Overview Of Humoral Immunity

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. 12-1). As we shall see later, antibody-mediated elimination of antigens involves a number of effector mechanisms and requires the participation of various cellular and humoral components of the immune system, including phagocytes and complement proteins.

• Antibodies are produced by plasma cells in the lymphoid organs and bone marrow, but antibodies perform their effector functions at sites distant from their production. Antibodies produced in the lymph nodes, spleen, and bone marrow may enter the blood and then circulate throughout the body. Antibodies produced in mucosa-associated lymphoid tissues are transported across epithelial barriers into the lumens of mucosal organs, such as the intestine and the airways, where these secreted antibodies block the entry of ingested and inhaled microbes (see Chapter 13). Antibodies are also actively transported across the placenta

FIGURE 12-1 Effector functions of antibodies. Antibodies against microbes (and their toxins, not shown here) 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.

FIGURE 12-1 Effector functions of antibodies. Antibodies against microbes (and their toxins, not shown here) 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.

into the circulation of the developing fetus. In cellmediated immunity, activated T lymphocytes are able to migrate to peripheral sites of infection and inflammation, but they are not transported into mucosal secretions or across the placenta.

• The antibodies that mediate protective immunity may be derived from short-lived or long-lived antibody-producing plasma cells that are generated by the activation of naive or memory B cells. The first exposure to an antigen, either by infection or by vaccination, leads to the activation of naive B lymphocytes and their differentiation into antibody-secreting plasma cells and memory cells (see Chapter 11). Subsequent exposure to the same antigens leads to the activation of memory B cells and a larger and more rapid antibody response. Plasma cells generated early in an immune response or from marginal zone or B-1 B cells tend to be short-lived. In contrast, germinal center-derived, class-switched antibody-secreting plasma cells migrate to the bone marrow and persist at this site, where they continue to produce antibodies for years after the antigen is eliminated. Much of the immunoglobulin G (IgG) found in the serum of normal individuals is derived from these long-lived plasma cells, which were induced by the exposure of naive and memory B cells to various antigens throughout the life of the individual. If an immune individual is exposed to a previously encountered microbe, the level of circulating antibody produced by the long-lived plasma cells provides immediate protection against the infection. At the same time, activation of memory B cells generates a larger burst of antibody that provides a second and more effective wave of protection.

• Many of the effector functions of antibodies are mediated by the heavy chain constant regions of Ig molecules, and different Ig heavy chain isotypes serve distinct effector functions (Table 12-1). For instance, some IgG subclasses bind to phagocyte Fc receptors and promote the phagocytosis of antibody-coated particles, IgM and some subclasses of IgG activate the complement system, and IgE binds to the Fc receptors of mast cells and triggers their activation. Each of these antibody-mediated opsonization and phagocytosis 271

TABLE 12-1 Functions of Antibody Isotypes

Antibody Isotype

Isotype-Specific Effector Functions

IgG

Opsonization of antigens for phagocytosis by macrophages and neutrophils Activation of the classical pathway of complement Antibody-dependent cell-mediated cytotoxicity mediated by natural killer cells Neonatal immunity: transfer of maternal antibody across the placenta and gut Feedback inhibition of B cell activation

IgM

Activation of the classical pathway of complement Antigen receptor of naive B lymphocytes*

IgA

Mucosal immunity: secretion of IgA into the lumens of the gastrointestinal and respiratory tracts Activation of complement by the lectin pathway or by the alternative pathway

IgE

Mast cell degranulation (immediate hypersensitivity reactions)

IgD

Antigen receptor of naive B lymphocytes*

*These functions are mediated by membrane-bound and not secreted antibodies.

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 isotypes that are best for combating these microbes. The major stimuli for isotype switching during the process of B cell activation are helper T cell-derived cytokines together with CD40 ligand expressed by activated helper T cells (see Chapter 11). As we discussed in Chapters 10 and 11, TH1-stimulated antibody isotypes are induced by and particularly effective at clearing viruses and bacteria, and TH2-dependent antibodies are induced by and especially effective against helminthic parasites. Neutralization is the only function of antibodies that is mediated entirely by binding of antigen and does not require participation of the Ig constant regions.

• Although many effector functions of antibodies are mediated by the Ig heavy chain constant regions, all these functions 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 the Fc regions of antibodies 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.

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