B cell (B lymphocyte)- Definition, Types, Development, Applications

B cells, also known as B lymphocytes, are a type of white blood cells that play a vital role in the adaptive immune system. They are responsible for producing antibodies that can recognize and neutralize foreign invaders such as bacteria, viruses, and toxins. B cells are also involved in presenting antigens to helper T cells, which can activate other immune cells and enhance the immune response. B cells are named after the bursa of Fabricius, an organ in birds where they were first discovered. In mammals, B cells develop in the bone marrow and then migrate to various lymphoid organs such as the spleen, lymph nodes, and mucosal tissues.

The immune system consists of two main branches: the innate immune system and the adaptive immune system. The innate immune system is the first line of defense against pathogens and provides a rapid and nonspecific response. It includes physical barriers such as skin and mucous membranes, as well as cellular components such as macrophages, neutrophils, natural killer cells, and dendritic cells. The adaptive immune system is the second line of defense and provides a specific and long-lasting response. It involves two types of lymphocytes: B cells and T cells. B cells mediate humoral immunity, which is based on the production of antibodies that circulate in the blood and lymph. T cells mediate cellular immunity, which is based on the direct killing of infected or abnormal cells by cytotoxic T cells or the regulation of other immune cells by helper T cells.

B cells and T cells have different mechanisms of recognizing antigens. Antigens are molecules that can elicit an immune response by binding to specific receptors on lymphocytes. B cells have receptors called B cell receptors (BCRs) that are composed of membrane-bound immunoglobulins (Igs). Each B cell has a unique BCR that can bind to a specific antigen. T cells have receptors called T cell receptors (TCRs) that are composed of two different chains: alpha and beta. Each T cell has a unique TCR that can bind to a specific antigen only when it is presented by a major histocompatibility complex (MHC) molecule on another cell. MHC molecules are proteins that display fragments of antigens on the surface of antigen-presenting cells (APCs) such as dendritic cells, macrophages, or B cells.

When B cells encounter an antigen that matches their BCR, they become activated and undergo several processes such as proliferation, differentiation, class switching, affinity maturation, and memory formation. These processes enable B cells to produce large amounts of antibodies with high specificity and diversity, as well as to generate long-lived memory B cells that can provide protection against future infections by the same antigen. The antibodies produced by B cells can perform various functions such as neutralizing pathogens or toxins, opsonizing pathogens for phagocytosis by macrophages or neutrophils, activating complement system for lysis of pathogens or infected cells, or facilitating antibody-dependent cellular cytotoxicity (ADCC) by natural killer cells or eosinophils.

B cells are essential for the immune system as they can protect the body from various infections and diseases. However, B cells can also cause problems when they malfunction or become dysregulated. For example, B cells can produce autoantibodies that attack self-tissues and cause autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis. B cells can also undergo malignant transformation and give rise to cancers such as leukemia or lymphoma. Therefore, understanding the biology and function of B cells is important for developing new strategies for immunotherapy and immunomodulation.

B cells or B lymphocytes are a type of white blood cells that play a crucial role in the humoral immunity of the adaptive immune system. Humoral immunity refers to the immune response mediated by antibodies that are produced by B cells and secreted into the blood and other body fluids. Antibodies are proteins that can bind to specific antigens (foreign substances) and neutralize or eliminate them from the body.

B cells have receptors on their surface called B cell receptors (BCRs), which are composed of two heavy chains and two light chains. Each BCR has a unique antigen-binding site that can recognize a specific antigen. When a B cell encounters an antigen that matches its BCR, it becomes activated and undergoes clonal expansion and differentiation. Clonal expansion is the process of rapid proliferation of the activated B cell to produce many identical copies of itself. Differentiation is the process of transforming the activated B cell into either plasma cells or memory cells.

Plasma cells are the effector cells of humoral immunity, as they secrete large amounts of antibodies that can bind to the same antigen that triggered the activation of the B cell. Plasma cells have a short lifespan and die after the primary immune response. Memory cells are the long-lived cells of humoral immunity, as they persist in the body for years and can quickly respond to the same antigen if it reappears in the future. Memory cells have a higher affinity for the antigen than naïve B cells and can produce more potent antibodies.

B cells can be activated by two different mechanisms: T cell-dependent and T cell-independent. T cell-dependent activation requires the help of helper T cells, which are another type of lymphocytes that can recognize antigens presented by antigen-presenting cells (APCs) such as dendritic cells, macrophages, or B cells themselves. Helper T cells can provide signals to B cells through direct contact or cytokine secretion, which enhance the clonal expansion, differentiation, and antibody production of B cells. T cell-dependent activation results in high-affinity antibodies of various classes (IgM, IgG, IgA, IgE) and memory cell formation.

T cell-independent activation does not require the help of helper T cells, but rather relies on the cross-linking of multiple BCRs by antigens that have repeating epitopes (such as polysaccharides or lipopolysaccharides). T cell-independent activation results in low-affinity antibodies of mainly IgM class and no memory cell formation.

B cells are essential for humoral immunity as they provide protection against extracellular pathogens (such as bacteria, viruses, fungi, parasites) and toxins that can enter the body through mucosal surfaces or wounds. B cells can also regulate other aspects of the immune system, such as antigen presentation, cytokine secretion, and T cell activation. B cells can also be involved in autoimmune diseases, allergies, and cancer immunotherapy.

B cells are derived from hematopoietic stem cells (HSCs) that reside in the bone marrow. HSCs are multipotent cells that can give rise to all types of blood cells, including lymphocytes. The generation of B cells from HSCs involves several stages of differentiation and rearrangement of immunoglobulin genes.

The first stage of B cell development is the formation of early lymphoid progenitors (ELPs) from HSCs. ELPs are characterized by the expression of CD34, a surface marker for stem cells, and the lack of expression of lineage-specific markers (Lin^-). ELPs can differentiate into either T cells or B cells depending on the signals they receive from the microenvironment.

The second stage is the commitment to the B cell lineage by the expression of B cell-specific transcription factors, such as E2A, EBF1, and PAX5. These factors activate the expression of genes involved in B cell development and function, such as CD19, CD79a, and CD79b. These genes encode for components of the pre-B cell receptor (pre-BCR), which is essential for the survival and proliferation of developing B cells.

The third stage is the rearrangement of immunoglobulin heavy chain (IgH) genes by a process called V(D)J recombination. This process involves the random joining of variable (V), diversity (D), and joining (J) gene segments to create a unique IgH gene that encodes for the antigen-binding domain of the antibody. The rearranged IgH gene is then expressed as a membrane-bound protein called mu chain, which pairs with a surrogate light chain (SLC) to form the pre-BCR.

The fourth stage is the proliferation and selection of pre-B cells that express a functional pre-BCR. The pre-BCR signals through downstream pathways to promote cell survival, cell cycle progression, and allelic exclusion. Allelic exclusion is a mechanism that ensures that each B cell expresses only one allele of IgH gene, thus maintaining antibody diversity. Pre-B cells that fail to express a functional pre-BCR undergo apoptosis.

The fifth stage is the rearrangement of immunoglobulin light chain (IgL) genes by V(J) recombination. This process involves the random joining of V and J gene segments to create a unique IgL gene that encodes for the other antigen-binding domain of the antibody. The rearranged IgL gene is then expressed as a membrane-bound protein called kappa or lambda chain, which pairs with the mu chain to form the B cell receptor (BCR).

The sixth stage is the maturation and selection of immature B cells that express a functional BCR. The BCR signals through downstream pathways to induce further differentiation and activation of B cells. Immature B cells also undergo negative selection to eliminate self-reactive B cells that bind to self-antigens in the bone marrow. Self-reactive B cells can either undergo receptor editing, which is a process that allows them to change their IgL gene and create a new BCR, or apoptosis.

The final stage is the migration and differentiation of mature B cells from the bone marrow to the peripheral lymphoid organs, such as spleen and lymph nodes. Mature B cells are characterized by the expression of surface markers such as CD20, CD21, CD23, IgM, and IgD. Mature B cells can further differentiate into different types of B cells depending on their interaction with antigens and other immune cells in the periphery.

B cells can be classified into four main types based on their stage of development and function: transitional, naïve, plasma, and memory cells. Each type of B cell has distinct characteristics and roles in the immune system.

Transitional B cells

Transitional B cells are immature B cells that have left the bone marrow but have not fully matured into functional B cells. They are named transitional because they represent a transitional stage between the immature B cells in the bone marrow and the mature B cells in the peripheral lymphoid tissues.

Transitional B cells can be found in the blood, spleen, and lymph nodes, but only a small fraction of them survive and develop into mature B cells. The rest undergo apoptosis or are eliminated by negative selection if they recognize self-antigens.

Transitional B cells can be further divided into two subtypes: T1 and T2. T1 transitional B cells are the first to exit the bone marrow and enter the spleen. They express low levels of IgM and IgD on their surface and have a short lifespan. T2 transitional B cells are derived from T1 cells in the spleen. They express higher levels of IgM and IgD and also acquire other surface markers such as CD21 and CD23. They are more resistant to apoptosis and can differentiate into either follicular B cells or marginal zone B cells.

Naïve B cells

Naïve B cells are mature B cells that have not encountered their specific antigen yet. They are also called virgin or resting B cells because they are not activated or differentiated.

Naïve B cells circulate in the blood and lymph and reside in the secondary lymphoid organs such as the spleen and lymph nodes. They express high levels of IgM and IgD on their surface and have a diverse repertoire of antigen receptors.

Naïve B cells can recognize antigens that are free or bound to the surface of pathogens. Upon antigen recognition, they undergo activation and clonal expansion. Some of them also undergo class switching and somatic hypermutation to produce antibodies with different isotypes and higher affinity.

Naïve B cells can also give rise to a subset of regulatory B cells (Breg) that modulate the immune response by producing anti-inflammatory cytokines and inhibiting T cell activation.

Plasma Cells

Plasma cells are differentiated B cells that secrete large amounts of antibodies. They are also called effector or antibody-secreting B cells because they are the main effectors of humoral immunity.

Plasma cells are derived from activated naïve or memory B cells in response to antigen stimulation. They require help from helper T cells (Tfh) that provide co-stimulatory signals and cytokines.

Plasma cells can produce antibodies of different classes (IgM, IgG, IgA, IgE) depending on the type of antigen and the cytokine environment. The antibodies produced by plasma cells are specific for the antigen that triggered their differentiation. A plasma cell can only secrete one type of antibody.

Plasma cells have a short lifespan and die after a few days or weeks. However, some plasma cells can survive for months or years in the bone marrow or mucosal tissues as long-lived plasma cells. These plasma cells provide long-term protection against recurrent infections by maintaining high levels of antibodies in the serum or secretions.

Plasma cells have a distinctive morphology with abundant cytoplasm, eccentric nucleus, and prominent Golgi apparatus. They also express low levels of surface markers such as CD19, CD20, and CD27.

Memory Cells

Memory B cells are long-lived B cells that retain the memory of a previous antigen encounter. They are responsible for the secondary or anamnestic immune response that is faster and stronger than the primary response.

Memory B cells are generated from activated naïve or memory B cells that do not differentiate into plasma cells but instead enter a resting state. They express low levels of IgM and IgD but high levels of other isotypes such as IgG, IgA, or IgE depending on their previous class switching.

Memory B cells circulate in the blood and lymph and reside in various tissues such as the spleen, lymph nodes, bone marrow, mucosa, and subcutaneous areas. They have a diverse repertoire of antigen receptors with high affinity due to somatic hypermutation.

Memory B cells can recognize antigens that are free or bound to the surface of pathogens. Upon re-exposure to the same antigen, they rapidly reactivate and differentiate into plasma cells or more memory B cells without requiring T cell help.

Memory B cells have a longer lifespan than plasma cells and can persist for years or decades. They provide long-term immunity against repeated infections by producing high-affinity antibodies and enhancing the activation of other immune cells.

The development of B cells within the bone marrow and peripheral lymphoid tissues is a complex and dynamic process that involves multiple stages of gene rearrangement, cell proliferation, selection, and differentiation. The development of B cells can be divided into two phases: early B cell development in the bone marrow and late B cell development in the peripheral lymphoid tissues.

Early B cell development in the bone marrow

The early B cell development in the bone marrow begins with the differentiation of hematopoietic stem cells (HSCs) into common lymphoid progenitors (CLPs), which have the potential to give rise to both B and T cells. The CLPs then undergo a series of gene rearrangements at the immunoglobulin (Ig) heavy chain (IgH) locus to generate diverse B cell receptors (BCRs). The gene rearrangements are mediated by two enzymes: RAG1 and RAG2, which recognize specific DNA sequences called recombination signal sequences (RSSs) and cut and join the DNA segments. The gene rearrangements occur in a specific order: first, the diversity (D) segment is joined to the joining (J) segment (D-J recombination), then the variable (V) segment is joined to the D-J segment (V-D-J recombination). The resulting V-D-J segment encodes the variable region of the IgH chain.

The early B cell development in the bone marrow can be further divided into several stages based on the expression of surface markers and IgH gene rearrangements:

• Pro-B cells: These are the earliest identifiable B cell precursors that express CD19, CD45R, and CD43 on their surface. They undergo D-J recombination at the IgH locus and express a surrogate light chain called VpreB/lambda5 on their surface, which pairs with the IgH chain to form a pre-BCR complex.
• Pre-B cells: These are the next stage of B cell precursors that express CD19, CD45R, CD25, and CD20 on their surface. They undergo V-D-J recombination at the IgH locus and express a functional pre-BCR complex on their surface. The pre-BCR complex signals for the proliferation and survival of pre-B cells and also inhibits further IgH gene rearrangements (allelic exclusion). Pre-B cells can be further subdivided into large pre-B cells and small pre-B cells based on their size and cell cycle status.
• Immature B cells: These are the final stage of B cell precursors in the bone marrow that express CD19, CD45R, CD20, and IgM on their surface. They undergo gene rearrangements at the Ig light chain (IgL) locus to generate either kappa or lambda light chains, which pair with the IgH chain to form a mature BCR complex. The BCR complex signals for the cessation of proliferation and differentiation of immature B cells into mature B cells.

The early B cell development in the bone marrow is also regulated by several checkpoints that ensure the quality and diversity of BCRs. The first checkpoint occurs at the pro-B to pre-B transition, where only cells that have successfully undergone D-J recombination at the IgH locus and expressed a functional pre-BCR complex can proceed to the next stage. The second checkpoint occurs at the pre-B to immature B transition, where only cells that have successfully undergone V-D-J recombination at the IgH locus and expressed a functional BCR complex can proceed to the next stage. The third checkpoint occurs at the immature B stage, where cells that have self-reactive BCRs are either deleted or edited by receptor editing or anergy induction.

Late B cell development in the peripheral lymphoid tissues

The late B cell development in the peripheral lymphoid tissues begins with the migration of immature B cells from the bone marrow to the spleen via the blood circulation. The spleen is the primary site for further maturation and diversification of B cells in response to antigens. The late B cell development in the spleen can be divided into two pathways: follicular B cell pathway and marginal zone B cell pathway.

• Follicular B cell pathway: This is the main pathway for generating conventional mature B cells that express CD19, CD45R, CD20, CD21, CD23, IgM, and IgD on their surface. These cells migrate to follicles within secondary lymphoid organs such as lymph nodes or Peyer`s patches, where they encounter antigens and helper T cells. Depending on the nature of antigens and T cell help, follicular B cells can either undergo T cell-dependent or T cell-independent activation. T cell-dependent activation involves the formation of germinal centers, where follicular B cells undergo somatic hypermutation and class switch recombination to generate high-affinity and isotype-switched antibodies. Some of the activated follicular B cells also differentiate into memory B cells or long-lived plasma cells that provide long-term immunity. T cell-independent activation involves the direct stimulation of follicular B cells by multivalent or repetitive antigens, such as polysaccharides or lipids, without the need for T cell help. This results in the production of low-affinity and mainly IgM antibodies that provide short-term immunity.
• Marginal zone B cell pathway: This is an alternative pathway for generating a specialized subset of mature B cells that express CD19, CD45R, CD20, CD21, CD23, IgM, and IgD on their surface. These cells reside in the marginal zone of the spleen, where they encounter blood-borne antigens and innate immune cells. Marginal zone B cells are particularly responsive to T cell-independent antigens, such as polysaccharides or lipids, and can rapidly produce IgM antibodies that provide short-term immunity. Some of the activated marginal zone B cells also differentiate into memory B cells or long-lived plasma cells that provide long-term immunity.

The late B cell development in the peripheral lymphoid tissues is also regulated by several factors that influence the survival, migration, and differentiation of B cells. Some of these factors include cytokines, chemokines, complement components, toll-like receptors, and transcription factors. The late B cell development in the peripheral lymphoid tissues is also influenced by the microenvironmental cues and cellular interactions within different anatomical regions of the spleen and other secondary lymphoid organs.

B cells undergo a complex process of development and differentiation that involves several stages and checkpoints. The process begins in the bone marrow, where B cells are generated from hematopoietic stem cells and undergo rearrangement of their immunoglobulin genes to produce diverse B cell receptors (BCRs). The BCRs are essential for recognizing and binding to specific antigens. The immature B cells that successfully express functional BCRs on their surface are then exported to the periphery, where they encounter antigens and undergo further maturation and activation.

The maturation of B cells in the periphery involves two main pathways: the follicular pathway and the marginal zone pathway. The follicular pathway leads to the generation of follicular B cells, which are responsible for the T cell-dependent antibody response. These B cells migrate to the secondary lymphoid organs, such as the spleen and lymph nodes, where they interact with follicular dendritic cells (FDCs) and T helper cells. The FDCs provide survival signals and present antigens to the B cells, while the T helper cells provide costimulatory signals and cytokines that activate the B cells. The activated B cells then form germinal centers within the follicles, where they undergo somatic hypermutation and class switch recombination of their immunoglobulin genes. These processes increase the affinity and diversity of the antibodies produced by the B cells. The germinal center B cells then differentiate into either plasma cells or memory B cells. Plasma cells are antibody-secreting effector cells that migrate to the bone marrow or other sites of inflammation and infection. Memory B cells are long-lived cells that persist in the circulation or in the lymphoid organs and provide a rapid and enhanced secondary antibody response upon re-exposure to the same antigen.

The marginal zone pathway leads to the generation of marginal zone B cells, which are responsible for the T cell-independent antibody response. These B cells reside in the marginal zone of the spleen, where they encounter blood-borne antigens, such as polysaccharides and lipids, that can directly activate them without requiring T cell help. The activated marginal zone B cells then differentiate into plasma cells or memory B cells without forming germinal centers. The antibodies produced by these B cells are mainly of the IgM class and have a lower affinity than those produced by the follicular B cells.

The differentiation of B cells into plasma cells or memory B cells is regulated by several factors, such as antigen affinity, antigen dose, antigen persistence, cytokine environment, and transcription factors. Some of the key transcription factors involved in B cell differentiation are Pax5, Bach2, Blimp-1, XBP-1, IRF4, and Bcl-6. Pax5 and Bach2 maintain the identity and function of naïve and memory B cells by suppressing plasma cell differentiation. Blimp-1 and XBP-1 induce plasma cell differentiation by activating genes involved in antibody secretion and suppressing genes involved in memory formation. IRF4 is required for both plasma cell and memory B cell differentiation by regulating Blimp-1 and Bach2 expression. Bcl-6 is essential for germinal center formation and maintenance by promoting proliferation and survival of germinal center B cells.

The maturation, activation, and differentiation of B cells are crucial for generating a robust and diverse antibody response that can protect against various pathogens and diseases. However, dysregulation of these processes can also lead to autoimmune disorders, immunodeficiencies, or malignancies. Therefore, understanding the molecular mechanisms underlying these processes can provide insights into the pathogenesis and treatment of these conditions.

B cells are not only involved in humoral immunity by producing antibodies, but also have other important functions and applications in the immune system and immunotherapy. Some of the applications of B cells are:

• Antigen presentation: B cells can act as professional antigen-presenting cells (APCs) that can process and present antigens to T cells via MHC class II molecules. This can activate T cells and enhance their proliferation and differentiation. B cells can also present antigens to other B cells, leading to affinity maturation and class switching of antibodies. B cells can also modulate T cell responses by presenting antigens in a tolerogenic or immunogenic manner, depending on the context and signals received by the B cells.

• Cytokine secretion: B cells can produce various cytokines that can influence the immune response in different ways. For example, B cells can secrete IL-4, IL-6, IL-10, and TGF-β that can promote antibody production, inflammation, or immune regulation. B cells can also secrete chemokines that can attract other immune cells to the site of infection or inflammation. The cytokine secretion by B cells depends on their activation status, differentiation stage, and microenvironment.

• Antibody production: B cells are the main source of antibodies that can bind to specific antigens and neutralize them or mark them for destruction by other immune cells. Antibodies are essential for humoral immunity and can protect against various pathogens and toxins. Antibodies can also mediate allergic reactions, autoimmunity, and transplant rejection. The diversity and specificity of antibodies are generated by somatic recombination and hypermutation of immunoglobulin genes in B cells.

• B cell-based immunotherapy: B cells can also be used as therapeutic tools for cancer immunotherapy. One approach is to use CD40-activated B cells as cancer vaccines that can present tumor antigens to T cells and induce antitumor immunity. CD40-activated B cells are potent APCs that can express high levels of costimulatory molecules and cytokines that activate T cells. In preclinical models of mice and dogs, CD40-activated B cell-based cancer immunotherapy was able to induce effective antitumor immunity. Another approach is to use gene editing techniques to engineer B cells to produce therapeutic antibodies or CARs that can target tumor antigens. This could provide a long-lasting source of tumor-specific antibodies or CARs that could eliminate tumor cells without the need for repeated injections. B cell-based immunotherapy could also be combined with other immunotherapies such as checkpoint inhibitors or adoptive T cell transfer to enhance the antitumor response .

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