Immunology. Richard Coico
by specialized cells (lymphocytes) that bear on their surface antigen‐specific receptors.
Memory, a property shared with the nervous system, is the ability to recall previous contact with a foreign molecule and respond to it in a learned manner, that is, with a more rapid and larger response. Another term often used to describe immunological memory is anamnestic response.
When you reach the end of this book, you should understand the cellular and molecular bases of these features of the immune response.
Cells Involved in Adaptive Immune Responses
For many years, immunology remained an empirical subject in which the effects of injecting various substances into hosts were studied primarily in terms of the products elicited. Most progress came in the form of more quantitative methods for detecting these products of the immune response. A major change in emphasis came in the 1950s with the recognition that lymphocytes were the major cellular players in the immune response, and the field of cellular immunology came to life.
A convenient way to define the cell types involved in adaptive immunity is to divide the host defense mechanisms into two categories, namely B‐cell and T‐cell responses. While this is an oversimplified definition, it is, by and large, the functional outcome of adaptive immune responses. Thus, defining the cells involved begins with a short list, namely B and T cells. These cells are derived from a common lymphoid precursor cell but differentiate along different developmental lines, as discussed in detail in Chapters 8–10. In short, B cells develop and mature in the bone marrow whereas T‐cell precursors emerge from the bone marrow and undergo critical maturation steps in the thymus.
Antigen‐presenting cells, such as macrophages and dendritic cells, constitute the third cell type that participates in the adaptive immune response. Although these cells do not have antigen‐specific receptors as do the lymphocytes, they process and present antigen to the antigen‐specific receptors expressed by T cells. The APCs express a variety of cell‐surface molecules that facilitate their ability to interact with T cells. Among these are the major histocompatibility complex (MHC) molecules as discussed in Chapter 8. MHC molecules are encoded by a set of polymorphic genes expressed within a population. While we now understand that their physiological role is concerned with T cell–APC interactions, in clinical settings, MHC molecules determine the success or failure of organ and tissue transplantation. In fact, this observation facilitated their discovery and the current terminology (major histocompatibility complex) used to define these molecules. Physiologically, APCs process protein antigens intracellularly, resulting in the constellation of peptides that noncovalently bind to MHC molecules and ultimately get displayed on the cell surface.
Other cell types, such as neutrophils and mast cells, also participate in adaptive immune responses. In fact, they participate in both innate and adaptive immunity. While these cells have no specific antigen recognition properties and can be activated by a variety of substances, they are an integral part of the network of cells that participate in host defenses and often display potent immunoregulatory properties.
HUMORAL AND CELLULAR IMMUNITY
Adaptive immune responses have historically been divided into two separate arms of defense: B‐cell‐mediated or humoral immune responses, and T‐cell‐mediated or cellular responses. Today, while we recognize that B and T cells have very distinct yet complementary molecular and functional roles within our immune system, we understand that the two arms are fundamentally interconnected at many levels. “Experiments of nature,” a term coined by Robert A. Good in the 1950s when describing the immune status of humans with a congenital mutation associated with an athymic phenotype, have provided significant insights related to the interdependence of these two arms of the immune system. Athymic mice that fail to develop thymic tissue (a similar phenomenon in humans is called DiGeorge syndrome) results in a profound T‐cell deficiency with accompanying abnormalities in B‐cell function. The molecular explanation for the latter is now well understood. Without T‐cell help, B cells are unable to generate normal antibody responses and, in particular, to undergo immunoglobulin class switching (see Chapter 9). The help normally provided by T cells is delivered in several ways, including 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