Review of Medical Microbiology and Immunology, 13th Edition

57. Immunity

CHAPTER CONTENTS

Function of the Immune System

Specificity of the Immune Response

1. Cell-Mediated Immunity

2. Antibody-Mediated Immunity

Innate & Adaptive Immunity

1. Innate Immunity

2. Adaptive (Acquired) Immunity

Active & Passive Immunity

Antigens

Age & The Immune Response

Self-Assessment Questions

Practice Questions: USMLE & Course Examinations

FUNCTION OF THE IMMUNE SYSTEM

The main function of the immune system is to prevent or limit infections, fungi, and parasites, such as protozoa and worms. The first line of defense against microorganisms is the intact skin and mucous membranes. If microorganisms breach this line and enter the body, then the innate arm of the immune system (second line of defense) is available to destroy the invaders. Because the components of the innate arm (Table 57–1) are preformed and fully active, they can function immediately upon entry of the microorganisms. The ability of the innate arm to kill microorganisms is not specific. For example, a neutrophil can ingest and destroy many different kinds of bacteria.

TABLE 57–1 Main Components of Innate and Adaptive Immunity That Contribute to Humoral (Antibody-Mediated) Immunity and Cell-Mediated Immunity

image

Highly specific protection is provided by the adaptive (acquired) arm of the immune system (third line of defense), but it takes several days for this arm to become fully functional. The two components of the adaptive arm are cell-mediated immunity and antibody-mediated (humoral) immunity. An overview of the functions and interactions between many of the important members of the innate and adaptive arms of the immune response is provided in Figure 57–1. (The features of the innate and the adaptive arms of the immune system are contrasted in Table 57–2.)

TABLE 57–2 Important Features of Innate and Adaptive Immunity

image

image

FIGURE 57–1 Introduction to the interactions and functions of the major components of the immune system. Left: Antibody-mediated (humoral) immunity. This is our main defense against extracellular, encapsulated, pyogenic bacteria such as staphylococci and streptococci. Antibodies also neutralize toxins, such as tetanus toxin, as well as viruses, such as hepatitis B virus. Right: Cell-mediated immunity. There are two distinct components. (1) Helper T cells and macrophages are our main defense against intracellular bacteria, such as Mycobacterium tuberculosis, and fungi, such as Histoplasma capsulatum. (2) Cytotoxic T cells are an important defense against viruses and act by destroying virus-infected cells. (IL-4 and IL-5 are interleukin-4 and interleukin-5, respectively.)

The cell-mediated arm consists primarily of T lymphocytes (e.g., helper T cells and cytotoxic T cells), whereas the antibody-mediated arm consists of antibodies (immunoglobulins) and B lymphocytes (and plasma cells). Some of the major functions of T cells and B cells are shown in Table 57–3.

TABLE 57–3 Major Functions of T Cells and B Cells

image

The main functions of antibodies are (1) to neutralize toxins and viruses and (2) to opsonize bacteria, making them easier to phagocytize. Opsonization is the process by which immunoglobulin G (IgG) antibody and the C3b component of complement enhance phagocytosis (see Figure 8–3). Cell-mediated immunity, on the other hand, inhibits organisms such as fungi, parasites, and certain intracellular bacteria such as Mycobacterium tuberculosis; it also kills virus-infected cells and tumor cells.

Both the cell-mediated and antibody-mediated responses are characterized by three important features: (1) they exhibit remarkable diversity (i.e., they can respond to millions of different antigens); (2) they have a long memory (i.e., they can respond many years after the initial exposure because memory T cells and memory B cells are produced); and (3) they exhibit exquisite specificity (i.e., their actions are specifically directed against the antigen that initiated the response).

The combined effects of certain cells (e.g., T cells, B cells, macrophages, and neutrophils) and certain proteins (e.g., interleukins, antibodies, and complement) produce an inflammatory response, one of the body’s main defense mechanisms. The process by which these components interact to cause inflammation is described in Chapter 8.

Macrophages and certain other phagocytic cells such as dendritic cells participate in both the innate and adaptive arms of the immune response. They are, in effect, a bridge between the two arms. As part of the innate arm, they ingest and kill various microbes. They also present antigen to helper T cells, which is the essential first step in the activation of the adaptive arm (see later). It is interesting to note that neutrophils, which are also phagocytes and have excellent microbicidal abilities, do not present antigen to helper T cells and therefore function in innate but not acquired immunity.

SPECIFICITY OF THE IMMUNE RESPONSE

Cell-mediated immunity and antibody are both highly specific for the invading organism. How do these specific protective mechanisms originate? The process by which these host defenses originate can be summarized by three actions: (1) the recognition of the foreign organism by specific immune cells, (2) the activation of these immune cells to produce a specific response (e.g., antibodies), and (3) the response that specifically targets the organism for destruction. The following examples briefly describe how specific immunity to microorganisms occurs. An overview of these processes with a viral infection as the model is shown in Figure 57–2. A detailed description is presented in Chapter 58.

image

FIGURE 57–2 Overview of the process by which cell-mediated immunity and antibody-mediated immunity are induced by exposure to a virus. Note that the figure shows a virus as the immunogen in the top left corner, but the same processes occur for other microbes, such as bacteria or fungi. IL, interleukin; MHC, major histocompatibility complex. (Modified and reproduced with permission from Stites D, Terr A, Parslow T, eds. Basic & Clinical Immunology. 9th ed. Originally published by Appleton & Lange. Copyright 1997 McGraw-Hill.)

1. Cell-Mediated Immunity

In the following example, a bacterium (e.g., Mycobacterium tuberculosis) enters the body and is ingested by a macrophage. The bacterium is broken down, and fragments of it called antigens or epitopes appear on the surface of the macrophage in association with class II major histocompatibility complex (MHC) proteins. The antigen–class II MHC protein complex interacts with an antigen-specific receptor on the surface of a helper T lymphocyte. Activation and clonal proliferation of this antigen-specific helper T cell occur as a result of the production of interleukins, the most important of which are interleukin-2 (T cell growth factor) and gamma interferon (activates macrophages). These activated helper T cells, aided by activated macrophages, mediate one important component of cellular immunity (i.e., a delayed hypersensitivity reaction specifically against M. tuberculosis).

Cytotoxic (cytolytic) T lymphocytes are also specific effectors of the cellular immune response, particularly against virus-infected cells. In this example, a virus (e.g., influenza virus) is inhaled and infects a cell of the respiratory tract. Viral envelope glycoproteins appear on the surface of the infected cell in association with class I MHC proteins. A cytotoxic T cell binds via its antigen-specific receptor to the viral antigen–class I MHC protein complex and is stimulated to grow into a clone of cells by interleukin-2 produced by helper T cells. These cytotoxic T cells specifically kill influenza virus–infected cells (and not cells infected by other viruses) by recognizing viral antigen–class I MHC protein complexes on the cell surface and releasing perforins that destroy the membrane of the infected cell.

2. Antibody-Mediated Immunity

Antibody synthesis typically involves the cooperation of three cells: antigen-presenting cells (e.g., dendritic cells and macrophages), helper T cells, and B cells. After processing by an antigen-presenting cell, fragments of antigen appear on the surface of that cell in association with class II MHC proteins. The antigen–class II MHC protein complex binds to receptors on the surface of a helper T cell specific for that antigen. This activates the helper T cells to produce interleukins such as interleukin-2 (IL-2), IL-4, and IL-5. These interleukins activate the B cell to produce antibodies specific for that antigen. (Note that the interleukins are nonspecific; the specificity lies in the T cells and B cells and is mediated by the antigen receptors on the surface of these cells.) The activated B cell proliferates and differentiates to form many plasma cells that secrete large amounts of immunoglobulins (antibodies).

Although antibody formation usually involves helper T cells, certain antigens (e.g., bacterial polysaccharides) can activate B cells directly, without the help of T cells, and are called T-cell–independent antigens. In this T-cell–independent response, only IgM is produced by B cells because it requires IL-4 and IL-5 made by the helper T cell for the B cell to “class switch” to produce IgG, IgA, and IgE. See Chapter 59 for a discussion of “class switching,” the process by which the B cell switches the antibody it produces from IgM to one of the other classes.

Figure 57–3 summarizes the human host defenses against virus-infected cells and illustrates the close interaction of various cells in mounting a coordinated attack against the pathogen. The specificity of the response is provided by the antigen receptor (T-cell receptor [TCR]) on the surface of both the CD4-positive T cell and the CD8-positive T cell and by the antigen receptor (IgM) on the surface of the B cell. The interleukins, on the other hand, are not specific.

image

FIGURE 57–3 Induction of cell-mediated immunity and antibody against a viral infection. Right: Virus released by an infected cell is ingested and processed by an antigen-presenting cell (APC) (e.g., a macrophage). The viral epitope is presented in association with a class II major histocompatibility complex (MHC) protein to the virus-specific T-cell receptor (TCR) on the CD4 cell. The macrophage makes interleukin (IL) -1, which helps activate the CD4 cell. The activated CD4 cell makes interleukins (e.g., IL-2, which activates the CD8 cell to attack the virus-infected cell, and IL-4 and IL-5, which activate the B cell to produce antibody). The specificity of the cytotoxic response mounted by the CD8 cell is provided by its TCR, which recognizes the viral epitope presented by the virus-infected cell in association with a class I MHC protein. Left: Virus released by an infected cell interacts with the antigen receptor (IgM monomer) specific for that virus located on the surface of a B cell. The virus is internalized, and the viral proteins are broken down into small peptides. B cells (as well as macrophages) can present viral epitopes in association with class II MHC proteins and activate CD4 cells. The CD4-positive helper cell produces IL-4 and IL-5, which induce the B cell to differentiate into a plasma cell that produces antibody specifically against this virus.

As depicted in Figure 57–3, B cells can perform two important functions during the induction process: (1) they recognize antigens with their surface IgM that acts as an antigen receptor, and (2) they present epitopes to helper T cells in association with class II MHC proteins. Note that the IgM antigen receptor on the B cell can recognize not only foreign proteins but also carbohydrates, lipids, DNA, RNA, and other types of molecules. The class II MHC proteins of the B cell, however, can only present peptide fragments to the helper T cells. This distinction will become important when haptens are discussed later in this chapter. It is this remarkable ability of the IgM antigen receptor on the B cell to bind to an incredibly broad range of molecules that enables B cells to produce antibodies against virtually every molecule known. How the B cell generates such a diverse array of antibodies is described on page 512.

INNATE & ADAPTIVE IMMUNITY

Our immune host defenses can be divided into two major categories: innate (natural) and adaptive (acquired). The features of these two important components of our host defenses are compared in Table 57–2.

1. Innate Immunity

Innate immunity is resistance that exists prior to exposure to the microbe (antigen). It is nonspecific and includes host defenses such as barriers to infectious agents (e.g., skin and mucous membranes), certain cells (e.g., natural killer cells), and certain proteins (e.g., the complement cascade and interferons) and involves processes such as phagocytosis and inflammation (Table 57–4). Innate immunity does not improve after exposure to the organism, in contrast to acquired immunity, which does. In addition, innate immune processes have no memory, whereas acquired immunity is characterized by long-term memory.

TABLE 57–4 Important Components of Innate Immunity

image

Note that the innate arm of our host defenses performs two major functions: killing invading microbes and activating adaptive immune processes. Some components of the innate arm, such as neutrophils, only kill microbes, whereas others, such as macrophages and dendritic cells, perform both functions (i.e., they kill microbes and present antigen to helper T cells, which activates adaptive immune processes).

Although innate immunity is often successful in eliminating microbes and preventing infectious diseases, it is not sufficient for human survival. This conclusion is based on the observation that children with severe combined immunodeficiency disease (SCID), who have intact innate immunity but no adaptive immunity, suffer from repeated, life-threatening infections.

Several components of the innate arm recognize what is foreign by detecting certain carbohydrates or lipids on the surface of microorganisms that are different from those on human cells. Components of the innate arm have receptors called pattern-recognition receptors that recognize a molecular pattern called a pathogen-associated molecular pattern (PAMP) that is present on the surface of many microbes but—very importantly—is not present on human cells. By using this strategy, these components of the innate arm do not have to have a highly specific receptor for every different microbe but can still distinguish between what is foreign and what is self.

There are two classes of receptors on the surface of cells (Toll-like receptors and mannan-binding lectin receptors) that recognize microbes outside of cells and two classes of receptors in the cytoplasm of cells (NOD receptors and RIG-I helicase receptors) that recognize microbes within cells. Mutations in the genes encoding these pattern receptors result in a failure to recognize the pathogen and predispose to severe bacterial, viral, and fungal infections.

The most important of these pattern-recognition receptors are the Toll-like receptors (TLR). This is a family of 10 receptors found mainly on the surface of three types of cells: macrophages, dendritic cells, and mast cells. TLRs recognize various microbial components and then activate transcription factors that enhance the synthesis of several proinflammatory cytokines. This initiates an immune response appropriate to defend against that type of microbe.

Note that the type of host defense mounted by the body differs depending on the type of organism. For example, a humoral (antibody-mediated) response is produced against one type of bacteria, but a cell-mediated response occurs in response to a different type of bacteria. The process that determines the type of response depends on the cytokines produced by the macrophages, and this in turn depends on which pattern-recognition receptor is activated by the organism, as described in the next paragraph.

Four important examples of this pattern recognition are as follows:

(1) Endotoxin is a lipopolysaccharide (LPS) found on the surface of most gram-negative bacteria (but not on human cells). The lipid A portion of LPS is the most important cause of septic shock and death in hospitalized patients. When released from the bacterial surface, LPS combines with LPS-binding protein, a normal component of plasma. This binding protein transfers LPS to a receptor on the surface of macrophages called CD14. LPS stimulates a pattern-recognition receptor called Toll-like receptor 4 (TLR4), which transmits a signal, via several intermediates, to the nucleus of the cell. This induces the production of cytokines, such as IL-1, IL-6, IL-8, and tumor necrosis factor (TNF), and induces the costimulator protein, B7, which is required to activate helper T cells and to produce antibodies. Note that a different Toll-like receptor, TLR2, signals the presence of gram-positive bacteria and yeasts because they have a different molecular pattern on their surface. Drugs that modify the action of these Toll-like receptors may become important in preventing endotoxin-mediated septic shock, a leading cause of death in hospitalized patients.

(2) Many bacteria and yeasts have a polysaccharide called mannan on their surface that is not present on human cells. (Mannan is a polymer of the sugar, mannose.) A pattern-recognition receptor called mannan-binding lectin (MBL) (also known as mannose-binding protein) binds to the mannan on the surface of the microbes, which then activates complement (see Chapter 63), resulting in death of the microbe. MBL also enhances phagocytosis (acts as an opsonin) via receptors to which it binds on the surface of phagocytes, such as macrophages. MBL is a normal serum protein whose concentration in the plasma is greatly increased during the acute-phase response (see later).

(3) Part of the peptidoglycan (cell wall) of bacteria is recognized by NOD receptors. These receptors are located within the cytoplasm of human cells (e.g., macrophages, dendritic cells, and epithelial cells); hence they are important in the innate response to intracellular bacteria such as Listeria.

(4) RIG-I helicase receptors recognize the nucleic acids of viruses in the cytoplasm of infected cells. For example, members of the orthomyxovirus, paramyxovirus, and rhabdovirus families synthesize double-stranded RNA during replication that are recognized by RIG-I helicase receptors.

The acute-phase response, which consists of an increase in the levels of various plasma proteins (e.g., C-reactive protein and mannose-binding protein), is also part of innate immunity. These proteins are synthesized by the liver and are nonspecific responses to microorganisms and other forms of tissue injury. The liver synthesizes these proteins in response to certain cytokines, namely, IL-1, IL-6, and TNF, produced by the macrophage after exposure to microorganisms. These cytokines, IL-1, IL-6, and TNF, are often called the proinflammatory cytokines, meaning that they enhance the inflammatory response. The inflammasome is a multi-protein complex with protease activity that enhances inflammation by producing IL-1 from its precursor protein. Anti-inflammatory cytokines, such as IL-10 and transforming growth factor-β (TGF-β), restore homeostasis after the inflammatory response is no longer needed.

Some acute-phase proteins bind to the surface of bacteria and activate complement, which can kill the bacteria. For example, C-reactive protein binds to a carbohydrate in the cell wall of Streptococcus pneumoniae and, as mentioned earlier, MBL binds to mannan (mannose) on the surface of many bacteria.

Defensins are another important component of innate immunity. Defensins are highly positively charged (i.e., cationic) peptides that create pores in the membranes of bacteria and thereby kill them. How they distinguish between microbes and our cells is unknown. Defensins are located primarily in the gastrointestinal and lower respiratory tracts. Neutrophils and Paneth cells in the intestinal crypts contain one type of defensin (α-defensins), whereas the respiratory tract produces different defensins called β-defensins.

α-Defensins also have antiviral activity. They interfere with human immunodeficiency virus (HIV) binding to the CXCR4 receptor and block entry of the virus into the cell. The production of α-defensins may explain why some HIV-infected individuals are long-term “nonprogressors.”

APOBEC3G (apolipoprotein B RNA-editing enzyme) is an important member of the innate host defenses against retroviral infection, especially against HIV. APOBEC3G is an enzyme that causes hypermutation in retroviral DNA by deaminating cytosines in both mRNA and retroviral DNA, thereby inactivating these molecules and reducing infectivity. HIV defends itself against this innate host defense by producing Vif (viral infectivity protein), which counteracts APOBEC3G, thereby preventing hypermutation from occurring.

Alpha and beta interferons are important antiviral proteins. They are synthesized early in infection within virus-infected cells. They exit that cell, bind to the surface of an adjacent cell, and induce an anti-viral state in that adjacent cell. The anti-viral state is mediated by a ribonuclease and a protein kinase that, acting together, inhibit viral protein synthesis. See Chapter 33 for more information on the action of these interferons. Gamma interferon is an important mediator of inflammation but has only modest antiviral activity. It acts primarily to enhance killing by macrophages and other phagocytes, and to increase the synthesis of class 1 and class 2 MHC proteins. See pages 495 and 505 for more information on the action of gamma interferon.

2. Adaptive (Acquired) Immunity

Adaptive immunity occurs after exposure to an agent, improves upon repeated exposure, and is specific. It is mediated by antibody produced by B lymphocytes and by two types of T lymphocytes, namely, helper T cells and cytotoxic T cells. The cells responsible for adaptive immunity have long-term memory for a specific antigen. Adaptive immunity can be active or passive. Chapter 58 describes how the specificity and memory of acquired immunity is produced.

Macrophages and other antigen-presenting cells such as dendritic cells play an important role in both the innate and the adaptive arms of the immune system (Figure 57–4). When they phagocytose and kill microbes, they function as part of the innate arm, but when they present antigen to a helper T lymphocyte, they activate the adaptive arm that leads to the production of antibody and of cells such as cytotoxic T lymphocytes. Note that the adaptive arm can be activated only after the innate arm has interacted with the microbe.

image

FIGURE 57–4 Macrophages and other antigen-presenting cells, such as dendritic cells, participate in both the innate arm and the adaptive arm of the immune system. These cells are considered part of the innate arm because they phagocytose and kill many types of microbes and also produce cytokines that cause inflammation. They are also part of the adaptive arm because they present antigen in association with class II major histocompatibility complex (MHC) proteins to CD4-positive helper T cells. (In common with all other nucleated cells, they also can present antigen in association with class I MHC proteins to CD8-positive cytotoxic T cells.)

ACTIVE & PASSIVE IMMUNITY

Active immunity is resistance induced after contact with foreign antigens (e.g., microorganisms). This contact may consist of clinical or subclinical infection, immunization with live or killed infectious agents or their antigens, or exposure to microbial products (e.g., toxins and toxoids). In all these instances, the host actively produces an immune response consisting of antibodies and activated helper and cytotoxic T lymphocytes.

The main advantage of active immunity is that resistance is long-term (Table 57–5). Its major disadvantage is its slow onset, especially the primary response (see Chapter 60).

TABLE 57–5 Characteristics of Active and Passive Immunity

image

Passive immunity is resistance based on antibodies preformed in another host. Administration of antibody against diphtheria, tetanus, botulism, etc., makes large amounts of antitoxin immediately available to neutralize the toxins. Likewise, preformed antibodies to certain viruses (e.g., rabies and hepatitis A and B viruses) can be injected during the incubation period to limit viral multiplication. Other forms of passive immunity are IgG passed from mother to fetus during pregnancy and IgA passed from mother to newborn during breast feeding.

The main advantage of passive immunization is the prompt availability of large amounts of antibody; disadvantages are the short life span of these antibodies and possible hypersensitivity reactions if globulins from another species are used. (See serum sickness in Chapter 65.)

Passive–active immunity involves giving both preformed antibodies (immune globulins) to provide immediate protection and a vaccine to provide long-term protection. These preparations should be given at different sites in the body to prevent the antibodies from neutralizing the immunogens in the vaccine. This approach is used in the prevention of tetanus (see Chapters 12 and 17), rabies (see Chapters 36 and 39), and hepatitis B (see Chapters 36 and 41).

ANTIGENS

Antigens are molecules that react with antibodies, whereas immunogens are molecules that induce an immune response. In most cases, antigens are immunogens, and the terms are used interchangeably. However, there are certain important exceptions (e.g., haptens). A hapten is a molecule that is not immunogenic by itself but can react with specific antibody. Haptens are usually small molecules, but some high-molecular-weight nucleic acids are haptens as well. Many drugs (e.g., penicillins) are haptens, and the catechol in the plant oil that causes poison oak and poison ivy is a hapten.

Haptens are not immunogenic because they cannot activate helper T cells. The failure of haptens to activate is due to their inability to bind to MHC proteins; they cannot bind because they are not polypeptides and only polypeptides can be presented by MHC proteins. Furthermore, haptens are univalent and therefore cannot activate B cells by themselves. (Compare with the T-independent response of multivalent antigens discussed earlier in the chapter and in Chapter 58.)

Although haptens cannot stimulate a primary or secondary response by themselves, they can do so when covalently bound to a “carrier” protein (Figure 57–5). In this process, the hapten interacts with an IgM receptor on the B cell and the hapten–carrier protein complex is internalized. A peptide of the carrier protein is presented in association with class II MHC protein to the helper T cells. The activated helper T cell then produces interleukins, which stimulate the B cells to produce antibody to the hapten (see Chapter 58page 497, for additional information).

image

FIGURE 57–5 Hapten–carrier conjugate induces antibody against the hapten. A hapten covalently bound to a carrier protein can induce antibody to a hapten by the mechanism depicted in the figure. A hapten alone cannot induce antibody, because the helper T cells are not activated by the hapten. Although the hapten alone (without the carrier protein) can bind to the IgM receptor on the B-cell surface, the interleukins essential for the B cell to become a plasma cell are not made. TCR, T-cell receptor.

Two additional ideas are needed to understand how haptens interact with our immune system. The first is that many haptens, such as drugs (e.g., penicillin) and poison oak oil, bind to our normal proteins, to which we are tolerant. The hapten–protein combination now becomes immunogenic (i.e., the hapten modifies the protein sufficiently such that when the hapten–peptide combination is presented by the MHC protein, it is recognized as foreign).

The second idea is that although most haptens are univalent, type I hypersensitivity reactions such as anaphylaxis (see Chapter 65) require cross-linking of adjacent IgEs to trigger the release of the mediators. By itself, a univalent hapten cannot cross-link, but when many hapten molecules are bound to the carrier protein, they are arranged in such a way that cross-linking can occur. This is how a univalent hapten, such as penicillin, causes anaphylaxis. Sufficient penicillin binds to one of our proteins to cross-link IgE. An excellent example of this is penicilloyl polylysine, which is used in skin tests to determine whether a patient is allergic to penicillin. Each lysine in the polylysine has a penicillin molecule attached to it. These univalent penicillin molecules form a “multivalent” array and can cross-link adjacent IgEs on the surface of mast cells. The consequent release of mediators causes a “wheal and flare” reaction in the skin of the penicillin-allergic patient.

Another medically important concept that is related to the hapten–carrier protein model is that of conjugate vaccines such as the pneumococcal and meningococcal vaccines and the vaccine against Haemophilus influenzae. In these conjugate vaccines, the capsular polysaccharide is conjugated to a carrier protein. The capsular polysaccharide is not a hapten because it can induce IgM via the T-independent response. However, adding a carrier protein causes helper T cells to be involved, and large amounts of IgG are produced via the T-dependent response.

The interaction of antigen and antibody is highly specific, and this characteristic is frequently used in the diagnostic laboratory to identify microorganisms. Antigen and antibody bind by weak forces such as hydrogen bonds and van der Waals’ forces rather than by covalent bonds. The strength of the binding (the affinity) is proportionate to the fit of the antigen with its antibody-combining site (i.e., its ability to form more of these bonds). The affinity of antibodies increases with successive exposures to the specific antigen (see Chapter 60). Another term, avidity, is also used to express certain aspects of binding. It need not concern us here.

The features of molecules that determine immunogenicity are as follows.

Foreignness

In general, molecules recognized as “self” are not immunogenic (i.e., we are tolerant to those self-molecules) (see Chapter 66). To be immunogenic, molecules must be recognized as “nonself” (i.e., foreign).

Molecular Size

The most potent immunogens are proteins with high molecular weights (i.e., above 100,000). Generally, molecules with molecular weight below 10,000 are weakly immunogenic, and very small ones (e.g., an amino acid) are nonimmunogenic. Certain small molecules (e.g., haptens) become immunogenic only when linked to a carrier protein.

Chemical–Structural Complexity

A certain amount of chemical complexity is required (e.g., amino acid homopolymers are less immunogenic than heteropolymers containing two or three different amino acids).

Antigenic Determinants (Epitopes)

Epitopes are small chemical groups on the antigen molecule that can elicit and react with antibody. An antigen can have one or more determinants (epitopes). Most antigens have many determinants (i.e., they are multivalent). In general, a determinant is roughly five amino acids or sugars in size. The overall three-dimensional structure is the main criterion of antigenic specificity.

Dosage, Route, and Timing of Antigen Administration

These factors also affect immunogenicity. In addition, the genetic constitution of the host (HLA genes) determines whether a molecule is immunogenic. Different strains of the same species of animal may respond differently to the same antigen.

Adjuvants

Adjuvants enhance the immune response to an immunogen. They are chemically unrelated to the immunogen and differ from a carrier protein because the adjuvant is not covalently bound to the immunogen, whereas the carrier protein is. Adjuvants can act in a variety of ways; they can cause slow release of immunogen, thereby prolonging the stimulus; enhance uptake of immunogen by antigen-presenting cells; and induce costimulatory molecules (“second signals”). (See Chapter 58 regarding costimulators.) Another important mechanism of action of some adjuvants is to stimulate Toll-like receptors (see pages 480 and 490) on the surface of macrophages, which results in cytokine production that enhances the response of T cells and B cells to the immunogen (antigen). Some human vaccines contain adjuvants such as aluminum hydroxide or lipids.

AGE & THE IMMUNE RESPONSE

Immunity is less than optimal at both ends of life (i.e., in the newborn and the elderly). The reason for the relatively poor immune response in newborns is unclear, but newborns appear to have less effective T-cell function than do adults. In newborns, antibodies are provided primarily by the transfer of maternal IgG across the placenta. Because maternal antibody decays over time (little remains by 3–6 months of age), the risk of infection in the child is high. Colostrum also contains antibodies, especially secretory IgA, which can protect the newborn against various respiratory and intestinal infections.

The fetus can mount an IgM response to certain (probably T-cell–independent) antigens (e.g., to Treponema pallidum, the cause of syphilis, which can be acquired congenitally). IgG and IgA begin to be made shortly after birth. The response to protein antigens is usually good; hence hepatitis B vaccine can be given at birth and poliovirus immunization can begin at 2 months of age. However, young children respond poorly to polysaccharide antigens unless they are conjugated to a carrier protein. For example, the pneumococcal vaccine containing the unconjugated polysaccharides does not induce protective immunity when given prior to 18 months of age, but the pneumococcal vaccine containing the polysaccharides conjugated to a carrier protein is effective when given as early as 2 months of age.

In the elderly, immunity generally declines. There is a reduced IgG response to certain antigens, fewer T cells, and a reduced delayed hypersensitivity response. As in the very young, the frequency and severity of infections are high. The frequency of autoimmune diseases is also high in the elderly, possibly because of a decline in the number of regulatory T cells, which allows autoreactive T cells to proliferate and cause disease.

SELF-ASSESSMENT QUESTIONS

1. Which one of the following is an attribute of the innate, rather than the adaptive (acquired), arm of our host defenses?

(A) Is highly specific in its response to bacteria

(B) Responds to viruses and fungi, but not bacteria

(C) Exhibits memory following exposure to bacteria

(D) Is part of our host defense against bacteria but not against fungi

(E) Is as effective the first time it is exposed to bacteria as it is subsequent times

2. Regarding antibody-mediated immunity and cell-mediated immunity, which one of the following is the most accurate?

(A) Antibody-mediated immunity helps prevent graft rejection.

(B) Antibody-mediated immunity protects against anaphylactic shock.

(C) Antibody-mediated immunity protects against autoimmune diseases.

(D) Cell-mediated immunity neutralizes extracellular viruses.

(E) Cell-mediated immunity protects against fungal infections.

3. Which one of the following is most likely to induce an IgM antibody response without the participation of helper T cells?

(A) Diphtheria toxoid

(B) Pneumococcal capsular polysaccharide

(C) Pneumococcal polysaccharide conjugated to diphtheria toxoid

(D) Tetanus toxoid

(E) Toxic shock syndrome toxin

4. Regarding haptens, which one of the following is the most accurate?

(A) A hapten is the antigen-binding site in the hypervariable region of IgG.

(B) A hapten cannot induce antibody by itself but can do so when covalently bound to a carrier protein.

(C) A hapten can bind to the antigen receptor of CD4-positive T cells without being processed by macrophages.

(D) A hapten is defined by its ability to bind to the smaller of the two polypeptides that comprise the class I MHC proteins.

5. Certain components of our immune system are characterized by two attributes: being able (1) to respond specifically to microbes and (2) to exhibit memory of having responded to a particular microbe previously. Which one of the following has BOTH specificity and memory?

(A) B cells

(B) Basophils

(C) Dendritic cells

(D) Macrophages

(E) Neutrophils

6. Your patient says that she must travel on business 3 days from now to a country where hepatitis A is endemic. She just read in the newspaper that there are two types of protection against this disease: one is a vaccine that contains killed hepatitis A virus, and the other is serum globulin preparation that contains anti-bodies to the virus. She asks which you would recommend and for what reason?

(A) The vaccine containing killed hepatitis A virus is best because it induces the most antibody.

(B) The vaccine containing killed hepatitis A virus is best because it provides the most long-lived immunity.

(C) The serum globulin preparation containing antibodies against the virus is best because it provides immunity in the shortest time.

(D) The serum globulin preparation containing antibodies against the virus is best because it provides the most long-lived immunity.

ANSWERS

1. (E)

2. (E)

3. (B)

4. (B)

5. (A)

6. (C)

PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS

Questions on the topics discussed in this chapter can be found in the Immunology section of PART XIII: USMLE (National Board) Practice Questions starting on page 713. Also see PART XIV: USMLE (National Board) Practice Examinations starting on page 731.