system are induced and how they protect the body from infection is important for understanding how vaccines work, how they are designed, and why different vaccines are administered in different ways. Although vaccines have been important in preventing disease, the yield of successful vaccines has been disappointingly small. This is due to the fact that scientists are only now beginning to understand certain important nuances of the adaptive immune response, such as autoimmunity, a condition in which the adaptive immune system begins producing an unwanted immune response directed against the host’s own body. In this way, just as the innate immune system has its dark side (septic shock) that we discussed in the previous chapter, the adaptive immune system also has its own dark side (autoimmune reactions). Obviously, it is important that vaccines do not evoke this dark side. New insights into how the adaptive immune response develops, together with new insights into how to better deliver vaccines, are beginning to break down some of the barriers that have prevented development of vaccines and other treatment strategies against diseases such as AIDS, gonorrhea, chlamydial disease, tuberculosis, and malaria, which are serious causes of morbidity and mortality throughout the world.
In this chapter, we start with a description of two of the main products of an adaptive immune response, antibodies and cytotoxic T cells. We will then delve into the complex series of steps that produce these defenses. Finally, we will discuss how the body is able to “remember” past encounters with particular pathogens so as to more rapidly mount an effective immune response upon subsequent attacks by those pathogens.
B Cells: Producers of Antibodies
The Humoral (Antibody) Immune Response
Antibodies are immunoglobulin (Ig) protein complexes produced by mature B lymphocytes (B cells). Humoral immunity refers to the production of antibodies by mature B cells, as well as complement, antimicrobial peptides, and other immune components found in body fluids (archaically called the “humors”), but here we will confine the term to mean primarily the antibody response. Humoral immunity involves activation of naïve B cells through one of two pathways. The first pathway is a T-cell-dependent process, which is followed by clonal expansion and proliferation of the activated mature B cells and their terminal differentiation into plasma cells (mature, nonproliferating B cells that act as professional antibody-producing factories). Alternatively, T-cell-independent activation of B cells can occur through direct binding of highly repetitive structures on their surfaces, which leads to proliferation, maturation, and production of antibodies. Antibodies generated through this T-cell-independent pathway tend to have lower affinity for their targets than those generated through the T-cell-dependent activation of B cells.
Antibodies are found in blood (serum) and tissue fluids, as well as many bodily secretions (e.g., saliva, mucosal fluids, vaginal fluids, and breast milk). Antibodies carry out a number of the adaptive immune system’s critical tasks, including: binding and neutralizing the activities of foreign substances, such as toxins, bacteria, and other pathogens; coating foreign substances for enhanced opsonization and clearance from the body; and targeting infected host cells for the killing action of cytotoxic T cells (CTLs) and natural killer (NK) cells. To understand how different antibodies perform such diverse tasks, it is first necessary to understand how each type of antibody is put together and how they work.
Characteristics of Antibodies and Their Diverse Roles in Preventing Infection
The basic structures of the five types of antibodies (IgG, IgM, IgD, IgE, and IgA/sIgA) are shown in Figure 4-1. The antibody monomer consists of a complex of two heavy chains (H-chains) and two light chains (L-chains). The words “heavy” and “light” refer to the size of the peptide chain, with the H-chain being the larger of the two. The H-chains and L-chains are held together by a combination of disulfide bonds and noncovalent interactions. The H-chains define the type of antibody, with the H-chains for IgE and IgM being longer than those for IgA, IgD, and IgG.
Figure 4-1. Structures of IgG, sIgA, IgM, IgD, and IgE antibodies. Each antibody monomer is a complex comprised of four peptide chains: two identical, larger heavy chains (H-chains) and two identical, smaller light chains (L -chains) that are covalently attached through disulfide bonds. The type of H-chain defines the antibody class, with the H-chains for IgE and IgM being longer than those of IgA, IgD, and IgG. IgG is the major class of circulating antibodies. Each monomer recognizes the target epitope via two antigen-binding sites that are located in the variable regions (Fv) of the Fab portion of the monomer. There are four IgG subtypes (IgG1, IgG2, IgG3, and IgG4). The Fc region of the molecule is responsible for complement activation through binding C1q and for enhanced opsonization through binding to phagocyte Fc receptors. IgA has two subtypes: IgA1, which is found mostly in serum, and IgA2, which forms a dimer of two IgA monomers linked via a polypeptide joining chain (J-chain) and is secreted at mucosal surfaces. The IgA dimer acquires a secretory piece during transport through mucosal epithelial cells and is released as secretory IgA (sIgA) into the lumen, where it binds to mucin. IgD is a monomer that is expressed on the surface of mature B cells or is secreted. IgM is a multimer (mostly pentamer) of IgM molecules linked via disulfide bonds and a J-chain. IgM is highly agglutinating (binds and clumps antigens) and strongly activates complement (thousandfold better than IgG). IgE binds to IgE receptors on mast cells and basophils that, upon binding of antigen, trigger release of histamine and inflammatory cytokines.
Antibodies have two important regions: an N-terminal antigen-binding region (Fab) that harbors the end of the antibody that binds to a substance considered foreign by the body and a C-terminal constant region (Fc) that confers host specificity and interacts with host cells. In the most common antibody, IgG, the Fc region interacts with complement component C1q via a glycosylated region or with phagocytic cells via an Fc receptor-binding region. The Fab region contains a constant region and a variable region (Fv) that binds to a specific antigen. An antigen is defined as any material the body recognizes as foreign (nonself) that binds to an antibody. An antigen that binds to an antibody molecule can be an infectious microbe or some protein, nucleic acid, or carbohydrate component of the microbe. Additional examples of types of antigens are proteins, macromolecules, or organs from noncompatible human donors or other animals, as well as molecules from pets, plants, or insects, including dander, pollens, and toxins.
The humoral adaptive immune system’s ability to recognize a wide range of antigens and subsequently adapt to new invading pathogens relies on the ability of the B cell population to produce a vast array of antibodies with enormous diversity. This vast diversity of antigen specificity is possible because the immunoglobulin (Ig) genes undergo many gene recombination, rearrangement, insertion, deletion, and splicing events from separate, different gene segments encoding different regions of the antibody molecule during B cell development. A detailed description of the mechanism that generates the large, highly diverse population of B cells, each producing a different specific antibody that can bind to the different kinds of antigens, is beyond the scope of this book. But briefly, an amazing DNA recombination process, called V(D)J recombination, randomly shuffles a wide repertoire of variable (V), diversity (D), and joining (J) gene segments that form the N-terminal Fab regions of H-chain proteins (or just V and J gene segments in the case of L-chain proteins) and fuses them to gene segments corresponding to the constant regions in the Ig genes during the development of B cells. The exact pattern of rearrangements occurs independently in each B cell. RNA transcripts of the resulting mosaic Ig genes are further processed to give expression of the specific antibody produced by each B cell in the population. Normally during this developmental process, any B cells that produce Ig molecules that recognize self-antigens are eliminated. All of the antibodies produced by any given B cell have identical antigen-binding sites. But, during clonal expansion, when an antigen and Th cells stimulate a particular subset of B cells, a fairly high rate of spontaneous mutations, termed somatic hypermutation, is introduced, which serves to increase the diversity of the antibody pool even more and leads to proliferation of B cells that produce antibodies with high affinity to their cognate antigens.
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