No activation of macrophage, no destruction of bacterium Activation of macrophage, leading to phagocytosis and destruction of bacterium Free immunoglobulin does not cross-link Fc receptors Aggregation of immunoglobulin on bacterial surface allows cross-linking of Fc receptors Fc receptors macrophage bacterium of phagocytosis by complement-coated antigens binding to complement receptors is particularly important early in the immune response, before isotype-switched antibodies have been made. Capsular polysaccharides belong to the TI-2 class of thymus-independent antigens, and can therefore stimulate the early production of IgM antibodies, which are very effective at activating the complement system. IgM binding to encapsulated bacteria thus triggers the opsonization of these bacteria by complement and their prompt ingestion and destruction by phagocytes bearing complement receptors. Recently, Fcα/μR was discovered as a receptor that binds both IgA and IgM. Fcα/μR is expressed primarily on macrophages and B cells in the lamina propria of the intestine and in germinal centers. It is thought to have a role in the endocytosis of IgM antibody complexed with bacteria such as Staphylococcus aureus.
Phagocyte activation can initiate an inflammatory response that causes tissue damage, and so Fc receptors on phagocytes must be able to distinguish antibody molecules bound to a pathogen from the much larger number of free antibody molecules that are not bound to anything. This distinction is made possible by the aggregation of antibodies that occurs when they bind to multimeric antigens or to multivalent particulate antigens such as viruses and bacteria. Individual Fc receptors on a cell surface bind monomers of free antibody with low affinity, but when presented with an antibody-coated particle, the simultaneous binding by multiple Fc receptors results in binding of high avidity, and this is the principal mechanism by which bound antibodies are distinguished from free immunoglobulin (Fig. 10.40). The result is that Fc receptors enable cells to detect pathogens via the antibody molecules bound to them. Fc receptors therefore give phagocytic cells that lack intrinsic specificity the ability to identify and remove specific pathogens and their products from the extracellular spaces.
Fig. 10.40 Bound antibody is distinguishable from free immunoglobulin by its state of aggregation. Free immunoglobulin molecules bind most Fc receptors with very low affinity and cannot cross-link Fc receptors. Antigen-bound immunoglobulin, however, binds to Fc receptors with high avidity because several antibody molecules that are bound to the same surface bind to multiple Fc receptors on the surface of the accessory cell. This Fc receptor cross-linking sends a signal to activate the cell bearing it. With Fc receptors that have ITIMs, the result is inhibition.
Phagocytosis is greatly enhanced by interactions between the molecules coating an opsonized microorganism and receptors on the phagocyte surface. When an antibody-coated pathogen binds to Fcγ receptors, for example, the cell surface of the phagocyte extends around the surface of the pathogen through successive binding of the Fcγ receptors to the antibody Fc regions bound to the pathogen. This is an active process that is triggered by the stimulation of the Fcγ receptors. Phagocytosis leads to enclosure of the pathogen (or particle) in an acidified cytoplasmic vesicle—the phagosome. This then fuses with one or more lysosomes to generate a phagolysosome; lysosomal enzymes are released into the vesicle interior, where they destroy the bacterium (see Fig. 10.39). The process of intracellular killing by phagocytes was described in more detail in Chapter 3.