Before we discuss the principal mechanisms by which antibodies provide protection against microbes, we will summarize some of the salient features of antibody-mediated host defense.
The main functions of antibodies are to neutralize and eliminate infectious microbes and microbial toxins (Fig. 1). As we will see later, antibody-mediated elimination of antigens involves a number of mechanisms that require the participation of various cells and secreted proteins of the immune system, including phagocytes and complement proteins.
Fig1. Effector functions of antibodies. Antibodies against microbes (and their toxins, not shown) neutralize these agents, opsonize them for phagocytosis, sensitize them for antibody-dependent cellular cytotoxicity, and activate the complement system. These various effector functions may be mediated by different antibody isotypes. NK, Natural killer.
Antibodies are produced by plasma cells in secondary (peripheral) lymphoid organs, inflamed tissues, healthy mucosal tissues, and bone marrow, and antibodies can perform their effector functions where they are secreted and at distant sites. Antibodies are produced in the lymph nodes, spleen, and bone marrow by short-lived or long-lived plasma cells, the latter residing mainly in the bone marrow. These secreted antibodies enter the blood and then circulate throughout the body. In mucosal organs, such as the intestine and the airways, antibodies are produced in the lamina propria and transported across epithelia into the lumens, where these secreted antibodies block the entry of ingested and inhaled microbes. Antibodies are also actively transported across the placenta into the circulation of the developing fetus. In disease states, antibodies may be produced in peripheral nonlymphoid tis sues, at sites of infection or chronic inflammation that are sometimes called tertiary lymphoid structures. In cell-mediated immunity, activated T lymphocytes migrate to peripheral sites of infection and inflammation, but they are not transported into mucosal secretions or across the placenta. Therefore, antibodies are the only host defense mechanism used to combat microbes in the lumens of mucosal organs and in the fetus and newborn.
Other than neutralization, the effector functions of antibodies are mediated by the Fc regions of Ig molecules, and different Ig heavy-chain classes serve distinct effector functions (Table 1). For instance, some IgG subclasses (IgG1 and IgG3) bind to activating phagocyte Fc receptors and promote the phagocytosis of antibody-coated particles and the activation of phagocytes; IgM and some subclasses of IgG (IgG1, IgG2 to a limited extent, and IgG3 but not IgG4) activate the complement system; and IgE binds to the Fc receptors of mast cells and triggers their activation. Each of these effector mechanisms will be discussed later in this chapter. The humoral immune system is specialized in such a way that different microbes or antigen exposures stimulate B-cell switching to the Ig classes (isotypes) that are best for combating these microbes. The major stimuli for class switching during the process of B-cell activation are cytokines together with CD40 ligand expressed by activated helper T cells. Neutralization is the only function of antibodies that is mediated entirely by the binding of antigens and does not require the participation of the Ig constant regions.
Table1. Functions of Antibody Classes
The effector functions of antibodies that are mediated by the Fc regions are triggered by the binding of antigens to the variable regions. The binding of antibodies to a multivalent antigen, such as a polysaccharide or a repeated epitope on a microbial surface, brings multiple antibody molecules close together, and this clustering of antibody molecules leads to complement activation and allows the antibodies to bind to and activate Fc receptors on phagocytes. The requirement for antigen binding ensures that antibodies activate various effector mechanisms only when they are needed; that is, when the antibodies encounter and specifically bind antigens, not when the antibodies are circulating in an antigen-free form.
With this introduction to humoral immunity, we proceed to a discussion of the various functions of antibodies in host defense.
