Humoral immunity is the type of host defense mediated by secreted antibodies that is necessary for protection against extracellular microbes and their toxins. Antibodies prevent infections by blocking microbes from binding to and entering host cells. Antibodies also bind to microbial toxins and prevent them from damaging host cells. In addition, antibodies function to eliminate microbes, toxins, and infected cells from the body. Although antibodies are a major mechanism of adaptive immunity against extracellular microbes, they cannot reach microbes that live inside cells. However, humoral immunity is vital even for defense against microbes that live inside cells, such as viruses, because antibodies can bind to these microbes before they enter host cells or during passage from infected to uninfected cells, thus preventing spread of infection. Defects in antibody production are associated with increased susceptibility to infections by many bacteria, viruses, and parasites. All the vaccines that are currently in use work by stimulating the production of antibodies.
This chapter describes how antibodies provide defense against infections, addressing the following questions:
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What are the mechanisms used by secreted antibodies to combat different types of infectious agents and their toxins?
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What is the role of the complement system in defense against microbes?
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How do antibodies combat microbes that enter through the gastrointestinal and respiratory tracts?
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How do antibodies protect the fetus and newborn from infections?
Before describing the mechanisms by which antibodies function in host defense, we summarize the features of antibody molecules that are important for these functions.
Properties of Antibodies that Determine Effector Function
Several features of the production and structure of antibodies contribute in important ways to the functions of these molecules in host defense.
Antibodies function in the circulation, in tissues throughout the body, and in the lumens of mucosal organs . Antibodies are produced after stimulation of B lymphocytes by antigens in peripheral (secondary) lymphoid organs (lymph nodes, spleen, mucosal lymphoid tissues) and at tissue sites of inflammation. Many of the antigen-stimulated B lymphocytes differentiate into antibody-secreting plasma cells, some of which remain in lymphoid organs or inflamed tissues and others migrate to and reside in the bone marrow. Different plasma cells synthesize and secrete antibodies of different heavy-chain isotypes (classes). These secreted antibodies enter the blood, from where they may reach any peripheral site of infection, or enter mucosal secretions, where they prevent infections by microbes that try to enter through epithelia.
Protective antibodies are produced during the first (primary) response to a microbe and in larger amounts during subsequent (secondary) responses (see Fig. 7.3 in Chapter 7 ). Antibody production begins within the first week after infection or vaccination. The plasma cells that migrate to the bone marrow continue to produce antibodies for months or years. If the microbe again tries to infect the host, the continuously secreted antibodies provide immediate protection. At the same time, memory cells that had developed during the initial B cell response rapidly differentiate into antibody-producing cells upon encounter with the antigen, providing a large burst of antibody for more effective defense against the infection. A goal of vaccination is to stimulate the development of long-lived plasma cells and memory cells.
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 ( Fig. 8.1 ). This spatial segregation of the antigen recognition and effector functions of antibody molecules was introduced in Chapter 4 . Antibodies block the infectivity of microbes and the injurious effects of microbial toxins simply by binding to the microbes and toxins, using only their Fab regions to do so. Other functions of antibodies require the participation of various components of host defense, such as phagocytes and the complement system. The Fc portions of immunoglobulin (Ig) molecules, made up of the heavy-chain constant regions, contain the binding sites for Fc receptors on phagocytes and for complement proteins. The binding of antibodies to Fc receptors and complement proteins occurs only after several Ig molecules recognize and become attached to a microbe or microbial antigen. Therefore, even the Fc-dependent functions of antibodies require antigen recognition by the Fab regions. This feature of antibodies ensures that they activate effector mechanisms only when needed—that is, when they recognize their target antigens.
Heavy-chain isotype (class) switching and affinity maturation enhance the protective functions of antibodies . Isotype switching and affinity maturation are two changes that occur in the antibodies produced by antigen-stimulated B lymphocytes, especially during responses to protein antigens (see Chapter 7 ). Heavy-chain isotype switching results in the production of antibodies with distinct Fc regions, capable of different effector functions (see Fig. 8.1 ). By switching to different antibody isotypes in response to various microbes, the humoral immune system is able to engage diverse host mechanisms that are optimal for combating those microbes. Affinity maturation is induced by prolonged or repeated stimulation with protein antigens, and it leads to the production of antibodies with higher and higher affinities for the antigen, compared to the antibodies initially secreted. This change increases the ability of antibodies to bind to and neutralize or eliminate microbes. The progressive increase in antibody affinity with repeated stimulation of B cells is one of the reasons for the recommended practice of giving multiple rounds of immunizations with the same antigen for generating protective immunity.
Switching to the IgG isotype prolongs the duration that an antibody remains in the blood and therefore increases the functional activity of the antibody . Most circulating proteins have half-lives of hours to days in the blood, but IgG has an unusually long half-life because of a special mechanism involving a particular Fc receptor. The neonatal Fc receptor (FcRn) is expressed in placenta, endothelium, phagocytes, and a few other cell types. In the placenta, the FcRn transports antibodies from the mother’s circulation to the fetus (discussed later). In other cell types, the FcRn protects IgG antibodies from intracellular catabolism ( Fig. 8.2 ). FcRn is found in the endosomes of endothelial cells and phagocytes, where it binds to IgG that has been taken up by the cells. Once bound to the FcRn, the IgG is recycled back into the circulation or tissue fluids, thus avoiding lysosomal degradation. This unique mechanism for protecting a blood protein is the reason why IgG antibodies have a half-life of about 3 weeks, much longer than that of other Ig isotypes and most other plasma proteins. This property of Fc regions of IgG has been exploited to increase the half-life of other proteins by coupling the proteins to an IgG Fc region ( Fig. 8.3 ). One of several therapeutic agents based on this principle is the tumor necrosis factor (TNF) receptor–Fc fusion protein, which functions as an antagonist of TNF and is used to treat various inflammatory diseases. By coupling the extracellular domain of the TNF receptor to the Fc portion of a human IgG molecule using a genetic engineering approach, the half-life of the hybrid protein becomes much greater than that of the soluble receptor by itself.
With this introduction, we proceed to a discussion of the mechanisms used by antibodies to combat infections. Much of the chapter is devoted to effector mechanisms that are not influenced by anatomic considerations; that is, they may be active anywhere in the body. At the end of the chapter, we describe the special features of antibody functions at particular anatomic locations.
Neutralization of Microbes and Microbial Toxins
Antibodies bind to and block, or neutralize, the infectivity of microbes and the interactions of microbial toxins with host cells ( Fig. 8.4 ). Antibodies in mucosal secretions in the gut and airways block the entry of ingested and inhaled microbes (discussed later in the chapter). After microbes enter the host, they use molecules in their envelopes or cell walls to bind to and gain entry into host cells. Antibodies may attach to these microbial surface molecules, thereby preventing the microbes from infecting host cells. The most effective vaccines available today work by stimulating the production of neutralizing antibodies that block initial infection. Microbes that are able to enter host cells may replicate inside the cells and then be released and go on to infect other neighboring cells. Antibodies can neutralize the microbes during their transit from cell to cell and thus also limit the spread of infection. If an infectious microbe does colonize the host, its harmful effects may be caused by endotoxins or exotoxins, which often bind to specific receptors on host cells in order to mediate their effects. Antibodies prevent binding of the toxins to host cells and thus block their harmful effects. Emil von Behring and Shibasaburo Kitasato’s demonstration of this type of protection mediated by the administration of antibodies against diphtheria toxin was the first formal demonstration of therapeutic immunity against a microbe or its toxin, then called serum therapy, and the basis for awarding Behring the first Nobel Prize in Physiology or Medicine in 1901.
Opsonization and Phagocytosis
Antibodies coat microbes and promote their ingestion by phagocytes ( Fig. 8.5 ). The process of coating particles for subsequent phagocytosis is called opsonization, and the molecules that coat microbes and enhance their phagocytosis are called opsonins. When several IgG molecules bind to a microbe, an array of their Fc regions projects away from the microbial surface. If the antibodies belong to certain isotypes (IgG1 and IgG3 in humans), their Fc regions bind to a high-affinity receptor for the Fc regions of γ heavy chains, called FcγRI (CD64), which is expressed on neutrophils and macrophages ( Fig. 8.6 ). The phagocyte extends its plasma membrane around the attached microbe and ingests the microbe into a vesicle called a phagosome, which fuses with lysosomes. The binding of antibody Fc tails to FcγRI also activates the phagocytes, because the FcγRI contains a signaling chain that triggers numerous biochemical pathways in the phagocytes. Large amounts of reactive oxygen species, nitric oxide, and proteolytic enzymes are produced in the lysosomes of the activated neutrophils and macrophages, all of which contribute to the destruction of the ingested microbe.
Antibody-mediated phagocytosis is the major mechanism of defense against encapsulated bacteria, such as pneumococci. The polysaccharide-rich capsules of these bacteria protect the organisms from phagocytosis in the absence of antibody, but opsonization by antibody promotes phagocytosis and destruction of the bacteria. The spleen contains large numbers of phagocytes and is an important site of phagocytic clearance of opsonized bacteria. This is why patients who have undergone splenectomy are susceptible to disseminated infections by encapsulated bacteria.
One of the Fc γ receptors, Fc γ RIIB, does not mediate effector functions of antibodies but rather shuts down antibody production and reduces inflammation . The role of FcγRIIB in feedback inhibition of B cell activation was discussed in Chapter 7 (see Fig. 7.16 ). FcγRIIB also inhibits activation of macrophages and dendritic cells and may thus serve an antiinflammatory function as well. Pooled IgG from healthy donors is given intravenously to treat various inflammatory diseases. This preparation is called intravenous immune globulin (IVIG), and its beneficial effect in these diseases is partly mediated by its binding to FcγRIIB on various cells.
Antibody-Dependent Cellular Cytotoxicity
Natural killer (NK) cells bind to antibody-coated cells and destroy these cells ( Fig. 8.7 ). NK cells express an Fcγ receptor called FcγRIII (CD16), which is one of several kinds of NK cell–activating receptors (see Chapter 2 ). FcγRIII binds to arrays of IgG antibodies attached to the surface of a cell, generating signals that cause the NK cell to discharge its granule proteins, which kill the antibody-coated cell by the same mechanisms that CD8 + cytotoxic T lymphocytes use to kill infected cells (see Chapter 6 ). This process is called antibody-dependent cellular cytotoxicity (ADCC). Cells infected with enveloped viruses typically express viral glycoproteins on their surface that can be recognized by specific antibodies, and this may facilitate ADCC-mediated destruction of the infected cells. ADCC is also one of the mechanisms by which therapeutic antibodies used to treat cancers eliminate tumor cells.
