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22.5
Adaptive Immunity
    LEARNING OUTCOMES

    After reading this section, you should be able to:

  1. Define antigen and describe the two groups of antigens.
  2. Explain the role of haptens in allergic reactions.
  3. Describe the origin, development, activation, proliferation, and inhibition of lymphocytes.
  4. Describe the function of major histocompatibility complex (MHC) molecules in immunity.
  5. Distinguish between class I MHC molecules and class II MHC molecules.
  6. Define antibody-mediated immunity and cell-mediated immunity, and name the cells responsible for each.
  7. Diagram the structure of an antibody, and describe the effects produced by antibodies.
  8. Discuss the primary and secondary responses to an antigen, and explain the basis for long-lasting immunity.
  9. Describe the types and functions of T cells.
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Adaptive immunity can recognize, respond to, and remember a particular substance. Substances that stimulate adaptive immunity are called antigens (an′ti-jenz). They are usually large molecules with a molecular weight of 10,000 or more.

Antigens are divided into two groups: foreign antigens and self-antigens. Foreign antigens are not produced by the body but are introduced from outside it. Components of bacteria, viruses, and other microorganisms are examples of foreign antigens. Other foreign antigens include pollen, animal dander (scaly, dried skin), feces of house dust mites, foods, and drugs, and these sometimes trigger an allergic reaction, an overreaction of the immune system in some people. Transplanted tissues and organs that contain foreign antigens cause rejection of the transplant. Self-antigens are molecules the body produces to stimulate an adaptive immune system response. The response to self-antigens can be beneficial or harmful. For example, the recognition of tumor antigens can result in tumor destruction, whereas autoimmune disease can develop when self-antigens stimulate unwanted tissue destruction. An example is rheumatoid arthritis, which destroys the tissues within joints.

Adaptive immunity can be divided into antibody-mediated immunity and cell-mediated immunity. Antibody-mediated immunity involves proteins called antibodies, which are found in fluids outside cells, such as blood, interstitial fluid, and lymph. B cells give rise to cells that produce antibodies. Cell-mediated immunity involves the actions of a second type of lymphocyte, called T cells. Several subpopulations of T cells exist, each responsible for a particular aspect of cell-mediated immunity. For example, effector T cells, such as cytotoxic T cells and delayed hypersensitivity T cells, are responsible for producing the effects of cell-mediated immunity. Regulatory T cells, such as helper T cells and suppressor T cells, can promote or inhibit the activities of both antibody-mediated immunity and cell-mediated immunity.

Haptens and Allergic Reactions

Haptens(hap′tenz), often referred to as incomplete antigens, are small molecules (of low molecular weight) that can combine with large molecules, such as blood proteins, to stimulate an adaptive immune response. In many cases, however, haptens lead to allergic reactions (see the Diseases and Disorders table later in this chapter). For example, penicillin, a common antibiotic prescribed to combat bacterial infections, is a hapten that can break down and bind to other molecules in the blood. The combined molecule can then stimulate an allergic reaction that ranges from a rash and fever to severe symptoms that can lead to death. It is estimated that 20% of patients have allergic reactions when administered penicillin. Research indicates that the likelihood of a reaction increases with subsequent prescriptions. Skin tests are available to determine a patient's susceptibility to an allergic reaction to penicillin.

Cytotoxic (Type II Hypersensitivity)

Delayed (Type IV) Hypersensitivity

IgE (Type I) Hypersensitivity

Immune Complex (Type 3) Hypersensitivity

Table 22.3 summarizes and contrasts the main features of innate immunity and the two categories of adaptive immunity.

TABLE 22.3
Comparison of Innate and Adaptive Immunity
    Adaptive Immunity
Characteristics Innate Immunity Antibody-Mediated Immunity Cell-Mediated Immunity
Primary cells Neutrophils, eosinophils, basophils, mast cells, monocytes, and macrophages B cells T cells
Origin of cells Red bone marrow Red bone marrow Red bone marrow
Site of maturation Red bone marrow (neutrophils, eosinophils, basophils, and monocytes) and tissues (mast cells and macrophages) Red bone marrow Thymus
Location of mature cells Blood, connective tissue, and lymphatic tissue Blood and lymphatic tissue Blood and lymphatic tissue
Primary secretory products Histamine, kinins, complement, prostaglandins, leukotrienes, and interferons Antibodies Cytokines
Primary actions Inflammatory response and phagocytosis Protection against extracellular antigens (bacteria, toxins, parasites, and viruses outside cells) Protection against intracellular antigens (viruses, intracellular bacteria, and intracellular fungi) and tumors; regulates antibody-mediated immunity and cell-mediated immunity responses (helper T and suppressor T cells)
Hypersensitivity reactions None Immediate hypersensitivity (atopy, anaphylaxis, cytotoxic reactions, and immune complex disease) Delayed hypersensitivity (allergic reaction to infection or contact hypersensitivity)
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ASSESS YOUR PROGRESS
  1. Define antigen. Distinguish between a foreign antigen and a self-antigen.

  2. What are allergic reactions and autoimmune diseases?

  3. What is a hapten? How can a hapten cause an allergic reaction?

  4. What are the two types of adaptive immunity?

Origin and Development of Lymphocytes

All blood cells, including lymphocytes, are derived from stem cells in the red bone marrow (see chapter 19). The process of blood cell formation begins during embryonic development and continues throughout life. Some stem cells give rise to pre-T cells, which migrate through the blood to the thymus, where they divide and are processed into T cells (figure 22.12; see figure 22.9). The thymus produces hormones, such as thymosin, which stimulate T-cell maturation. Other stem cells produce pre-B cells, which are processed in the red bone marrow into B cells. A positive selection process results in the survival of pre-B and pre-T cells that are capable of an immune response. Cells that are incapable of an immune response die.

FIGURE 22.12
Origin and Processing of B Cells and T CellsPre-B cells and pre-T cells originate from stem cells in red bone marrow. The pre-B cells remain in the red bone marrow and become B cells. The pre-T cells circulate to the thymus, where they become T cells. Both B cells and T cells circulate to other lymphatic tissues, such as lymph nodes, where they can divide and increase in number in response to antigens.

The B cells and T cells that can respond to antigens are composed of small groups of identical lymphocytes called clones. Although each clone can respond only to a particular antigen, such a large number of clones exist that the immune system can react to most molecules. Some of the clones can also respond to self-antigens. A negative selection process eliminates or suppresses clones acting against self-antigens, thereby preventing the destruction of a person's own cells. Although the negative selection process occurs mostly during prenatal development, it continues throughout life (see “Inhibition of Lymphocytes” later in this section).

Clonal Selection

B cells are released from red bone marrow, T cells are released from the thymus, and both types of cells move through the blood to lymphatic tissue. There are approximately five T cells for every B cell in the blood. These lymphocytes live for a few months to many years and continually circulate between the blood and the lymphatic tissues. Antigens can come into contact with and activate lymphocytes, resulting in cell divisions that increase the number of lymphocytes able to recognize the antigen. These lymphocytes can circulate in blood and lymph to reach antigens in tissues throughout the body.

Lymphocytes mature into functional cells in the primary lymphatic organs, which are the red bone marrow and thymus. In the secondary lymphatic organs and tissues, lymphocytes interact with each other, antigen-presenting cells, and antigens to produce an immune response. The secondary lymphatic organs and tissues include the diffuse lymphatic tissue, lymphatic nodules, tonsils, lymph nodes, and spleen.

Activation of Lymphocytes

Antigens activate lymphocytes in different ways, depending on the type of lymphocyte and the type of antigen involved. Despite these differences, however, two general principles of lymphocyte activation exist: (1) Lymphocytes must be able to recognize the antigen; (2) after recognition, the lymphocytes must increase in number to destroy the antigen.

Antigenic Determinants and Antigen Receptors

Antigenic Determinants (Epitopes)

If an adaptive immune system response is to occur, lymphocytes must recognize an antigen. However, lymphocytes do not interact with an entire antigen. Instead, antigenic determinants, or epitopes (ep′i-tōps), are specific regions of a given antigen recognized by a lymphocyte, and each antigen has many different antigenic determinants (figure 22.13). All the lymphocytes of a given clone have, on their surfaces, identical proteins called antigen receptors, which combine with a specific antigenic determinant. The immune system response to an antigen with a particular antigenic determinant is similar to the lock-and-key model for enzymes (see chapter 2), and any given antigenic determinant can combine only with a specific antigen receptor. The T-cell receptor consists of two polypeptide chains, which are subdivided into a variable and a constant region (figure 22.14). The variable region can bind to an antigen. The many different types of T-cell receptors respond to different antigens because they have different variable regions. The B-cell receptor, consisting of four polypeptide chains with two identical variable regions, is a type of antibody.

FIGURE 22.13
Antigenic DeterminantsAn antigen has many antigenic determinants to which lymphocytes can respond.
 
FIGURE 22.14
T-Cell ReceptorA T-cell receptor consists of two polypeptide chains. The variable region of each type of T-cell receptor is specific for a given antigen. The constant region attaches the T-cell receptor to the plasma membrane.
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Major Histocompatibility Complex Molecules

Although some antigens bind to their receptors and directly activate B cells and some T cells, most lymphocyte activation involves glycoproteins on the surfaces of cells, called major histocompatibility complex (MHC) molecules. MHC molecules are glycoproteins found on the plasma membranes of most of the body's cells. Each MHC molecule has a variable region that can bind to foreign and self-antigens. The immune system cannot directly respond to an antigen inside a cell. Instead, MHC molecules display antigens produced or processed inside the cell on the cell's surface. Two classes of MHC molecules are present in the body: MHC class I and MHC class II.

MHC class I molecules are found on nucleated cells; they display antigens produced inside the cell on the cells surface (figure 22.15a). For example, viruses reproduce inside a cell, forming viral proteins that are foreign antigens. Some of these viral proteins are broken down in the cytoplasm. The protein fragments enter the rough endoplasmic reticulum and combine with MHC class I molecules to form complexes that move through the Golgi apparatus to be distributed on the cell's surface (see chapter 3)

 

FUNDAMENTAL Figure

PROCESS FIGURE 22.15
Antigen Processing(a) Foreign proteins, such as viral proteins, or self-proteins in the cytosol are processed and presented at the cell surface by MHC class I molecules. (b) Foreign antigens are taken into an antigen-presenting cell, processed, and presented at the cell surface by MHC class II molecules.

MHC class I/antigen complexes on the surface of cells can bind to T-cell receptors on the surface of T cells. This combination is a signal that activates T cells. Activated T cells can destroy infected cells, which effectively stops viral replication (see “Cell-Mediated Immunity” later in this section). Thus, the MHC class I/antigen complex functions as a signal, or “red flag,” that prompts the immune system to destroy the displaying cell. In essence, the cell is displaying a sign that says, “Kill me!” This process is said to be MHC-restricted because both the antigen and the individual organism's own MHC molecule are required.

Predict 3

In mouse A, T cells can respond to virus X. If these T cells are transferred to mouse B, which is infected with virus X, will the T cells respond to the virus? Explain.

Predict 3
(Your score will be reported to your instructor)

The same process that moves foreign protein fragments to the cell's surface can also inadvertently transport self-protein fragments (figure 22.15a). As part of normal protein metabolism, cells continually break down old proteins and synthesize new ones. Some self-protein fragments that result from protein breakdown can combine with MHC class I molecules and be displayed on the surface of the cell, thus becoming self-antigens. Normally, the immune system does not respond to self-antigens in combination with MHC molecules because the lymphocytes that could respond have been eliminated or inactivated (see “Inhibition of Lymphocytes” later in this section).

MHC class II molecules are found on antigen-presenting cells, which include B cells, macrophages, monocytes, and dendritic cells. Dendritic (den-drit′k) cells are large, motile cells with long cytoplasmic extensions. These cells are scattered throughout most tissues (except the brain), with their highest concentrations in lymphatic tissues and the skin. Dendritic cells in the skin are often called Langerhans cells.

Antigen-presenting cells can take in foreign antigens by endocytosis (figure 22.15b). Within the endocytotic vesicle, the antigen is broken down into fragments to form processed antigens. Vesicles from the Golgi apparatus containing MHC class II molecules combine with the endocytotic vesicles. The MHC class II molecules and processed antigens combine, and the MHC class II/antigen complexes are transported to the cell's surface, where they are displayed to other immune cells.

MHC class II/antigen complexes on the cell's surface can bind to T-cell receptors on the surfaces of T cells. The presentation of antigen using MHC class II molecules is MHC-restricted because both the antigen and the individual's own MHC class II molecule are required. Unlike MHC class I molecules, however, this display does not result in the destruction of the antigen-presenting cell. Instead, the MHC class II/antigen complex is a “rally around the flag” signal that stimulates other immune system cells to respond to the antigen. The displaying cell is like Paul Revere, who spread the alarm for the militia to arm and organize. The militia then went out and killed the enemy. For example, when the lymphocytes of the B-cell clone that can recognize the antigen come into contact with the MHC class II/antigen complex, they are stimulated to divide. The activities of these lymphocytes, such as the production of antibodies, then destroy the antigen.

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ASSESS YOUR PROGRESS
  1. Describe the origin and development of B cells and T cells.

  2. What are lymphocyte clones? What is the difference between positive and negative lymphocyte selection?

  3. What are the primary lymphatic organs? What are the secondary lymphatic organs and tissues?

  4. Define antigenic determinant and antigen receptor. How are they related to each other?

  5. What types of cells display MHC class I and class II antigen complexes, and what happens as a result?

  6. What types of antigens are displayed by MHC class I molecules? By MHC class II molecules?

  7. What does MHC-restricted mean?

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Transplant Rejection
G

enes that code for the production of MHC molecules are generally called major histocompatibility complex genes. Histocompatibility is the tissues' ability (Gr. histo) to get along (compatibility) when tissues are transplanted from one individual to another. In humans, the major histocompatibility complex genes are often referred to as human leukocyte antigen (HLA) genes because they were first identified in leukocytes. The HLA genes control the production of MHC antigens, which are found on the plasma membrane of cells. Millions of possible combinations of the HLA genes exist, and it is very rare for two individuals (except identical twins) to have the same set of HLA genes. The closer the relationship between two people, the greater the likelihood they share the same HLA genes.

The immune system can distinguish between self cells and foreign cells because they are both marked with MHCs. Rejection of a transplanted tissue is caused by a normal immune system response to the foreign MHCs. Acute rejection occurs several weeks after transplantation and results from a delayed hypersensitivity reaction and cell lysis. Lymphocytes and macrophages infiltrate the area, a strong inflammatory response occurs, and the foreign tissue is destroyed. If acute rejection does not develop, chronic rejection may occur at a later time. In chronic rejection, immune complexes form in the arteries supplying the graft, the blood supply fails, and the transplanted tissue is rejected.

Graft rejection can occur in two different directions. In host-versus-graft rejection, the recipient's immune system recognizes the donor's tissue as foreign and rejects the transplant. In graft-versus-host rejection, the donor tissue recognizes the recipient's tissue as foreign, and the transplant rejects the recipient, causing destruction of the recipient's tissues and death.

To reduce graft rejection, a tissue match is performed. Only tissues with MHCs similar to the recipient's have a chance of acceptance. Even when the match is close, immunosuppressive drugs must be administered throughout the person's life to prevent rejection. Unfortunately, the person then has a drug-produced immunodeficiency and is more susceptible to infections. An exact match is possible only for a graft from one part to another part of a person's body or between identical twins.

Predict 4

Antibodies bind to a foreign antigen, resulting in removal of that foreign antigen from the body. Explain what happens to antibody production as the foreign antigens decrease.

Predict 4
(Your score will be reported to your instructor)

Antigen Processing

Costimulation

The combination of an MHC class II/antigen complex with an antigen receptor is usually only the first signal necessary to produce a response from a B cell or a T cell. In many cases, costimulation by additional signals is also required. Costimulation is accomplished by cytokines released from cells and by molecules attached to the surfaces of cells (figure 22.16a). Cytokines produced by lymphocytes are often called lymphokines (lim′fō-kīnz). Table 22.4 lists important cytokines and their functions.

 
FIGURE 22.16
Costimulation
TABLE 22.4
Cytokines and Their Functions
Cytokine* Description
Interferon alpha (IFNα) Prevents viral replication and inhibits cell growth; secreted by virus-infected cells
Interferon beta (IFNβ) Prevents viral replication, inhibits cell growth, and decreases the expression of major histocompatibility complex (MHC) class I and II molecules; secreted by virus-infected fibroblasts
Interferon gamma (IFNγ) About 20 different proteins that activate macrophages and natural killer (NK) cells, stimulate adaptive immunity by increasing the expression of MHC class I and II molecules, and prevent viral replication; secreted by helper T, cytotoxic T, and NK cells
Interleukin-1 (IL-1) Costimulation of B cells and T cells; promotes inflammation through prostaglandin production and induces fever acting through the hypothalamus (pyrogen); secreted by macrophages, B cells, and fibroblasts
Interleukin-2 (IL-2) Costimulation of B cells and T cells and activation of macrophages and NK cells; secreted by helper T cells
Interleukin-4 (IL-4) Plays a role in allergic reactions by activation of B cells, resulting in the production of immunoglobulin E (lgE); secreted by helper T cells
Interleukin-5 (IL-5) Part of the response against parasites by stimulating eosinophil production; secreted by helper T cells
Interleukin-8 (IL-8) Chemotactic factor that promotes inflammation by attracting neutrophils and basophils; secreted by macrophages
Interleukin-10 (IL-10) Inhibits the secretion of interferon gamma and interleukins; secreted by suppressor T cells
Interleukin-15 (IL-15) Promotes inflammation and activates memory T cells and natural killer cells
Lymphotoxin Kills target cells; secreted by cytotoxic T cells
Perforin Makes a hole in the membrane of target cells, resulting in lysis of the cell; secreted by cytotoxic T cells
Tumor necrosis factor α (TNFα) Activates macrophages and promotes fever (pyrogen); secreted by macrophages

Certain pairs of surface molecules can also be involved in costimulation (figure 22.16b). When the surface molecule on one cell combines with the surface molecule on another, the combination can act as a signal that stimulates one of the cells to respond, or the combination can hold the cells together. Typically, several kinds of surface molecules are necessary to produce a response. For example, a molecule called B7 on macrophages must bind with a molecule called CD28 on helper T cells before the helper T cells can respond to the antigen presented by the macrophage. In addition, helper T cells have a glycoprotein called CD4, which helps connect helper T cells to the macrophage by binding to MHC class II molecules. For this reason, helper T cells are sometimes referred to as CD4 cells or T4 cells. In a similar fashion, cytotoxic T cells are sometimes called CD8 cells or T8 cells because they have a glycoprotein called CD8, which helps connect cytotoxic T cells to cells displaying MHC class I molecules. The CD designation stands for “cluster of differentiation,” which is a system used to classify many surface molecules.

Lymphocyte Proliferation

Before exposure to an antigen, the number of lymphocytes in a clone is too small to produce an effective response against the antigen. Exposure to an antigen results in an increase in lymphocyte number. First, the number of helper T cells increases. This is important because the increased number of helper T cells responding to the antigen can find and stimulate B cells or effector T cells. Second, the number of B cells or effector T cells increases. This is important because these cells are responsible for the immune response that destroys the antigen.

  1. Proliferation of helper T cells (figure 22.17). Antigen-presenting cells use MHC class II molecules to present processed antigens to helper T cells. Only the helper T cells with the T-cell receptors that can bind to the antigen respond. These helper T cells respond to the MHC class II/antigen complex and costimulation by dividing. As a result, the number of helper T cells that recognize the antigen increases.

  2. Proliferation and activation of B cells or effector T cells. Typically, the proliferation and activation of B cells or effector T cells involve helper T cells. This process is illustrated in figure 22.18 for B cells (see “Cell-Mediated Immunity” later in this section for activation of effector T cells). The clone of B cells that can recognize a particular antigen has B-cell receptors that can bind to that antigen. The antigens and receptors enter the B cell by receptor-mediated endocytosis. The antigens break down into fragments to form processed antigens that combine with MHC class II molecules. B cells use MHC class II/antigen complexes to present antigens to the helper T cells that increased in number in response to the same antigen. These helper T cells stimulate the B cells to divide. Many of the resulting daughter cells differentiate to become specialized cells, called plasma cells, which produce antibodies. The increased number of cells, each producing antibodies, can produce an immune response that destroys the antigens (see “Effects of Antibodies” later in this section).

 
PROCESS FIGURE 22.17
Proliferation of Helper T CellsAn antigen-presenting cell (macrophage) stimulates helper T cells to divide and produce cytokines.
 

FUNDAMENTAL Figure

PROCESS FIGURE 22.18
Proliferation of B CellsA helper T cell stimulates a B cell to divide and produce antibodies.
Page 800
Inhibition of Lymphocytes

Tolerance is a state of unresponsiveness of lymphocytes to a specific antigen. The most important function of tolerance is to prevent the immune system from responding to self-antigens, although foreign antigens can also induce tolerance. The need to maintain tolerance and to avoid the development of autoimmune disease is obvious. Tolerance can be induced in three primary ways:

  1. Deletion of self-reactive lymphocytes. During prenatal development and after birth, stem cells in red bone marrow and the thymus give rise to immature lymphocytes that develop into mature lymphocytes capable of an immune response. When immature lymphocytes are exposed to antigens, instead of responding in ways that cause elimination of the antigen, they respond by dying. Because immature lymphocytes are exposed to self-antigens, this process eliminates self-reactive lymphocytes. In addition, immature lymphocytes that escape deletion during their development and become mature, self-reacting lymphocytes can still be deleted in ways that are not clearly understood.

  2. Prevention of the activation of lymphocytes. For lymphocytes to be activated, two signals are usually required: (1) the MHC/antigen complex binding with an antigen receptor and (2) costimulation. Preventing either of these events stops lymphocyte activation. For example, blocking, altering, or deleting an antigen receptor prevents activation. Anergy (an′er-jē; without working) is a condition of inactivity in which a B cell or T cell does not respond to an antigen. Anergy develops when an MHC-antigen complex binds to an antigen receptor and no costimulation occurs. For example, if a helper T cell encounters a self-antigen on a cell that cannot provide costimulation, the T cell is turned off. It is likely that only antigen-presenting cells can provide costimulation.

  3. Page 801
  4. Activation of suppressor T cells. Suppressor T cells are a poorly understood group of T cells that are defined by their ability to suppress immune responses. It is likely that suppressor T cells are subpopulations of helper T cells and cytotoxic T cells. Either the suppressor (helper) T cells release suppressive cytokines or the suppressor (cytotoxic) T cells kill antigen-presenting cells.

Decreasing the production or activity of cytokines can suppress the immune system. For example, cyclosporine, a drug used to prevent the rejection of transplanted organs, inhibits the production of interleukin-2. Conversely, genetically engineered interleukins can be used to stimulate the immune system. Administering interleukin-2 has promoted the destruction of cancer cells in some cases by increasing the activities of effector T cells.

ASSESS YOUR PROGRESS
  1. What is costimulation? State two ways it can happen.

  2. Why are helper T cells sometimes called CD4 or T4 cells? Why are cytotoxic T cells sometimes called CD8 or T8 cells?

  3. Describe how antigen-presenting cells stimulate an increase in the number of helper T cells. Why is this important?

  4. Describe how helper T cells stimulate an increase in the number of B cells or T cells. Why is this important?

  5. What is tolerance? Explain three ways it is accomplished.

Page 802
Antibody-Mediated Immunity

Exposure of the body to an antigen can lead to the activation of B cells and to the production of antibodies, which are responsible for destroying the antigen. Because antibodies occur in body fluids, antibody-mediated immunity is effective against extracellular antigens, such as bacteria, viruses, protozoans, fungi, parasites, and toxins, when they are outside cells. Antibody-mediated immunity can also cause immediate hypersensitivity reactions (see the Diseases and Disorders table later in this chapter).

Structure of Antibodies

Antibodies are proteins produced in response to an antigen. Large numbers of antibodies exist in plasma, although plasma also contains other proteins. On the basis of protein type and associated lipids, plasma proteins are separated into albumin and alpha-(α), beta-(β), and gamma-(γ)globulin parts. As a group, antibodies are sometimes called gamma globulins because they are found mostly in the γ-globulin part of plasma, or immunoglobulins (Ig) because they are globulin proteins involved in immunity.

The five general classes of antibodies are denoted IgG, IgM, IgA, IgE, and IgD (table 22.5). All classes of antibodies have a similar structure, consisting of four polypeptide chains: two identical heavy chains and two identical light chains (figure 22.19). Each light chain is attached to a heavy chain, and the ends of the combined heavy and light chains form the variable region of the antibody, which is the part that combines with the antigenic determinant of the antigen. Different antibodies have different variable regions, and they are specific for different antigens. The rest of the antibody is the constant region, which is responsible for the activities of antibodies, such as the ability to activate complement or to attach the antibody to cells such as macrophages, basophils, mast cells, and eosinophils. All the antibodies of a particular class have nearly the same constant regions.

Antibody Diversity

TABLE 22.5
Classes of Antibodies and Their Functions
Antibody Total Serum Antibody (%) Description Structure
IgG 80–85 Activates complement and promotes phagocytosis; can cross the placenta and provide immune protection to the fetus and newborn; responsible for Rh reactions, such as hemolytic disease of the newborn
IgM 5–10 Activates complement and acts as an antigen-binding receptor on the surface of B cells; responsible for transfusion reactions in the ABO blood system; often the first antibody produced in response to an antigen
IgA 15 Secreted into saliva, into tears, and onto mucous membranes to provide protection on body surfaces; found in colostrum and milk to provide immune protection to newborns
IgE 0.002 Binds to mast cells and basophils and stimulates the inflammatory response
IgD 0.2 Functions as antigen-binding receptors on B cells
 
FIGURE 22.19
Structure of an AntibodyAntibodies consist of two heavy and two light polypeptide chains. The variable region of the antibody binds to the antigen. The constant region of the antibody can activate the classical pathway of the complement cascade. The constant region can also attach the antibody to the plasma membrane of cells such as macrophages, basophils, or mast cells.
Uses of Monoclonal Antibodies
A

monoclonal antibody is a pure antibody preparation that is specific for only one antigen. A monoclonal antibody preparation can be produced by injecting a laboratory animal with a specific antigen. The antigen activates a B-cell clone against the antigen. The B cells are removed from the animal and fused with tumor cells, which divide to form large numbers of cells. The tumor cells of a given clone produce only one kind of antibody.

Monoclonal antibodies are used for determining pregnancy and for diagnosing diseases, such as gonorrhea, syphilis, hepatitis, rabies, and cancer. These tests are specific and rapid because the monoclonal antibodies bind only to the antigen being tested. Monoclonal antibodies have been called “magic bullets” because someday they may be used to effectively treat cancer by delivering drugs to cancer cells (see sections 22.8).

Monoclonal Antibody Production

Effects of Antibodies

Antibodies can directly affect antigens in two ways. The antibody can bind to the antigenic determinant and interfere with the antigen's ability to function (figure 22.20a). Alternatively, the antibody can combine with an antigenic determinant on two different antigens, rendering the antigens ineffective (figure 22.20b). The ability of antibodies to join antigens together is the basis for many clinical tests, such as blood typing, because, when enough antigens are bound together, they become visible as a clump or a precipitate.

 

FUNDAMENTAL Figure

FIGURE 22.20
Effects of AntibodiesAntibodies directly affect antigens by inactivating the antigens or binding the antigens together. Antibodies indirectly affect antigens by activating other mechanisms through the constant region of the antibody. Indirect mechanisms include activation of complement, increased inflammation resulting from the release of inflammatory chemicals from mast cells or basophils, and increased phagocytosis resulting from antibody attachment to macrophages.
Page 803

Although antibodies can directly affect antigens, most of their effectiveness results from other mechanisms. When an antibody (IgG or IgM) combines with an antigen through the variable region, the constant region can activate the complement cascade through the classical pathway (figure 22.20c; see figure 22.10). Activated complement stimulates inflammation; attracts neutrophils, monocytes, macrophages, and eosinophils to sites of infection; and kills bacteria by lysis.

Antibodies (IgE) can initiate an inflammatory response (figure 22.20d). The antibodies attach to mast cells or basophils through their constant region. When antigens combine with the variable region of the antibodies, the mast cells or basophils release chemicals through exocytosis, and inflammation results. For example, people who have hay fever inhale antigens (usually, plant pollen), which are then absorbed through the respiratory mucous membrane. The combination of the antigens with antibodies stimulates mast cells to release inflammatory chemicals, such as histamine. The resulting localized inflammatory response produces swelling and increased mucus production in the respiratory tract.

Opsonins (op′sŏ-ninz) are substances that make an antigen more susceptible to phagocytosis. An antibody (IgG) acts as an opsonin by connecting to an antigen through the variable region of the antibody and to a macrophage through the constant region of the antibody. The macrophage then phagocytizes the antigen and the antibody (figure 22.20e).

Agglutination and Precipitation

Antibody Production

The production of antibodies after the first exposure to an antigen is different from that after a second or subsequent exposure. The first exposure of a B cell to an antigen for which it is specific produces the primary response, which includes a series of cell divisions, cell differentiation, and antibody production. The B-cell receptors on the surface of B cells are antibodies, usually IgM and IgD. The receptors have the same variable region as the antibodies that are eventually produced by the B cell. Before stimulation by an antigen, B cells are small lymphocytes. After activation, the B cells undergo a series of divisions to produce large lymphocytes. Some of these enlarged cells become plasma cells, which produce antibodies, and others revert back to small lymphocytes and become memory B cells (figure 22.21). Usually, IgM is the first antibody produced in response to an antigen, but later other classes of antibodies are produced as well. The primary response normally takes 3–14 days to produce enough antibodies to be effective against the antigen. In the meantime, disease symptoms usually develop because the antigen has had time to cause tissue damage.

 
PROCESS FIGURE 22.21
Antibody Production

The secondary response, or memory response, occurs when the immune system is exposed to an antigen against which it has already produced a primary response. When exposed to the antigen memory B cells rapidly divide to produce plasma cells, which produce large amounts of antibody. The secondary response provides better protection than the primary response for two reasons: (1) The time required to start producing antibodies is less (hours to a few days), and (2) the amount of antibody produced is much larger. As a consequence, the antigen is quickly destroyed, no disease symptoms develop, and the person is immune.

The secondary response also includes the formation of new memory B cells, which protect against additional exposures to the antigen. Memory B cells are the basis for adaptive immunity. After destruction of the antigen, plasma cells die, the antibodies they released are degraded, and antibody levels decline to the point at which they can no longer provide adequate protection. Memory B cells persist for many years—for life, in some cases. However, if memory cell production is not stimulated or if the memory B cells produced are short-lived, repeated infections of the same disease are possible. For example, the same cold virus can cause the common cold more than once in the same person.

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Predict 5

One theory for long-lasting immunity assumes that humans are continually exposed to the disease-causing agent. Explain how this exposure can produce lifelong immunity.

Predict 5
(Your score will be reported to your instructor)
ASSESS YOUR PROGRESS
  1. What type of lymphocyte is responsible for antibody-mediated immunity? What are the functions of antibody-mediated immunity?

  2. What are the functions of the variable and constant regions of an antibody?

  3. List the five classes of antibodies, and state their functions.

  4. Describe the different ways that antibodies participate in destroying antigens.

  5. What are plasma cells and memory B cells, and how do they function?

  6. What are the primary and secondary antibody responses? Why doesn't the primary response prevent illness while the secondary response does?

Cell-Mediated Immunity

Cell-mediated immunity is most effective against intracellular microorganisms through the action of cytotoxic T cells. Cell-mediated immunity involves delayed hypersensitivity reactions and the control of tumors (see the Diseases and Disorders table in this chapter).

Antibody-mediated immunity is not effective against intracellular microorganisms, such as viruses, fungi, intracellular bacteria, and parasites, because antibodies cannot cross the plasma membrane. However, cell-mediated immunity is effective against these intracellular microorganisms because it destroys the cells in which the microorganisms are located. For example, viruses enter cells and direct the cells to make new viruses, which are then released to infect other cells. Thus, cells are turned into virus-manufacturing plants. Cell-mediated immunity fights viral infections by destroying virally infected cells. When viruses infect cells, some viral proteins are broken down and become processed foreign antigens that are combined with MHC class I molecules and displayed on the surface of the infected cells (figure 22.22). T cells can distinguish between virally infected cells and noninfected cells because MHC class I/antigen complexes are on the surface of infected cells, but not on the surface of uninfected cells. Binding of the T-cell receptor to the MHC class I/antigen complex is a signal for activating cytotoxic T cells. Costimulation by other surface molecules, such as CD8, also occurs. Helper T cells provide costimulation by releasing cytokines, such as interleukin-2, which stimulates activation and cell division of T cells. However, unlike their interactions with macrophages and B cells, helper T cells do not connect to T cells through MHC class II/antigen complexes or other surface molecules.

 
PROCESS FIGURE 22.22
Proliferation of Cytotoxic T Cells

T-Cell Dependent Antigens

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An increased number of helper T cells results in greater stimulation of cytotoxic T cells. In cell-mediated responses, helper T cells are activated and stimulated to divide in the same fashion as in antibody-mediated responses (see figure 22.17).

After T cells are activated by an antigen on the surface of a target cell, they undergo a series of divisions to produce cytotoxic T cells and memory T cells (figure 22.23). The cytotoxic T cells are responsible for the cell-mediated immune response. Memory T cells can provide a secondary response and long-lasting immunity in the same fashion as memory B cells.

 
FIGURE 22.23
Stimulation and Effects of T CellsWhen activated, cytotoxic T cells form many additional cytotoxic T cells, as well as memory T cells. The cytotoxic T cells release cytokines that promote the destruction of the antigen or cause the lysis of target cells, such as virus-infected cells, tumor cells, or transplanted cells. The memory T cells are responsible for the secondary response.

Cytotoxic T-Cell Activity against Target Cells

Cytotoxic T Cells

Cytotoxic T cells have two main effects: They lyse cells and produce cytokines (figure 22.23). Cytotoxic T cells can come into contact with other cells and cause them to lyse. Virus-infected cells have viral antigens, tumor cells have tumor antigens, and tissue transplants have foreign antigens on their surfaces that can stimulate cytotoxic T-cell activity. A cytotoxic T cell binds to a target cell and releases chemicals that cause the target cell to lyse. The major method of lysis involves a protein called perforin, which is similar to the complement protein C9 (see figure 22.10). Perforin forms a channel in the plasma membrane of the target cell through which water enters the cell, causing lysis. The cytotoxic T cell then moves on to destroy additional target cells.

In addition to lysing cells, cytotoxic T cells release cytokines that activate additional components of the immune system. For example, one important function of cytokines is the recruitment of cells, such as macrophages. These cells are then responsible for phagocytosis and inflammation.

Predict 6

In patients with acquired immunodeficiency syndrome (AIDS), the HIV virus infects and destroys helper T cells. Patients often die of pneumonia caused by an intracellular fungus (Pneumocystis carinii) or of Kaposi sarcoma, which is characterized by tumorous growths in the skin and lymph nodes. Explain what is happening.

Predict 6
(Your score will be reported to your instructor)
Delayed Hypersensitivity T Cells

Delayed hypersensitivity T cells respond to antigens by releasing cytokines. Consequently, they promote phagocytosis and inflammation, especially in allergic reactions (see the Diseases and Disorders table in this chapter). For example, poison ivy antigens can be processed by Langerhans cells in the skin, which present the antigen to delayed hypersensitivity T cells, resulting in an intense inflammatory response with redness and itching.

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Gluten-Sensitive Enteropathy
G

luten-sensitive enteropathy, also called celiac (sē′lē-ăk) disease, is a malabsorption disorder, meaning that nutrients are poorly absorbed. Gluten-sensitive enteropathy results from damage to the lining of the small intestine, specifically the fingerlike projections, called villi, that increase the surface area for nutrient absorption (see figure 24.16). In a healthy intestine, the lining resembles a shag carpet. In gluten-sensitive enteropathy, the epithelium has become damaged, and the intestinal villi are flattened and inflamed.

Gluten-sensitive enteropathy is usually characterized by gastrointestinal symptoms, such as diarrhea, painful abdominal cramping, bloating, and intestinal gas. Prolonged gluten-sensitive enteropathy leads to additional complications, including anemia, osteoporosis, and neurological problems, in part due to nutritional deficiencies.

Gluten-sensitive enteropathy occurs in about 1 in 133 people, but the frequency may actually be even higher because the widely varying symptoms and severity of the disease make diagnosis difficult.

Gluten-sensitive enteropathy is an autoimmune disease and is often associated with other autoimmune diseases, such as systemic lupus erythematosus (see Systems Pathology later in this chapter). The damage to the intestinal lining is caused by an inappropriate immune response, which is triggered by the gluten proteins in wheat, barley, and rye. Although neither rice nor corn contains gluten proteins, gluten is often hidden as an additive in prepared foods and sauces.

Gluten-sensitive enteropathy has a genetic component. Most patients have mutated variants of some of the MHC class II genes on chromosome 6. As a result, abnormal MHC class II molecules are produced and can bind to digested fragments of gluten. However, the genetics of gluten-sensitive enteropathy are complex and not fully understood. For example, the variant MHC alleles alone are not sufficient to cause the disease, since many people who have the variant alleles do not develop gluten-sensitive enteropathy. Furthermore, the genetic expression of the disease is influenced by variable environmental factors because the onset and severity of the disease can be triggered by unknown factors at any time in life.

Gluten-sensitive enteropathy results from both adaptive and innate immune responses. On the surface of antigen-presenting cells, the MHC class II/gluten complex is presented to helper T cells to initiate an adaptive immune response (see figure 22.15b). The adaptive immune response includes antibody production and the activation of cytotoxic T cells. The innate immune response promotes inflammation through the activation of the alternative complement pathway and the release of cytokines, such as interleukin-15 (IL-15), from macrophages, dendritic cells, and other cells. In addition, exposure to gluten can activate natural killer cells and dendritic cells. The result of these immune responses is a deleterious attack on the epithelial lining of the small intestine, leading to the damaged villi common to gluten-sensitive enteropathy.

The only treatment for gluten-sensitive enteropathy is a strict, gluten-free diet. Before embarking on a life-long gluten-free diet, however, it is important to have a definitive diagnosis. Tests for higher than normal levels of antibodies produced in gluten-sensitive enteropathy, such as anti-tissue transglutaminase, and a biopsy of the small intestine to examine the villi are recommended. In the future, early genetic diagnosis and manipulation of the immune response may be able to reduce the sensitivity to gluten.

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ASSESS YOUR PROGRESS
  1. What type of lymphocyte is responsible for cell-mediated immunity? What are the functions of cell-mediated immunity?

  2. How do intracellular microorganisms stimulate cytotoxic T cells? What role do helper T cells play in this process?

  3. State the two main responses of cytotoxic T cells.

  4. What kind of immune response is produced by delayed hypersensitivity T cells?

  5. How is long-lasting immunity achieved in cell-mediated immunity?