B cell-Mediated Immunity 2023.pdf

B cell-Mediated Immunity Dr Allison Imrie Learning Outcomes At the end of this lecture you should understand: The structure and function of the two forms of antibody molecules – membrane-bound and secreted The structure of the B cell receptor, including the major molecules of the signaling complex T...

B cell-Mediated Immunity Dr Allison Imrie Learning Outcomes At the end of this lecture you should understand: The structure and function of the two forms of antibody molecules – membrane-bound and secreted The structure of the B cell receptor, including the major molecules of the signaling complex The major events of antigen recognition, the types of antigens and the B cell lineages (TD and TI) that recognize them, and the anatomical sites where this recognition occurs The antibody classes (isotypes), their main effector functions, their structural similarities and differences, and their selective anatomical distribution The phases of the humoral immune response The major features of secondary antibody responses, from memory Antibodies exist in two forms: (1) membrane-bound antibodies on the surface of B lymphocytes function as antigen receptors, and (2) secreted antibodies neutralize toxins, prevent the entry and spread of pathogens, and eliminate microbes. The V region of one heavy chain (VH) and the adjoining V region of one light chain (VL) form an antigen-binding site Three hypervariable regions of a VL domain and the three hypervariable regions of a VH domain are brought together to create an antigen-binding surface The 3 hypervariable regions are also called complementarity-determining regions (CDRs): CDR1, CDR2, CDR3 Amino acid residues of the hypervariable regions form multiple contacts with bound antigen. The most extensive contact is with the third hypervariable region (CDR3), which is also the most variable of the three CDRs The recognition of antigen by antibody involves non-covalent, reversible binding The strength of the binding between a single combining site of an antibody and an epitope of an antigen is called the affinity of the antibody, represented by a dissociation constant (Kd) Smaller Kd indicates a stronger or higher affinity interaction because a lower concentration of antigen and of antibody is required for complex formation Kd of antibodies produced in typical humoral immune responses usually varies from about 10−7 M to 10−11 M Strength of attachment of the antibody to the antigen must take into account binding of all the sites to all the available epitopes. This overall strength of attachment is called the avidity and is much greater than the affinity of any one antigen-binding site The main functions of antibodies are to neutralize and eliminate infectious microbes and microbial toxins Class-switched, high-affinity antibodysecreting plasma cells, which are produced in germinal centres during Tdependent responses to protein antigens, migrate to the bone marrow and persist at this site, where they continue to produce antibodies for years after the antigen is eliminated. Antibody responses develop in lymphoid tissues under the direction of TFH cells Antigen is retained for long periods in these complexes, as iccosomes Opsonised antigens are captured and preserved by subcapsular macrophages Antigens are trapped in immune complexes that bind to the surface of follicular dendritic cells Activated B cells undergo rounds of mutation and selection for higher-affinity mutants in the germinal centre, resulting in highaffinity antibody-secreting plasma cells and high-affinity memory B cells Antibody-producing plasma cells and memory B cells, can quickly be reactivated following secondary challenge. Antibody isotypes have different half-lives in circulation IgE has a very short half-life of about 2 days in the circulation (although cell-bound IgE associated with the high-affinity IgE receptor on mast cells has a very long half-life Circulating IgA has a half-life of about 3 days Circulating IgM has a half-life of about 4 days Circulating IgG molecules have a half-life of about 21 to 28 days. The distributions and functions of immunoglobulin classes Antibodies of different classes operate in distinct places and have distinct effector functions. Transport proteins that bind to the Fc regions of antibodies carry particular isotypes across epithelial barriers. High-affinity IgG and IgA antibodies can neutralize bacterial toxins. High-affinity IgG and IgA antibodies can inhibit the infectivity of viruses. Antibodies can block the adherence of bacteria to host cells. Antibody:antigen complexes activate the classical pathway of complement by binding to C1q. Complement receptors are important in the removal of immune complexes from the circulation. Physical properties of the human immunoglobulin isotypes IgM and IgA molecules can form multimers, in association with an additional polypeptide chain, the J chain Immunoglobulin classes are selectively distributed throughout the body The major class of antibody present in the lumen of the gut is secretory dimeric IgA IgA is synthesized by plasma cells in the lamina propria and transported into the lumen of the gut through epithelial cells at the base of the crypts Dimeric IgA binds to the layer of mucous overlaying the gut epithelium and acts as an antigen-specific barrier to pathogens and toxins in the gut lumen The Poly-Ig Receptor: Transport of IgA across epithelial cells IgA produced by plasma cells in the lamina propria is in the form of a dimer that is held together by the J chain From the lamina propria, the dimeric IgA must be transported across the epithelium into the lumen, and this function is mediated by the poly-Ig receptor. IgM produced by lamina propria plasma cells is also a polymer (pentamer) associated covalently with the J chain, and the poly-Ig receptor also transports IgM into intestinal secretions The dominance of IgA production by intestinal plasma cells is due in part to selective induction of IgA isotype switching in B cells in GALT and mesenteric lymph nodes Neutralisation of Microbes and Microbial Toxins Antibodies against microbes and microbial toxins block the binding of these microbes and toxins to cellular receptors The classical Complement pathway is initiated by binding of the complement protein C1 to IgG or IgM molecules that have bound antigen Among IgG antibodies, IgG3 and IgG1 (in humans) are more efficient activators of complement than are other subclasses Only antibodies bound to antigens, and not free circulating antibodies, can initiate classical pathway activation Antibodies of the IgG isotype coat (opsonize) microbes and promote their phagocytosis by binding to Fc receptors on phagocytes The process of coating particles to promote phagocytosis is called opsonization, and substances that perform this function, including antibodies and complement proteins, are called opsonins. Neonatal Fc receptor Involved in the transport of IgG from the maternal circulation across the placental barrier as well as the transfer of maternal IgG across the intestine in neonates FcRn does not target bound IgG to lysosomes but recycles to the cell surface and releases it at neutral pH, returning the IgG to the circulation This intracellular sequestration of IgG away from lysosomes prevents it from being degraded as rapidly as most other serum proteins, including other antibody isotypes, and as a result, IgG has a relatively long half-life. Neonatal mammals are protected from infection by maternally produced antibodies transported across the placenta into the foetal circulation and by antibodies in ingested milk transported across the gut epithelium of newborns For several months after birth, their major defence against infection is passive immunity provided by maternal antibodies Maternal IgG is transported across the placenta, and maternal IgA and IgG in breast milk are ingested by the nursing infant Transepithelial transport of maternal IgA into breast milk depends on the poly-Ig receptor Mast cells are activated by cross-linking of FcεRI molecules, which occurs by binding of multivalent antigens to the IgE molecules that are attached to the Fc receptors Contents of the mast cell granules are released into the extracellular environment. This process can occur within seconds of FcεRI cross-linking, and can be visualized morphologically by loss of the dense granules of mast cells Antibody-Dependent Cellular Cytotoxicity (ADCC) Natural killer (NK) cells and other leukocytes bind to antibody-coated cells by Fc receptors and destroy these cells NK cells use their Fc receptor, FcγRIIIA, to bind to antibody-coated cells. FcγRIIIA (CD16) is a low-affinity receptor that binds clustered IgG molecules displayed on cell surfaces but does not bind circulating monomeric IgG. Therefore, ADCC occurs only when the target cell is coated with antibody molecules Complement receptors are important in the removal of immune complexes from the circulation Erythrocyte CR1 helps to clear immune complexes from the circulation Immune complexes bind to CR1 on RBC, which transport them to the liver and spleen, where they are removed by macrophages expressing receptors for both Fc and bound C’ Phases of the humoral immune response Anti-viral immunity after smallpox vaccination may be long-lived