their synthesis and secretion of a variety of cytokines that regulate many events in B cells required for proliferation and differentiation (see Chapter 11).
Humoral Immunity
B cells are initially activated to secrete antibodies after the binding of antigens to antigen‐specific membrane immunoglobulin (Ig) molecules (BCRs), which are expressed by these cells. It has been estimated that each B cell expresses approximately 100,000 BCRs of exactly the same specificity. Once ligated, the B cell receives signals to begin making the secreted form of this immunoglobulin, a process that initiates the full‐blown antibody response whose purpose is to eliminate the antigen from the host. Antibodies are a heterogeneous mixture of serum globulins, all of which share the ability to bind individually to specific antigens. All serum globulins with antibody activity are referred to as immunoglobulins (see Chapter 6). These molecules have common structural features, which enable them to do two things: (1) recognize and bind specifically to a unique structural entity on an antigen (namely, the epitope), and (2) perform a common biological function after combining with the antigen. Immunoglobulin molecules consist of two identical light (L) chains and two identical heavy (H) chains, linked by disulfide bridges. The resultant structure is shown in Figure 1.3. The portion of the molecule that binds antigen consists of an area composed of the amino‐terminal regions of both H and L chains. Thus each immunoglobulin molecule is symmetrical and is capable of binding two identical epitopes present on the same antigen molecule or on different molecules.
Figure 1.3. Typical antibody molecule composed of two heavy (H) and two light (L) chains. Antigen‐binding sites are noted.
In addition to differences in the antigen‐binding portion of different immunoglobulin molecules, there are other differences, the most important of which are those in the H chains. There are five major classes of H chains (termed γ, μ, α, ε, and δ). On the basis of differences in their H chains, immunoglobulin molecules are divided into five major classes—IgG, IgM, IgA, IgE, and IgD—each of which has several unique biological properties. For example, IgG is the only class of immunoglobulin that crosses the placenta, conferring the mother’s immunity on the fetus, and IgA is the major antibody found in secretions such as tears and saliva. It is important to remember that antibodies in all five classes may possess precisely the same specificity against an antigen (antigen‐combining regions), while at the same time having different functional (biological effector) properties. The binding between antigen and antibody is not covalent but depends on many relatively weak forces, such as hydrogen bonds, van der Waals forces, and hydrophobic interactions. Since these forces are weak, successful binding between antigen and antibody depends on a very close fit over a sizeable area, much like the contacts between a lock and a key.
Besides the help provided by T cells in the generation of antibody responses, noncellular components of the innate immune system, collectively termed the complement system, play a key role in the functional activity of antibodies when they interact with antigen (see Chapter 4). The reaction between antigen and antibody serves to activate this system, which consists of a series of serum enzymes, the end‐result of which is lysis of the target in the case of microbes such as bacteria or enhanced phagocytosis (ingestion of the antigen) by phagocytic cells. The activation of complement also results in the recruitment of highly phagocytic polymorphonuclear (PMN) cells or neutrophils, which are active in innate immunity.
Cell‐Mediated Immunity
In contrast to humoral immune responses that are mediated by antibody, cell‐mediated responses are T cell mediated. However, this is an oversimplified definition since the effector cell responsible for the elimination of a foreign antigen such as a pathogenic microbe can be an activated T cell expressing a pathogen‐specific TCR or a phagocytic cell that gets activated by innate receptors that they express and the cytokines produced by activated T cells (Figure 1.4). Unlike B cells, which produce soluble antibody that circulates to bind its specific antigens, each T cell, bearing approximately 100,000 identical antigen receptors (TCRs), circulates directly to the site of antigen expressed on APCs and interacts with these cells in a cognate (cell‐to‐cell) fashion (see Chapters 8 and 10). Activated T cells do release soluble mediators such as cytokines but these are not antigen specific.
There are several phenotypically distinct subpopulations of T cells, each of which may have the same specificity for an antigenic determinant (epitope), although each subpopulation may perform different functions. This is somewhat analogous to the different classes of immunoglobulin molecules, which may have identical specificity but different biological functions. Several major subsets of T cells exist: helper T cells (TH cells), which express molecules called CD4, and cytotoxic T cells (TC cells), which express CD8 molecules on their surface. Another population of T cells that possesses suppressor activity is the T regulatory (Treg) cells.
The functions ascribed to the various subsets of T cells include the following.
B‐cell help. TH helper cells cooperate with B cells to enhance the production of antibodies. Such T cells function by releasing cytokines, which provide various activation signals for the B cells. As mentioned earlier, cytokines are soluble substances or mediators that can regulate proliferation and differentiation of B cells, among other functions. Additional information about cytokines is presented in Chapter 11.
Inflammatory effects. On activation, certain TH cells release cytokines that induce the migration and activation of monocytes and macrophages, leading to inflammatory reactions (Chapter 15).
Cytotoxic effects. As illustrated in Figure 1.1, T cells differentiate into subpopulations commonly defined as TH helper cells (a.k.a. TH cells), discussed below, and TC cytotoxic cells (TC cells). As the name implies, the latter cells have cytotoxic effects on other cells, a phenomenon that will be discussed further in later chapters. Upon contact with a specific target cell, TC cells are able to deliver a lethal hit, leading to the death of the latter. TC cells all express membrane molecules called CD8 and are, therefore, CD8+ cells.Figure 1.4. Antigen receptors expressed as transmembrane molecules on B and T lymphocytes.
Regulatory effects. In contrast with TC cells, TH cells play a significant role in regulating immune responses. The other distinguishing feature of TH cells is their expression of membrane molecules called CD4 (hence, they are CD4+ cells). They can be further subdivided into different functional subsets that are commonly defined by the cytokines they release. As you will learn in subsequent chapters, these subsets (e.g., TH1, TH2) have distinct regulatory properties that are mediated by the cytokines they release (Chapter 11). TH1 cells can negatively cross‐regulate TH2 cells and vice versa. Another population of regulatory T cells, the Treg cells, co‐express CD4 and a molecule called CD25 (CD25 is part of a cytokine receptor known as the interleukin‐2 receptor α chain). The regulatory activity
