Cardinal Features Of Adaptive Immune Responses

All humoral and cell-mediated immune responses to foreign antigens have a number of fundamental properties that reflect the properties of the lymphocytes that mediate these responses (Table 1-3).

• Specificity and diversity. Immune responses are specific for distinct antigens and, in fact, for different portions of a single complex protein, polysaccharide, or other macromolecule (Fig. 1-4). The parts of such antigens that are specifically recognized by individual lymphocytes are called determinants or epitopes. This fine specificity exists because individual lymphocytes express membrane receptors that are able to distinguish subtle differences in structure between distinct epitopes. Clones of lymphocytes with different specificities are present in unimmunized individuals and are able to recognize and respond to foreign antigens. This concept is the basic tenet of the clonal selection hypothesis, which is discussed in more detail later in this chapter.

The total number of antigenic specificities of the lymphocytes in an individual, called the lymphocyte repertoire, is extremely large. It is estimated that the immune system of an individual can discriminate 107 to 109 distinct antigenic determinants. This ability of the lymphocyte repertoire to recognize a very large number of antigens is the result of variability in the structures of the antigen-binding sites of lymphocyte receptors for antigens, called diversity. In other words, there are many different clones of lymphocytes that differ in the structures of their antigen receptors and therefore in their specificity for antigens, contributing to a total repertoire that is extremely diverse. The variation of antigen receptors among different clones of T and B cells is the reason that these receptors are said to be "clonally distributed." The molecular mechanisms that generate such diverse antigen receptors are discussed in Chapter 8.

• Memory. Exposure of the immune system to a foreign antigen enhances its ability to respond again to that antigen. Responses to second and subsequent exposures to the same antigen, called secondary immune responses, are usually more rapid, larger, and often qualitatively different from the first, or primary, immune response to that antigen (see Fig. 1-4). Immu-nologic memory occurs because each exposure to an antigen generates long-lived memory cells specific for the antigen, which are more numerous than the naive T cells specific for the antigen that exist before antigen exposure. In addition, these memory cells have special characteristics that make them more efficient at responding to and eliminating the antigen than are naive lymphocytes that have not previously been exposed to the antigen. For instance, memory B lymphocytes produce antibodies that bind antigens with higher affinities than do antibodies produced in primary immune responses, and memory T cells react much more rapidly and vigorously to antigen challenge than do naive T cells.

• Clonal expansion. Lymphocytes specific for an antigen undergo considerable proliferation after exposure to that antigen. The term clonal expansion refers to an increase in the number of cells that express identical receptors for the antigen and thus belong to a clone. This increase in antigen-specific cells enables the adaptive immune response to keep pace with rapidly dividing infectious pathogens.

• Specialization. As we have already noted, the immune system responds in distinct and special ways to

TABLE 1-3 Cardinal Features of Adaptive Immune Responses

Feature

Functional Significance

Specificity

Ensures that the immune response to a microbe (or nonmicrobial antigen) is targeted to that microbe (or antigen)

Diversity

Enables immune system to respond to a large variety of antigens

Memory

Increases ability to combat repeat infections by the same microbe

Clonal expansion

Increases number of antigen-specific lymphocytes to keep pace with microbes

Specialization

Generates responses that are optimal for defense against different types of microbes

Contraction and homeostasis

Allows immune system to recover from one response so that it can effectively respond to newly encountered antigens

Nonreactivity to self

Prevents injury to host during responses to foreign antigens

FIGURE 1-4 Specificity, memory, and contraction of adaptive immune responses. Antigens X and Y induce the production of different antibodies (specificity). The secondary response to antigen X is more rapid and larger than the primary response (memory). Antibody levels decline with time after each immunization (contraction, the process that maintains homeostasis). The same features are seen in cell-mediated immune responses.

FIGURE 1-4 Specificity, memory, and contraction of adaptive immune responses. Antigens X and Y induce the production of different antibodies (specificity). The secondary response to antigen X is more rapid and larger than the primary response (memory). Antibody levels decline with time after each immunization (contraction, the process that maintains homeostasis). The same features are seen in cell-mediated immune responses.

different microbes, maximizing the effectiveness of antimicrobial defense mechanisms. Thus, humoral immunity and cell-mediated immunity are elicited by different classes of microbes or by the same microbe at different stages of infection (extracellular and intracellular), and each type of immune response protects the host against that class of microbe. Even within humoral or cell-mediated immune responses, the nature of the antibodies or T lymphocytes that are generated may vary from one class of microbe to another. We will return to the mechanisms and functional significance of such specialization in later chapters.

• Contraction and homeostasis. All normal immune responses wane with time after antigen stimulation, thus returning the immune system to its resting basal state, a state that is called homeostasis (see Fig. 1-4). This contraction of immune responses occurs largely because responses that are triggered by antigens function to eliminate the antigens, thus eliminating an essential stimulus for lymphocyte survival and activation. Lymphocytes, other than memory cells, that are deprived of these stimuli die by apoptosis.

• Nonreactivity to self. One of the most remarkable properties of every normal individual's immune system is its ability to recognize, respond to, and eliminate many foreign (non-self) antigens while not reacting harmfully to that individual's own (self) antigenic substances. Immunologic unresponsiveness is also called tolerance. Tolerance to self antigens, or self-tolerance, is maintained by several mechanisms. These include eliminating lymphocytes that express receptors specific for some self antigens, inactivating self-reactive lymphocytes, or suppressing these cells by the actions of other (regulatory) cells. Abnormalities in the induction or maintenance of self-tolerance lead to immune responses against self (autologous) antigens, which may result in disorders called autoimmune diseases. The mechanisms of self-tolerance and its failure are discussed in Chapter 14.

These features of adaptive immunity are necessary if the immune system is to perform its normal function of host defense (see Table 1-3). Specificity and memory enable the immune system to mount heightened responses to persistent or recurring exposure to the same antigen and thus to combat infections that are prolonged or occur repeatedly. Diversity is essential if the immune system is to defend individuals against the many potential pathogens in the environment. Specialization enables the host to "custom design" responses to best combat different types of microbes. Contraction of the response allows the system to return to a state of rest after it eliminates each foreign antigen and to be prepared to respond to other antigens. Self-tolerance is vital for preventing harmful reactions against one's own cells and tissues while maintaining a diverse repertoire of lymphocytes specific for foreign antigens.

Immune responses are regulated by a system of positive feedback loops that amplify the reaction and by control mechanisms that prevent inappropriate or pathologic reactions. When lymphocytes are activated, they trigger mechanisms that further increase the magnitude of the response. This positive feedback is important to enable the small number of lymphocytes that are specific for any microbe to generate the response needed to eradicate that infection. Many control mechanisms become active in immune responses to prevent excessive activation of lymphocytes, which may cause collateral damage to normal tissues, and to avoid responses against self antigens. In fact, a balance between activating and inhibitory signals is characteristic of all immune responses. We will mention specific examples of these fundamental features of the immune system throughout the book.

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