CD138hi TACI+ and/or BCMA+ CD126+ CD184+ CD320+, CD45R+ CD80+ CD73+ CD273+ CD38+ CD84+ CD86+. (2003). However, we understand much less about the BCR before activation. In the past two decades, significant advances have been made in B cell biology. Raff MC et al. B cell development begins with the migration of multipotent progenitor cells (MPPs) first into the fetal liver and then into the bone marrow. Ig, immunoglobulin; GC, germinal center. B cells with regulatory function have also been identified in humans (Tobòn et al. In adults, 75% of cases develop from precursors of the B-cell lineage, with the remainder of cases consisting of malignant T-cell precursors. In the mid-1960s to early 1970s, advances were made in the characterization of B cells using animal models, clinical evaluation of patients with immune deficiency diseases and the innovation of cell surface molecule characterization (LeBien and Tedder 2008). In contrast, the antibody response to protein antigens requires both B and T cell involvement, and these antigens are described as thymus dependent (TD) antigens. Metabolism is part of an integrated system to ensure that B cells receive all appropriate signals before activation is launched. Rituximab in B-cell hematologic malignancies: a review of 20 years of clinical experience. Prevention of arthritis by interleukin 10-producing B cells. B cells occupy follicular areas in lymphoid tissues and account for 5-25% of all human blood cells, which number 1000-2000 cells per mm3. To become a B cell, it has to develop into an immature B-cell in the bone marrow and then complete its maturation into an antibody secreting B cell, called a plasma cell, in the lymph nodes and spleen. Nunez C et al. Muramatsu M et al. Crit Rev Oncol Hematol. Early B cell development and commitment to the B cell lineage occurs in the foetal liver prenatally, before continuing in the bone marrow throughout life. 2001). After B cells mature in the bone marrow, they migrate through the blood to SLOs, which receive a constant supply of antigen through circulating lymph. 2019 Aug;85(8):1790-1797. doi: 10.1111/bcp.13970. 1. 2013). You will be able to modify only the cart that you have PunchedOut to, and won't have access to any other carts, Inspect mode – when you PunchOut to Bio-Rad from a previously created requisition but without initiating an Edit session, you will be in this mode. 2. Accordingly, about 80% of B cell non Hodgkin lymphomas are derived from GC B cells (Basso and Dalla-Favera 2015). The occurrence of B-ALL is known to correlate with a series of gene mutations, which often start at the pluripotent stem cell stage, followed by processes of clonal expansion, differentiation, cell proliferation and dysregulated cell apoptosis; the end result is the replacement of normal lymphoid cells by malignant cells . (1977). Characterization of peripheral B cell subsets in mouse and human, Migration from BM to secondary lymphoid organs, IgMlo CD23+ CD93- CD19+ CD20+ CD21+ CD22+, Shuttling between BM and secondary lymphoid organs, IgMhi IgDlo CD1c+ CD24+ CD19+ CD20+ CD21+, CD20- CD38hi CD27hi CD138+ TACI+ and/or BCMA+ CD126+ CD319+ CD78+, Long lived plasma cell in BM. These antibody secreting cells can be found in the extrafollicular sites of lymphoid tissue or they can migrate to the bone marrow 2-3 weeks after antigen exposure. 2009). eCollection 2020. 2013). 2014; Nunez et al. To become a T cell, it has to migrate to the thymus and become a thymocyte, where it completes its development into a mature T cell. 2014). In the literature, flow cytometry studies for the phenotypic characterization of B-lymphocytes are mainly focused on the description of a particular cell stage, or of specific cell stages observed in a single type of sample. Berger GK et al. Click through and see at a glance the key markers for immune cell phenotyping and for identifying specific stages of apoptosis. Yet, efforts to individualize therapy on the basis of this recognition have thus far been met with limited success. They are mature but not yet activated. B-Cell Functions . They function in the humoral immunity component of the adaptive immune system. 2017;109:42-50. T cell dependent B cell activation occurs in two anatomically distinct phases. B cell maturation in GCs is associated with somatic hypermutation of antibody V region genes, which provides the basis for the generation of antibodies with high affinity antigen receptors (see section 3) (Tobòn et al. B-cells are white blood cells that fight infection. In addition to producing antibodies, B cells are professional antigen presenting cells that can present antigens to T cells to generate effective immune responses. Our current understanding of B cell biology was initiated in 1965 with a landmark study by Max Cooper and Robert Good. Eur J Immunol. The T cell secreted cytokines function to amplify B cell proliferation and differentiation as well as to determine the type of antibody produced by promoting isotype class switching (Table 3). The abnormal B-cells (lymphoma cells) usually build up in lymph nodes, but they can affect other parts of the body. In addition to BLyS, these include A proliferation-inducing ligand (APRIL), BLyS receptor 3 (BR3 also known as BAFF-R), transmembrane activator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) (Naradikian et al. B cells are an integral part of the adaptive immune response. Potent B-cell-depleting activity in peripheral blood and lymphoid tissues was reported with rituximab in phase I and phase II studies [38, 39].Circulating CD20 + B cells underwent rapid depletion in the peripheral blood of patients with recurrent B-cell lymphoma treated with a single dose of rituximab. Within 2-3 weeks, the majority of these plasma cells die; however some persist long term and memory B cell formation is also observed (Obukhanych and Nussenzweigh 2006). Blüml S et al. When immobilized, epratuzimab also interferes with anti-IgM stimulated cell proliferation (Blüml et al. Influences on the lifespan of B cell subpopulations defined by different phenotypes. B cells, proliferation at various stages, and movement within the bone marrow microenvironment • Immature B cell leaves the bone marrow and undergoes further differentiation • Immune system must create a repertoire of receptors capable of recognizing a large array of antigens while at the same time eliminating self -reactive B cells Common variable immunodefiCienCy Causes: mature B cells are normal in number and morphology but fail to differentiate to plasma cells because of defective interaction between T and B cells, mostly caused by a T-cell defect. 1984). Kitamura D et al. Fig. 2013). & Gommerman, J.L. As discussed earlier in this review, Tfh cells are critical for the production of high-affinity B cell clones in the GC and thus the generation of long term memory, i.e., memory B cells and LLPCs . Type I TI antigens are mitogenic stimuli such as lipopolysaccharide (LPS), CpG or poly IC. Throughout B cell development, the developing cells are interacting closely with the stromal cells of the bone marrow, which are largely composed of mesenchymal stem cells. (2010). Abstract B cells are regarded for their capacity to produce antibody. Mice Deficient in NOX2 Display Severe Thymic Atrophy, Lymphopenia, and Reduced Lymphopoiesis in a Zymosan-Induced Model of Systemic Inflammation. The antigen is then processed internally and peptide fragments are presented on the cell surface via MHC Class II molecules to cognate CD4+ T cells. Ordered rearrangement of immunoglobulin heavy chain variable region segments. Antigen selected B cells that leave the GC go on to become memory B cells or plasmablasts. TI antigens can further be subdivided into type I and type II antigens. I. B cell activation occurs in the secondary lymphoid organs (SLOs), such as the spleen and lymph nodes. Without B-cells, your body would not be as effective at fighting off a number of very common bacteria and viruses; and you would lack the long-lasting \"memory antibody\" function that is typical after recovering from an infection or after being immunized against a specific infectious invader. Jerne NK (1955). 2013; Blüml et al. The antibodies generated by this response are typically IgM and demonstrate low affinity for antigen compared to antibodies derived using T cell help. Because the interaction of B cells with T cells is critical for inducing humoral immunity, impeding interactions of activated B cells with aspects of T cell help is a promising strategy for treating B cell diseases. Clipboard, Search History, and several other advanced features are temporarily unavailable. Mutations affecting the crucial pre-B cell checkpoint result in immunodeficiency, autoimmunity, and leukemia. In this Review, we describe these two main phases of memory B cell development, highlighting some of the key variables that predict success at each step. FDG PET/CT for the detection of bone marrow involvement in diffuse large B-cell lymphoma: Systematic review and meta-analysis. 2002; Mauri et al. (For simplicity, this review will still use the term DLBCL to cover all the related WHO entities, including high-grade B-cell lymphoma [HGBL].) This review examines both traditional and recent methods and discusses the influence of age, self-tolerance and randomness in the overall shaping of a kinetically stable mature B cell population. The antigen activated T and B cells interact at the interface of the follicles and the T cell area, which occurs 3-7 days after antigen exposure. ©2016 AACR. In this review we discuss how native antigen is presented to B cells and its impact at several stages of B cell responses. 2014). Below, we discuss current therapeutics that utilize these strategies for treating B cell diseases. Up until 1980, the molecular composition of the cell surface of B cells was largely uncharacterized, and the B cell surface was known to only consist of bound Ig, complement receptors and Fc receptors (LeBien and Tedder 2008). (2002). 2013). At low density, receptor cross-linking is insufficient to induce activation, however at too high density, the B cell becomes anergic. B-cell targeted therapeutics in clinical development. Inflammatory response. The pre-B cell is then formed following successful VHDJH recombination, the resulting heavy chain pairs with a surrogate light chain (SLC), comprised of two distinct proteins λ5 and VpreB, to form the pre-BCR. Because plasma cells secrete large amounts of antibody, inhibition of proteasome function has been a unique approach to removing this B cell subset since it results in apoptosis via the unfolded protein response. If you have read any of my previous “The Biology of Antibodies” blog posts, you are likely already well aware of my fascination and amazement of all things antibody. MEDI-551 is an affinity-optimized monoclonal antibody targeting human CD19 that functions primarily by inducing antibody dependent cellular cytotoxicity (ADCC) (Herbst et al. 2021 Feb;44(1):371-382. doi: 10.1007/s10753-020-01342-6. Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI. The occurrence of B-ALL is known to correlate with a series of gene mutations, which often start at the pluripotent stem cell stage, followed by processes of clonal expansion, differentiation, cell proliferation and dysregulated cell apoptosis; the end result is the replacement of normal lymphoid cells by malignant cells . The B cell receptor (BCR) is a transmembrane protein on the surface of a B cell.B cell receptors are composed of immunoglobulin molecules that form a type 1 transmembrane receptor protein, and are typically located on the outer surface of these lymphocyte cells. Pharmacodynamics of rituximab on B lymphocytes in paediatric patients with autoimmune diseases. 2003). B-cell NHL is the most common haematological cancer in adults. Ig, immunoglobulin; IFN-γ, interferon-gamma; TGF-β, transforming growth factor beta; IL, interleukin. B cells are cells of the B cell lineage that mature under the influence of the bursa of Fabricius in birds and the bursa equivalent (bone marrow) in mammals. However, the first indication of the existence of B cells was in 1890 when Emil von Behring and Shibasaburo Kitasato discovered that circulating “antitoxins” (now known to be antibodies) were important in immunity to diphtheria and tetanus (von Behring and Kitasato 1890). Table 1. (CD154) and cytokines for the B cells. LCA-2 receives signals from stromal bone marrow cells to induce the development of B cells. 1991). 2014). My review will be focused primarily on mouse B cell development (although there are great similarities with humans), as that has been the primary focus of my work as well as the host for monoclonal antibody development here at MBS. Upon encounter with a microbe or antigen, either by infection or vaccination, naïve B cells (antigen inexperienced) become activated and differentiate into antibody-producing plasma cells and memory B cells. Table 3. 2020 Dec 7;12(23):23578-23597. doi: 10.18632/aging.202346. B and T lymphocytes arise from common lymphoid progenitor cells within the bone marrow. 2021 Feb 9;13(4):703. doi: 10.3390/cancers13040703. Please amend your browser settings to enable third-party cookies and access this website’s full functionality. Such studies have largely resolved the issue, concluding that about 85% of peripheral B cells are phenotypically mature and display first-order exponential kinetics defined by a half-life of 5-6 weeks, whilst the remainder are short-lived with a life span of several days. Explore the latest full-text research PDFs, articles, conference papers, preprints and more on B CELL DEVELOPMENT. (1971). Rolink AG, ten Boekel E, Yamagami T, Ceredig R, Andersson J, Melchers F. Immunol Lett. A simple definition of B lymphocytes is a population of cells that express clonally diverse cell surface immunoglobulin (Ig) receptors recognizing specific antigenic epitopes. National Library of Medicine B cells are however, a heterogeneous population of cells at different stages of maturation along the lineage, each with unique functional properties. Summary. There are two routes to B cell activation and initiation of the humoral immune response, which depend on the nature of the antigen. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. TI type I antigens possess an intrinsic capacity to directly induce B cell division. Complications, such as neurotoxicity, cytokine release syndrome or persistent B-cell lymphopenia, must always be taken into consideration and diagnosed in a timely manner in patients with B-cell neoplasms to guarantee optimal management, thus avoiding they blunting the efficacy of immunotherapy. Of particular interest, is the development of B lymphocytes, the cells that produce antibodies. 73 likes. B-cell activation is triggered by the binding of antigen to the B-cell receptor (BCR). HSC, hematopoietic stem cells; MPPs, multipotent progenitors; CLPs, common lymphoid progenitors.