B Lymphocytes: Development, Biology, and Effector Mechanisms PDF

B lymphocytes: Development, Biology, and Effector Mechanisms Selim BADUR, PhD 8th lecture of Immunology  Today, we will look for answers to these questions - How are antigen receptor–exp...

B lymphocytes: Development, Biology, and Effector Mechanisms Selim BADUR, PhD 8th lecture of Immunology  Today, we will look for answers to these questions - How are antigen receptor–expressing naive B lymphocytes activated and converted to antibody secreting cells? - What are the mechanisms used by secreted antibodies to combat different types of infectious agents and their toxins? - How do antibodies combat microbes that enter through the gastrointestinal and respiratory tracts? - How do antibodies protect the fetus and newborn from infections?  Humoral immunity Humoral immunity is mediated by antibodies and is the arm of the adaptive immune response that functions to neutralize and eliminate extracellular microbes and microbial toxins Antibodies prevent infections by blocking microbes from binding to and entering host cells. Humoral immunity is the principal defense mechanism against microbes with capsules rich in polysaccharides and lipids, because antibodies can be produced against polysaccharides and lipids but T cells cannot respond to nonprotein antigens  Phases of humoral immune responses - Naive B lymphocytes recognize antigens, and under the influence of helper T cells and other stimuli, the B cells are activated to proliferate, leading to expansion of antigen-specific clones and to differentiate into antibody-secreting plasma cells. - Some of the activated B cells undergo heavy-chain isotype switching and affinity maturation, and some become long-lived memory cells.  T-dependent (TD) and T-independent (TI) antibody responses - Antibody responses to different antigens are classified as T-dependent (proteins) or T-independent (non- proteins), based on the requirement for T cell help - Antibody responses to protein antigens require T cell help, and the antibodies produced typically show isotype switching and are of high affinity. Nonprotein (e.g., polysaccharide) antigens are able to activate B cells without T cell help.  Features of primary and secondary antibody responses. - Antibody responses generated during the first exposure to an antigen, called primary responses, differ quantitatively and qualitatively from responses to subsequent exposures, called secondary responses - In a primary response, naive B cells in peripheral lymphoid tissues are activated to proliferate and differentiate into antibody-secreting plasma cells and memory cells. - In a secondary response, memory B cells are activated to produce larger amounts of antibodies, often with more heavy-chain class switching and affinity maturation.  Role of innate immune signals in B cell activation Signals generated during innate immune responses to microbes cooperate with recognition of antigen by antigen receptors to initiate B cell responses A)- Activation of complement leads to the binding of a complement breakdown product, C3d, to the microbes. The B cell simultaneously recognizes a microbial antigen and bound C3d by CR2. CR2 is attached to a complex of proteins (CD19, CD81) that are involved in delivering activating signals to the B cell. B)- Molecules derived from microbes (PAMPs) may activate Toll-like receptors (TLRs) of B cells at the same time as microbial antigens are being recognized by the antigen receptor.  Functional Consequences of B Cell Activation by Antigen - B cell activation by multivalent antigen may initiate the proliferation and differentiation of the cells and prepares them to interact with helper T lymphocytes if the antigen is a protein - The activation of B cells by antigen in lymphoid organs initiates the process of B cell proliferation and immunoglobulin M (IgM) secretion and prepares the B cell for interaction with helper T cells. Functions of helper T lymphocytes (Th) in humoral immune response A)- T and B lymphocytes independently recognize the antigen in different regions of peripheral lymphoid organs and are activated. The activated cells migrate toward one another and interact at the edges of lymphoid follicles. B)- Antibody secreting plasma cells are initially produced in the extrafollicular focus where the antigen-activated T and B cells interact. C)- Some of the activated B and T cells migrate back into the follicle to form the germinal center, where the antibody response develops fully.  Extrafollicular and germinal center responses to Protein antigens The early T-dependent humoral response occurs in extrafollicular foci and generates low levels of antibodies, with little isotype switching, that are produced by short-lived plasma cells. Activated B cells induce the further activation of T cells and their differentiation into Tfh cells. The B cells, together with the Tfh cells, migrate into follicles and form germinal centers The full T-dependent humoral response develops in germinal centers and leads to: - extensive isotype switching and affinity maturation; - generation of long-lived plasma cells that secrete antibodies for many years; - development of long-lived memory B cells, which rapidly respond to reencounter with antigen by proliferation and secretion of high-affinity antibodies. Plotkin S, Orenstein W, Offit P: Vaccines, 15 Edt, 2008 Presentation of Antigens by B Lymphocytes to Helper T Cells - B cells specific for a protein antigen bind and internalize that antigen, process it, and present peptides attached to class II major histocompatibility complex (MHC) molecules to helper T cells. - The B cells and helper T cells are specific for the same antigen, but the B cells recognize native (conformational) epitopes, and the helper T cells recognize peptide fragments of the antigen bound to class II MHC molecules. Mechanisms of helper T cell–mediated activation of B lymphocytes - Helper T cells recognize peptide antigens presented by B cells on the B cells. - The helper T cells are activated to express CD40 ligand (CD40L) and secrete cytokines, both of which bind to their receptors on the same B cells and activate the B cells.  Humoral immune responses to a protein antigen, called T-dependent responses, are initiated by binding of the protein to specific Ig receptors of naive B cells in lymphoid follicles. This results in the generation of signals that prepare the B cell for interaction with activated helper T cells that express CD40L and secrete cytokines The B cells internalize and process that antigen and present class II MHC–displayed peptides to activated helper T cells specific for the displayed peptide-MHC complex. These helper T cells contribute to early B cell activation at extrafollicular sites.  What is the structure of Ig? - The core structure of antibodies consists of two identical heavy chains and two identical light chains, forming a disulfide-linked complex. - Each chain consists of a variable (V) region, which is the portion that recognizes antigen, and a constant (C) region (Fc), which provides structural stability and, in heavy chains, performs the effector functions of antibodies - The V region of one heavy chain and of one light chain together form the antigen- binding site (Fab), and thus the core structure has two identical antigen-binding sites.  Immunoglobulin (Ig) heavy-chain isotype (class) switching - Helper T cells stimulate the progeny of IgM– and IgD– expressing B lymphocytes to change the heavy-chain isotypes (classes) of the antibodies they produce, without changing their antigen specificities - Antigen-stimulated B lymphocytes may differentiate into IgM antibody-secreting cells, or, under the influence of CD40 ligand (CD40L) and cytokines, some of the B cells may differentiate into cells that produce different Ig heavy-chain isotypes - B cell–activating factor belonging to the TNF family (BAFF) is a cytokine that may be involved in switching to IgA, especially in T-independent responses. - Switching to IgG subclasses is stimulated by the interferon (IFN)-γ in mice, but in humans it is thought to be stimulated by other cytokines.  Different Ig subclasses - Immunoglobulin class switching, is a biological mechanism that changes a B cell's production of immunoglobulin from one type to another, such as from the isotype IgM to the isotype IgG. - During this process, the constant-region portion of the antibody heavy chain is changed, but the variable region of the heavy chain stays the same - Since the variable region does not change, class switching does not affect antigen specificity. Instead, the antibody retains affinity for the same antigens, but can interact with different effector molecules.  Effector functions of antibodies - Antibodies use their antigen-binding (Fab) regions to bind to and block the harmful effects of microbes and toxins, and they use their Fc regions to activate diverse effector mechanisms that eliminate these microbes and toxins - Antibodies of different heavy-chain classes (isotypes) perform different effector functions  Functions of Antibody. Main function of IgA is to bind antigens on microbes before they invade tissues. IgD is present on the surface. IgA are also first defense for of B cells and plays a role in mucosal surfaces such as the the induction of antibody. IgM is involved in intestines, nose, and lungs. production. the ABO blood group antigens on the surface of RBCs.. IgM enhance ingestions of cells by phagocytosis. IgM is the primary response. IgG provides long term protection because it persists for months and. IgE bind to mast cells and years basophils wich participate in. IgG protect against bacteria, viruses, the immune response; play a neutralise bacterial toxins, trigger role also in parasitic complement protein systems and bind infections & allergic reactions antigens to enhance the effectiveness of phagocytosis.  Neutralization of microbes and microbial toxins by antibodies Antibodies bind to and block, or neutralize, the infectivity of microbes and the interactions of microbial toxins with host cells A)- Antibodies at epithelial surfaces, such as in the gastrointestinal and respiratory tracts, block the entry of ingested and inhaled microbes, respectively B)- Antibodies prevent the binding of microbes to cells, thereby blocking the ability of the microbes to infect host cells C)- Antibodies block the binding of toxins to cells, thereby inhibiting the pathologic effects of the toxins. Opsonization and phagocytosis * Antibodies coat microbes and promote their ingestion by phagocytes * Antibodies of IgG subclasse bind to microbes and are then recognized by Fc receptors on phagocytes. Signals from the Fc receptors promote the phagocytosis of the opsonized microbes and activate the phagocytes to destroy these microbes Antibody-dependent cellular cytotoxicity * Antibodies of certain immunoglobulin G (IgG) bind to antigens on the surface of infected cells, and their Fc regions are recognized by an Fcγ receptor on natural killer (NK) cells. The NK cells are activated, bind and kill the antibody-coated cells.  Immunoglobulin E (IgE)- and eosinophil-mediated killing of helminths IgE antibody binds to helminths and recruits and activates eosinophils via FcεRI, leading to degranulation of the cells and release of toxic mediators. Interleukin-5 (IL-5) secreted by Th2 cells enhances the ability of eosinophils to kill the parasites  Pathways of Complement Activation - There are three major pathways of complement activation: the alternative and lectin pathways are initiated by microbes in the absence of antibody, and the classical pathway is initiated by certain isotypes of antibodies attached to antigens - The classical pathway of complement activation is triggered when IgM or IgG bind to antigens - Adjacent Fc regions of the antibodies become accessible to and bind the C1 complement protein. - The attached C1 becomes enzymatically active, resulting in the binding and sequential cleavage of two proteins, C4 and C2. - One of the C4 fragments that is generated, C4b, becomes covalently attached to the antibody and then binds C2, which is cleaved by active C1 to yield the C4b2a complex. - This complex is the classical pathway C3 convertase, which functions to break down C3, and the C3b that is generated and binds to the C4b2a complex, and the resultant C4b2a3b complex functions as a C5 convertase, which cleaves the C5 complement protein.  Functions of antibodies at special anatomic sites - Immunoglobulin A (IgA) is produced in mucosal lymphoid tissues, transported across epithelia, and binds to and neutralizes microbes in the lumens of the mucosal organs - In the mucosa of the gastrointestinal and respiratory tracts, IgA is produced by plasma cells in the lamina propria and is actively transported through epithelial cells by an IgA-specific Fc receptor, called the poly-Ig receptor because it recognizes IgM as well. - On the luminal surface, the IgA with a portion of the bound receptor is released. Here the antibody recognizes ingested or inhaled microbes and blocks their entry through the epithelium.  Evasion of humoral immunity by microbes Microbes have evolved numerous mechanisms to evade humoral immunity Mechanisms by which microbes evade humoral immunity - Many bacteria and viruses mutate their antigenic surface molecules so that they can no longer be recognized by antibodies - HIV mutates its genome at a high rate, and change their surface antigen, called gp120; antibodies against exposed determinants on gp120 in any one HIV subtype may not protect against other virus subtypes that appear in infected individuals - Bacteria such as Escherichia coli vary the antigens contained in their pili and thus evade antibody-mediated defense - The trypanosome expresses new surface glycoproteins whenever it encounters antibodies against the original glycoprotein. As a result, infection with this protozoan parasite is characterized by waves of parasitemia, each wave consisting of an antigenically new parasite that is not recognized by antibodies produced against the parasites in the preceding wave. - Other microbes inhibit complement activation, or resist opsonization and phagocytosis by concealing surface antigens under a hyaluronic acid capsule. IN CONCLUSION: Naive B lymphocytes recognize antigens, and under the influence of helper T cells and other stimuli, the B cells are activated to proliferate, and to differentiate into antibody-secreting plasma cells. SUMMARY Humoral immunity is the type of adaptive immunity that is mediated by antibodies. Antibodies prevent infections by blocking the ability of microbes to invade host cells, and they eliminate microbes by activating several effector mechanisms. In antibody molecules, the antigen-binding (Fab) regions are spatially separate from the effector (Fc) regions. The ability of antibodies to neutralize microbes and toxins is entirely a function of the antigen binding regions. Even Fc-dependent effector functions are activated only after antibodies bind antigens. Antibodies neutralize the infectivity of microbes and the pathogenicity of microbial toxins by binding to and interfering with the ability of these microbes and toxins to attach to host cells. Antibodies coat (opsonize) microbes and promote their phagocytosis by binding to Fc receptors on phagocytes. The complement system may be activated after the binding of antibodies to antigens (classical pathway, a mechanism of adaptive humoral immunity). Microbes have developed strategies to resist or evade humoral immunity, such as varying their antigens and becoming resistant to complement and phagocytosis.