The adaptive, or acquired, immune response takes days or even weeks to become established—much longer than the innate response; however, adaptive immunity is more specific to an invading pathogen. Adaptive immunity is an immunity that occurs after exposure to an antigen either from a pathogen or a vaccination. An antigen is a molecule that stimulates a response in the immune system. This part of the immune system is activated when the innate immune response is insufficient to control an infection. In fact, without information from the innate immune system, the adaptive response could not be mobilized. There are two types of adaptive responses: the cell-mediated immune response, which is controlled by activated T cells, and the humoral immune response, which is controlled by activated B cells and antibodies. Activated T and B cells whose surface binding sites are specific to the molecules on the pathogen greatly increase in numbers and attack the invading pathogen. Their attack can kill pathogens directly or they can secrete antibodies that enhance the phagocytosis of pathogens and disrupt the infection. Adaptive immunity also involves a memory to give the host long-term protection from reinfection with the same type of pathogen; on reexposure, this host memory will facilitate a rapid and powerful response.

B and T Cells

Lymphocytes, which are white blood cells, are formed with other blood cells in the red bone marrow found in many flat bones, such as the shoulder or pelvic bones. The two types of lymphocytes of the adaptive immune response are B and T cells (Figure 17.12). Whether an immature lymphocyte becomes a B cell or T cell depends on where in the body it matures. The B cells remain in the bone marrow to mature (hence the name “B” for “bone marrow”), while T cells migrate to the thymus, where they mature (hence the name “T” for “thymus”).

Maturation of a B or T cell involves becoming immunocompetent, meaning that it can recognize, by binding, a specific molecule or antigen (discussed below). During the maturation process, B and T cells that bind too strongly to the body’s own cells are eliminated in order to minimize an immune response against the body’s own tissues. Those cells that react weakly to the body’s own cells, but have highly specific receptors on their cell surfaces that allow them to recognize a foreign molecule, or antigen, remain. This process occurs during fetal development and continues throughout life. The specificity of this receptor is determined by the genetics of the individual and is present before a foreign molecule is introduced to the body or encountered. Thus, it is genetics and not experience that initially provides a vast array of cells, each capable of binding to a different specific foreign molecule. Once they are immunocompetent, the T and B cells will migrate to the spleen and lymph nodes where they will remain until they are called on during an infection. B cells are involved in the humoral immune response, which targets pathogens loose in blood and lymph, and T cells are involved in the cell-mediated immune response, which targets infected cells.

Figure 17.12 This scanning electron micrograph shows a T lymphocyte. T and B cells are indistinguishable by light microscopy but can be differentiated experimentally by probing their surface receptors. (credit: modification of work by NCI; scale-bar data from Matt Russell)

Humoral Immune Response

As mentioned, an antigen is a molecule that stimulates a response in the immune system. Not every molecule is antigenic. B cells participate in a chemical response to antigens present in the body by producing specific antibodies that circulate throughout the body and bind with the antigen whenever it is encountered. This is known as the humoral immune response. As discussed, during maturation of B cells, a set of highly specific B cells are produced that have many antigen receptor molecules in their membrane (Figure 17.13).

Figure 17.13 B cell receptors are embedded in the membranes of B cells and bind a variety of antigens through their variable regions.

Each B cell has only one kind of antigen receptor, which makes every B cell different. Once the B cells mature in the bone marrow, they migrate to lymph nodes or other lymphatic organs. When a B cell encounters the antigen that binds to its receptor, the antigen molecule is brought into the cell by endocytosis and reappears on the surface of the cell bound to an MHC class II molecule. When this process is complete, the B cell is sensitized. In most cases, the sensitized B cell must then encounter a specific kind of T cell, called a helper T cell, before it is activated. The helper T cell must already have been activated through an encounter with the antigen (discussed below).

The helper T cell binds to the antigen-MHC class II complex and is induced to release cytokines that induce the B cell to divide rapidly, which makes thousands of identical (clonal) cells. These daughter cells become either plasma cells or memory B cells. The memory B cells remain inactive at this point, until another later encounter with the antigen, caused by a reinfection by the same bacteria or virus, results in them dividing into a new population of plasma cells. The plasma cells, on the other hand, produce and secrete large quantities, up to 100 million molecules per hour, of antibody molecules. An antibody, also known as an immunoglobulin (Ig), is a protein that is produced by plasma cells after stimulation by an antigen. Antibodies are the agents of humoral immunity. Antibodies occur in the blood, in gastric and mucus secretions, and in breast milk. Antibodies in these bodily fluids can bind pathogens and mark them for destruction by phagocytes before they can infect cells.

These antibodies circulate in the blood stream and lymphatic system and bind with the antigen whenever it is encountered. The binding can fight infection in several ways. Antibodies can bind to viruses or bacteria and interfere with the chemical interactions required for them to infect or bind to other cells. The antibodies may create bridges between different particles containing antigenic sites clumping them all together and preventing their proper functioning. The antigen-antibody complex stimulates the complement system described previously, destroying the cell bearing the antigen. Phagocytic cells, such as those already described, are attracted by the antigen-antibody complexes, and phagocytosis is enhanced when the complexes are present. Finally, antibodies stimulate inflammation, and their presence in mucus and on the skin prevents pathogen attack.

Antibodies coat extracellular pathogens and neutralize them by blocking key sites on the pathogen that enhance their infectivity (such as receptors that “dock” pathogens on host cells) (Figure 17.14). Antibody neutralization can prevent pathogens from entering and infecting host cells. The neutralized antibody-coated pathogens can then be filtered by the spleen and eliminated in urine or feces.

Antibodies also mark pathogens for destruction by phagocytic cells, such as macrophages or neutrophils, in a process called opsonization. In a process called complement fixation, some antibodies provide a place for complement proteins to bind. The combination of antibodies and complement promotes rapid clearing of pathogens.

The production of antibodies by plasma cells in response to an antigen is called active immunity and describes the host’s active response of the immune system to an infection or to a vaccination. There is also a passive immune response where antibodies come from an outside source, instead of the individual’s own plasma cells, and are introduced into the host. For example, antibodies circulating in a pregnant woman’s body move across the placenta into the developing fetus. The child benefits from the presence of these antibodies for up to several months after birth. In addition, a passive immune response is possible by injecting antibodies into an individual in the form of an antivenom to a snake-bite toxin or antibodies in blood serum to help fight a hepatitis infection. This gives immediate protection since the body does not need the time required to mount its own response.

Figure 17.14 Antibodies may inhibit infection by (a) preventing the antigen from binding its target, (b) tagging a pathogen for destruction by macrophages or neutrophils, or (c) activating the complement cascade.

Cell-Mediated Immunity

Unlike B cells, T lymphocytes are unable to recognize pathogens without assistance. Instead, dendritic cells and macrophages first engulf and digest pathogens into hundreds or thousands of antigens. Then, an antigen-presenting cell (APC) detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will engulf and break it down through phagocytosis. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells. A dendritic cell is an immune cell that mops up antigenic materials in its surroundings and presents them on its surface. Dendritic cells are located in the skin, the linings of the nose, lungs, stomach, and intestines. These positions are ideal locations to encounter invading pathogens. Once they are activated by pathogens and mature to become APCs they migrate to the spleen or a lymph node. Macrophages also function as APCs. After phagocytosis by a macrophage, the phagocytic vesicle fuses with an intracellular lysosome. Within the resulting phagolysosome, the components are broken down into fragments; the fragments are then loaded onto MHC class II molecules and are transported to the cell surface for antigen presentation (Figure 17.15). Helper T cells cannot properly respond to an antigen unless it is processed and embedded in an MHC class II molecule. The APCs express MHC class II on their surfaces, and when combined with a foreign antigen, these complexes signal an invader.

Figure 17.15 An antigen-presenting cell (APC), such as a macrophage, engulfs a foreign antigen, partially digests it in a lysosome, and then embeds it in an MHC class II molecule for presentation at the cell surface. Lymphocytes of the adaptive immune response must interact with antigen-embedded MHC class II molecules to mature into functional immune cells.

CONCEPTS IN ACTION

T cells have many functions. Some respond to APCs of the innate immune system and indirectly induce immune responses by releasing cytokines. Others stimulate B cells to start the humoral response as described previously. Another type of T cell detects APC signals and directly kills the infected cells, while some are involved in suppressing inappropriate immune reactions to harmless or “self” antigens.

There are two main types of T cells: helper T lymphocytes (T_H) and the cytotoxic T lymphocytes (T_C). The T_H lymphocytes function indirectly to tell other immune cells about potential pathogens. T_H lymphocytes recognize specific antigens presented by the MHC class II complexes of APCs. There are two populations of T_H cells: T_H1 and T_H2. T_H1 cells secrete cytokines to enhance the activities of macrophages and other T cells. T_H2 cells stimulate naïve B cells to secrete antibodies. Whether a T_H1 or a T_H2 immune response develops depends on the specific types of cytokines secreted by cells of the innate immune system, which in turn depends on the nature of the invading pathogen.

Cytotoxic T cells (T_C) are the key component of the cell-mediated part of the adaptive immune system and attack and destroy infected cells. T_C cells are particularly important in protecting against viral infections; this is because viruses replicate within cells where they are shielded from extracellular contact with circulating antibodies. Once activated, the T_C creates a large clone of cells with one specific set of cell-surface receptors, as in the case with proliferation of activated B cells. As with B cells, the clone includes active T_C cells and inactive memory T_C cells. The resulting active T_C cells then identify infected host cells. Because of the time required to generate a population of clonal T and B cells, there is a delay in the adaptive immune response compared to the innate immune response.

T_C cells attempt to identify and destroy infected cells before the pathogen can replicate and escape, thereby halting the progression of intracellular infections. T_C cells also support NK lymphocytes to destroy early cancers. Cytokines secreted by the T_H1 response that stimulates macrophages also stimulate T_C cells and enhance their ability to identify and destroy infected cells and tumors. A summary of how the humoral and cell-mediated immune responses are activated appears in Figure 17.16.

B plasma cells and T_C cells are collectively called effector cells because they are involved in “effecting” (bringing about) the immune response of killing pathogens and infected host cells.

Figure 17.16 A helper T cell becomes activated by binding to an antigen presented by an APC via the MHCII receptor, causing it to release cytokines. Depending on the cytokines released, this activates either the humoral or the cell-mediated immune response.

Immunological Memory

The adaptive immune system has a memory component that allows for a rapid and large response upon reinvasion of the same pathogen. During the adaptive immune response to a pathogen that has not been encountered before, known as the primary immune response, plasma cells secreting antibodies and differentiated T cells increase, then plateau over time. As B and T cells mature into effector cells, a subset of the naïve populations differentiates into B and T memory cells with the same antigen specificities (Figure 17.17). A memory cell is an antigen-specific B or T lymphocyte that does not differentiate into an effector cell during the primary immune response, but that can immediately become an effector cell on reexposure to the same pathogen. As the infection is cleared and pathogenic stimuli subside, the effectors are no longer needed and they undergo apoptosis. In contrast, the memory cells persist in the circulation.

VISUAL CONNECTION

Figure 17.17 After initially binding an antigen to the B cell receptor, a B cell internalizes the antigen and presents it on MHC class II. A helper T cell recognizes the MHC class II- antigen complex and activates the B cell. As a result, memory B cells and plasma cells are made.

The Rh antigen is found on Rh-positive red blood cells. An Rh-negative female can usually carry an Rh-positive fetus to term without difficulty. However, if she has a second Rh-positive fetus, her body may launch an immune attack that causes hemolytic disease of the newborn. Why do you think hemolytic disease is only a problem during the second or subsequent pregnancies?

If the pathogen is never encountered again during the individual’s lifetime, B and T memory cells will circulate for a few years or even several decades and will gradually die off, having never functioned as effector cells. However, if the host is re-exposed to the same pathogen type, circulating memory cells will immediately differentiate into plasma cells and T_C cells without input from APCs or T_H cells. This is known as the secondary immune response. One reason why the adaptive immune response is delayed is because it takes time for naïve B and T cells with the appropriate antigen specificities to be identified, activated, and proliferate. On reinfection, this step is skipped, and the result is a more rapid production of immune defenses. Memory B cells that differentiate into plasma cells output tens to hundreds-fold greater antibody amounts than were secreted during the primary response (Figure 17.18). This rapid and dramatic antibody response may stop the infection before it can even become established, and the individual may not realize they had been exposed.

Figure 17.18 In the primary response to infection, antibodies are secreted first from plasma cells. Upon re-exposure to the same pathogen, memory cells differentiate into antibody-secreting plasma cells that output a greater amount of antibody for a longer period of time.

Vaccination is based on the knowledge that exposure to noninfectious antigens, derived from known pathogens, generates a mild primary immune response. The immune response to vaccination may not be perceived by the host as illness but still confers immune memory. When exposed to the corresponding pathogen to which an individual was vaccinated, the reaction is similar to a secondary exposure. Because each reinfection generates more memory cells and increased resistance to the pathogen, some vaccine courses involve one or more booster vaccinations to mimic repeat exposures.

The Lymphatic System

Lymph is the watery fluid that bathes tissues and organs and contains protective white blood cells but does not contain erythrocytes. Lymph moves about the body through the lymphatic system, which is made up of vessels, lymph ducts, lymph glands, and organs, such as tonsils, adenoids, thymus, and spleen.

Although the immune system is characterized by circulating cells throughout the body, the regulation, maturation, and intercommunication of immune factors occur at specific sites. The blood circulates immune cells, proteins, and other factors through the body. Approximately 0.1 percent of all cells in the blood are leukocytes, which include monocytes (the precursor of macrophages) and lymphocytes. Most cells in the blood are red blood cells. Cells of the immune system can travel between the distinct lymphatic and blood circulatory systems, which are separated by interstitial space, by a process called extravasation (passing through to surrounding tissue).

Recall that cells of the immune system originate from stem cells in the bone marrow. B cell maturation occurs in the bone marrow, whereas progenitor cells migrate from the bone marrow and develop and mature into naïve T cells in the organ called the thymus.

On maturation, T and B lymphocytes circulate to various destinations. Lymph nodes scattered throughout the body house large populations of T and B cells, dendritic cells, and macrophages (Figure 17.19). Lymph gathers antigens as it drains from tissues. These antigens then are filtered through lymph nodes before the lymph is returned to circulation. APCs in the lymph nodes capture and process antigens and inform nearby lymphocytes about potential pathogens.

Figure 17.19 (a) Lymphatic vessels carry a clear fluid called lymph throughout the body. The liquid passes through (b) lymph nodes that filter the lymph that enters the node through afferent vessels and leaves through efferent vessels; lymph nodes are filled with lymphocytes that purge infecting cells. (credit a: modification of work by NIH; credit b: modification of work by NCI, NIH)

The spleen houses B and T cells, macrophages, dendritic cells, and NK cells (Figure 17.20). The spleen is the site where APCs that have trapped foreign particles in the blood can communicate with lymphocytes. Antibodies are synthesized and secreted by activated plasma cells in the spleen, and the spleen filters foreign substances and antibody-complexed pathogens from the blood. Functionally, the spleen is to the blood as lymph nodes are to the lymph.

Figure 17.20 The spleen functions to immunologically filter the blood and allow for communication between cells corresponding to the innate and adaptive immune responses. (credit: modification of work by NCI, NIH)

Mucosal Immune System

The innate and adaptive immune responses compose the systemic immune system (affecting the whole body), which is distinct from the mucosal immune system. Mucosa associated lymphoid tissue (MALT) is a crucial component of a functional immune system because mucosal surfaces, such as the nasal passages, are the first tissues onto which inhaled or ingested pathogens are deposited. The mucosal tissue includes the mouth, pharynx, and esophagus, and the gastrointestinal, respiratory, and urogenital tracts.

Mucosal immunity is formed by MALT, which functions independently of the systemic immune system, and which has its own innate and adaptive components. MALT is a collection of lymphatic tissue that combines with epithelial tissue lining the mucosa throughout the body. This tissue functions as the immune barrier and response in areas of the body with direct contact to the external environment. The systemic and mucosal immune systems use many of the same cell types. Foreign particles that make their way to MALT are taken up by absorptive epithelial cells and delivered to APCs located directly below the mucosal tissue. APCs of the mucosal immune system are primarily dendritic cells, with B cells and macrophages having minor roles. Processed antigens displayed on APCs are detected by T cells in the MALT and at the tonsils, adenoids, appendix, or the mesenteric lymph nodes of the intestine. Activated T cells then migrate through the lymphatic system and into the circulatory system to mucosal sites of infection.

Immune Tolerance

The immune system has to be regulated to prevent wasteful, unnecessary responses to harmless substances, and more importantly, so that it does not attack “self.” The acquired ability to prevent an unnecessary or harmful immune response to a detected foreign substance known not to cause disease, or self-antigens, is described as immune tolerance. The primary mechanism for developing immune tolerance to self-antigens occurs during the selection for weakly self-binding cells during T and B lymphocyte maturation. There are populations of T cells that suppress the immune response to self-antigens and that suppress the immune response after the infection has cleared to minimize host cell damage induced by inflammation and cell lysis. Immune tolerance is especially well developed in the mucosa of the upper digestive system because of the tremendous number of foreign substances (such as food proteins) that APCs of the oral cavity, pharynx, and gastrointestinal mucosa encounter. Immune tolerance is brought about by specialized APCs in the liver, lymph nodes, small intestine, and lung that present harmless antigens to a diverse population of regulatory T (T_reg) cells, specialized lymphocytes that suppress local inflammation and inhibit the secretion of stimulatory immune factors. The combined result of T_reg cells is to prevent immunologic activation and inflammation in undesired tissue compartments and to allow the immune system to focus on pathogens instead.

Adaptive immunity is defined by two important characteristics: specificity and memory. Specificity refers to the adaptive immune system’s ability to target specific pathogens, and memory refers to its ability to quickly respond to pathogens to which it has previously been exposed. For example, when an individual recovers from chickenpox, the body develops a memory of the infection that will specifically protect it from the causative agent, the varicella-zoster virus, if it is exposed to the virus again later.

Specificity and memory are achieved by essentially programming certain cells involved in the immune response to respond rapidly to subsequent exposures of the pathogen. This programming occurs as a result of the first exposure to a pathogen or vaccine, which triggers a primary response. Subsequent exposures result in a secondary response that is faster and stronger as a result of the body’s memory of the first exposure (Figure 18.2). This secondary response, however, is specific to the pathogen in question. For example, exposure to one virus (e.g., varicella-zoster virus) will not provide protection against other viral diseases (e.g., measles, mumps, or polio).

Adaptive specific immunity involves the actions of two distinct cell types: B lymphocytes (B cells) and T lymphocytes (T cells). Although B cells and T cells arise from a common hematopoietic stem cell differentiation pathway, their sites of maturation and their roles in adaptive immunity are very different.

B cells mature in the bone marrow and are responsible for the production of glycoproteins called antibodies, or immunoglobulins. Antibodies are involved in the body’s defense against pathogens and toxins in the extracellular environment. Mechanisms of adaptive specific immunity that involve B cells and antibody production are referred to as humoral immunity. The maturation of T cells occurs in the thymus. T cells function as the central orchestrator of both innate and adaptive immune responses. They are also responsible for destruction of cells infected with intracellular pathogens. The targeting and destruction of intracellular pathogens by T cells is called cell-mediated immunity, or cellular immunity.

Figure 18.2 This graph illustrates the primary and secondary immune responses related to antibody production after an initial and secondary exposure to an antigen. Notice that the secondary response is faster and provides a much higher concentration of antibody.

Antigens

Activation of the adaptive immune defenses is triggered by pathogen-specific molecular structures called antigens. Antigens are similar to the pathogen-associated molecular patterns (PAMPs) discussed in Pathogen Recognition and Phagocytosis; however, whereas PAMPs are molecular structures found on numerous pathogens, antigens are unique to a specific pathogen. The antigens that stimulate adaptive immunity to chickenpox, for example, are unique to the varicella-zoster virus but significantly different from the antigens associated with other viral pathogens.

The term antigen was initially used to describe molecules that stimulate the production of antibodies; in fact, the term comes from a combination of the words antibody and generator, and a molecule that stimulates antibody production is said to be antigenic. However, the role of antigens is not limited to humoral immunity and the production of antibodies; antigens also play an essential role in stimulating cellular immunity, and for this reason antigens are sometimes more accurately referred to as immunogens. In this text, however, we will typically refer to them as antigens.

Pathogens possess a variety of structures that may contain antigens. For example, antigens from bacterial cells may be associated with their capsules, cell walls, fimbriae, flagella, or pili. Bacterial antigens may also be associated with extracellular toxins and enzymes that they secrete. Viruses possess a variety of antigens associated with their capsids, envelopes, and the spike structures they use for attachment to cells.

Antigens may belong to any number of molecular classes, including carbohydrates, lipids, nucleic acids, proteins, and combinations of these molecules. Antigens of different classes vary in their ability to stimulate adaptive immune defenses as well as in the type of response they stimulate (humoral or cellular). The structural complexity of an antigenic molecule is an important factor in its antigenic potential. In general, more complex molecules are more effective as antigens. For example, the three-dimensional complex structure of proteins make them the most effective and potent antigens, capable of stimulating both humoral and cellular immunity. In comparison, carbohydrates are less complex in structure and therefore less effective as antigens; they can only stimulate humoral immune defenses. Lipids and nucleic acids are the least antigenic molecules, and in some cases may only become antigenic when combined with proteins or carbohydrates to form glycolipids, lipoproteins, or nucleoproteins.

One reason the three-dimensional complexity of antigens is so important is that antibodies and T cells do not recognize and interact with an entire antigen but with smaller exposed regions on the surface of antigens called epitopes. A single antigen may possess several different epitopes (Figure 18.3), and different antibodies may bind to different epitopes on the same antigen (Figure 18.4). For example, the bacterial flagellum is a large, complex protein structure that can possess hundreds or even thousands of epitopes with unique three-dimensional structures. Moreover, flagella from different bacterial species (or even strains of the same species) contain unique epitopes that can only be bound by specific antibodies.

An antigen’s size is another important factor in its antigenic potential. Whereas large antigenic structures like flagella possess multiple epitopes, some molecules are too small to be antigenic by themselves. Such molecules, called haptens, are essentially free epitopes that are not part of the complex three-dimensional structure of a larger antigen. For a hapten to become antigenic, it must first attach to a larger carrier molecule (usually a protein) to produce a conjugate antigen. The hapten-specific antibodies produced in response to the conjugate antigen are then able to interact with unconjugated free hapten molecules. Haptens are not known to be associated with any specific pathogens, but they are responsible for some allergic responses. For example, the hapten urushiol, a molecule found in the oil of plants that cause poison ivy, causes an immune response that can result in a severe rash (called contact dermatitis). Similarly, the hapten penicillin can cause allergic reactions to drugs in the penicillin class.

Figure 18.3 An antigen is a macromolecule that reacts with components of the immune system. A given antigen may contain several motifs that are recognized by immune cells.

Figure 18.4 A typical protein antigen has multiple epitopes, shown by the ability of three different antibodies to bind to different epitopes of the same antigen.

Antibodies

Antibodies (also called immunoglobulins) are glycoproteins that are present in both the blood and tissue fluids. The basic structure of an antibody monomer consists of four protein chains held together by disulfide bonds (Figure 18.5). A disulfide bond is a covalent bond between the sulfhydryl R groups found on two cysteine amino acids. The two largest chains are identical to each other and are called the heavy chains. The two smaller chains are also identical to each other and are called the light chains. Joined together, the heavy and light chains form a basic Y-shaped structure.

The two ‘arms’ of the Y-shaped antibody molecule are known as the Fab region, for “fragment of antigen binding.” The far end of the Fab region is the variable region, which serves as the site of antigen binding. The amino acid sequence in the variable region dictates the three-dimensional structure, and thus the specific three-dimensional epitope to which the Fab region is capable of binding. Although the epitope specificity of the Fab regions is identical for each arm of a single antibody molecule, this region displays a high degree of variability between antibodies with different epitope specificities. Binding to the Fab region is necessary for neutralization of pathogens, agglutination or aggregation of pathogens, and antibody-dependent cell-mediated cytotoxicity.

The constant region of the antibody molecule includes the trunk of the Y and lower portion of each arm of the Y. The trunk of the Y is also called the Fc region, for “fragment of crystallization,” and is the site of complement factor binding and binding to phagocytic cells during antibody-mediated opsonization.

Figure 18.5 (a) The typical four-chain structure of a generic antibody monomer. (b) The corresponding three-dimensional structure of the antibody IgG. (credit b: modification of work by Tim Vickers)

CHECK YOUR UNDERSTANDING

• Describe the different functions of the Fab region and the Fc region.

Antibody Classes

The constant region of an antibody molecule determines its class, or isotype. The five classes of antibodies are IgG, IgM, IgA, IgD, and IgE. Each class possesses unique heavy chains designated by Greek letters γ, μ, α, δ, and ε, respectively. Antibody classes also exhibit important differences in abundance in serum, arrangement, body sites of action, functional roles, and size (Figure 18.6).

IgG is a monomer that is by far the most abundant antibody in human blood, accounting for about 80% of total serum antibody. IgG penetrates efficiently into tissue spaces, and is the only antibody class with the ability to cross the placental barrier, providing passive immunity to the developing fetus during pregnancy. IgG is also the most versatile antibody class in terms of its role in the body’s defense against pathogens.

IgM is initially produced in a monomeric membrane-bound form that serves as an antigen-binding receptor on B cells. The secreted form of IgM assembles into a pentamer with five monomers of IgM bound together by a protein structure called the J chain. Although the location of the J chain relative to the Fc regions of the five monomers prevents IgM from performing some of the functions of IgG, the ten available Fab sites associated with a pentameric IgM make it an important antibody in the body’s arsenal of defenses. IgM is the first antibody produced and secreted by B cells during the primary and secondary immune responses, making pathogen-specific IgM a valuable diagnostic marker during active or recent infections.

IgA accounts for about 13% of total serum antibody, and secretory IgA is the most common and abundant antibody class found in the mucus secretions that protect the mucous membranes. IgA can also be found in other secretions such as breast milk, tears, and saliva. Secretory IgA is assembled into a dimeric form with two monomers joined by a protein structure called the secretory component. One of the important functions of secretory IgA is to trap pathogens in mucus so that they can later be eliminated from the body.

Similar to IgM, IgD is a membrane-bound monomer found on the surface of B cells, where it serves as an antigen-binding receptor. However, IgD is not secreted by B cells, and only trace amounts are detected in serum. These trace amounts most likely come from the degradation of old B cells and the release of IgD molecules from their cytoplasmic membranes.

IgE is the least abundant antibody class in serum. Like IgG, it is secreted as a monomer, but its role in adaptive immunity is restricted to anti-parasitic defenses. The Fc region of IgE binds to basophils and mast cells. The Fab region of the bound IgE then interacts with specific antigen epitopes, causing the cells to release potent pro-inflammatory mediators. The inflammatory reaction resulting from the activation of mast cells and basophils aids in the defense against parasites, but this reaction is also central to allergic reactions (see Diseases of the Immune System.

Figure 18.6

Antigen-Antibody Interactions

Different classes of antibody play important roles in the body’s defense against pathogens. These functions include neutralization of pathogens, opsonization for phagocytosis, agglutination, complement activation, and antibody-dependent cell-mediated cytotoxicity. For most of these functions, antibodies also provide an important link between adaptive specific immunity and innate nonspecific immunity.

Neutralization involves the binding of certain antibodies (IgG, IgM, or IgA) to epitopes on the surface of pathogens or toxins, preventing their attachment to cells. For example, Secretory IgA can bind to specific pathogens and block initial attachment to intestinal mucosal cells. Similarly, specific antibodies can bind to certain toxins, blocking them from attaching to target cells and thus neutralizing their toxic effects. Viruses can be neutralized and prevented from infecting a cell by the same mechanism (Figure 18.7).

As described in Chemical Defenses, opsonization is the coating of a pathogen with molecules, such as complement factors, C-reactive protein, and serum amyloid A, to assist in phagocyte binding to facilitate phagocytosis. IgG antibodies also serve as excellent opsonins, binding their Fab sites to specific epitopes on the surface of pathogens. Phagocytic cells such as macrophages, dendritic cells, and neutrophils have receptors on their surfaces that recognize and bind to the Fc portion of the IgG molecules; thus, IgG helps such phagocytes attach to and engulf the pathogens they have bound (Figure 18.8).

Agglutination or aggregation involves the cross-linking of pathogens by antibodies to create large aggregates (Figure 18.9). IgG has two Fab antigen-binding sites, which can bind to two separate pathogen cells, clumping them together. When multiple IgG antibodies are involved, large aggregates can develop; these aggregates are easier for the kidneys and spleen to filter from the blood and easier for phagocytes to ingest for destruction. The pentameric structure of IgM provides ten Fab binding sites per molecule, making it the most efficient antibody for agglutination.

Figure 18.7 Neutralization involves the binding of specific antibodies to antigens found on bacteria, viruses, and toxins, preventing them from attaching to target cells.

Figure 18.8 Antibodies serve as opsonins and inhibit infection by tagging pathogens for destruction by macrophages, dendritic cells, and neutrophils. These phagocytic cells use Fc receptors to bind to IgG-opsonized pathogens and initiate the first step of attachment before phagocytosis.

Figure 18.9 Antibodies, especially IgM antibodies, agglutinate bacteria by binding to epitopes on two or more bacteria simultaneously. When multiple pathogens and antibodies are present, aggregates form when the binding sites of antibodies bind with separate pathogens.

Another important function of antibodies is activation of the complement cascade. As discussed in the previous chapter, the complement system is an important component of the innate defenses, promoting the inflammatory response, recruiting phagocytes to site of infection, enhancing phagocytosis by opsonization, and killing gram-negative bacterial pathogens with the membrane attack complex (MAC). Complement activation can occur through three different pathways (see Figure 17.9), but the most efficient is the classical pathway, which requires the initial binding of IgG or IgM antibodies to the surface of a pathogen cell, allowing for recruitment and activation of the C1 complex.

Yet another important function of antibodies is antibody-dependent cell-mediated cytotoxicity (ADCC), which enhances killing of pathogens that are too large to be phagocytosed. This process is best characterized for natural killer cells (NK cells), as shown in Figure 18.10, but it can also involve macrophages and eosinophils. ADCC occurs when the Fab region of an IgG antibody binds to a large pathogen; Fc receptors on effector cells (e.g., NK cells) then bind to the Fc region of the antibody, bringing them into close proximity with the target pathogen. The effector cell then secretes powerful cytotoxins (e.g., perforin and granzymes) that kill the pathogen.

Figure 18.10 In this example of ADCC, antibodies bind to a large pathogenic cell that is too big for phagocytosis and then bind to Fc receptors on the membrane of a natural killer cell. This interaction brings the NK cell into close proximity, where it can kill the pathogen through release of lethal extracellular cytotoxins.

Mucosal tissues are major barriers to the entry of pathogens into the body. The IgA (and sometimes IgM) antibodies in mucus and other secretions can bind to the pathogen, and in the cases of many viruses and bacteria, neutralize them. Neutralization is the process of coating a pathogen with antibodies, making it physically impossible for the pathogen to bind to receptors. Neutralization, which occurs in the blood, lymph, and other body fluids and secretions, protects the body constantly. Neutralizing antibodies are the basis for the disease protection offered by vaccines. Vaccinations for diseases that commonly enter the body via mucous membranes, such as influenza, are usually formulated to enhance IgA production.

Immune responses in some mucosal tissues such as the Peyer’s patches (see image) in the small intestine take up particulate antigens by specialized cells known as microfold or M cells (image). These cells allow the body to sample potential pathogens from the intestinal lumen. Dendritic cells then take the antigen to the regional lymph nodes, where an immune response is mounted.

The body fights bacterial pathogens with a wide variety of immunological mechanisms, essentially trying to find one that is effective. Bacteria such as Mycobacterium leprae, the cause of leprosy, are resistant to lysosomal enzymes and can persist in macrophage organelles or escape into the cytosol. In such situations, infected macrophages receiving cytokine signals from Th1 cells turn on special metabolic pathways. Macrophage oxidative metabolism is hostile to intracellular bacteria, often relying on the production of nitric oxide to kill the bacteria inside the macrophage.

Fungal infections, such as those from Aspergillus, Candida, and Pneumocystis, are largely opportunistic infections that take advantage of suppressed immune responses. Most of the same immune mechanisms effective against bacteria have similar effects on fungi, both of which have characteristic cell wall structures that protect their cells.

Worm parasites such as helminths are seen as the primary reason why the mucosal immune response, IgE-mediated allergy and asthma, and eosinophils evolved. These parasites were at one time very common in human society. When infecting a human, often via contaminated food, some worms take up residence in the gastrointestinal tract. Eosinophils are attracted to the site by T cell cytokines, which release their granule contents upon their arrival. Mast cell degranulation also occurs, and the fluid leakage caused by the increase in local vascular permeability is thought to have a flushing action on the parasite, expelling its larvae from the body. Furthermore, if IgE labels the parasite, the eosinophils can bind to it by its Fc receptor.

Now that you understand the development of mature, naïve B cells and T cells, and some of their major functions, how do all of these various cells, proteins, and cytokines come together to actually resolve an infection? Ideally, the immune response will rid the body of a pathogen entirely. The adaptive immune response, with its rapid clonal expansion, is well suited to this purpose. Think of a primary infection as a race between the pathogen and the immune system. The pathogen bypasses barrier defenses and starts multiplying in the host’s body. During the first 4 to 5 days, the innate immune response will partially control, but not stop, pathogen growth. As the adaptive immune response gears up, however, it will begin to clear the pathogen from the body, while at the same time becoming stronger and stronger. When following antibody responses in patients with a particular disease such as a virus, this clearance is referred to as seroconversion (sero- = “serum”). Seroconversion is the reciprocal relationship between virus levels in the blood and antibody levels. As the antibody levels rise, the virus levels decline, and this is a sign that the immune response is being at least partially effective (partially, because in many diseases, seroconversion does not necessarily mean a patient is getting well).

An excellent example of this is seroconversion during HIV disease (Figure). Notice that antibodies are made early in this disease, and the increase in anti-HIV antibodies correlates with a decrease in detectable virus in the blood. Although these antibodies are an important marker for diagnosing the disease, they are not sufficient to completely clear the virus. Several years later, the vast majority of these individuals, if untreated, will lose their entire adaptive immune response, including the ability to make antibodies, during the final stages of AIDS.

HIV Disease Progression

Seroconversion, the rise of anti-HIV antibody levels and the concomitant decline in measurable virus levels, happens during the first several months of HIV disease. Unfortunately, this antibody response is ineffective at controlling the disease, as seen by the progression of the disease towards AIDS, in which all adaptive immune responses are compromised.

DISINFECTANTS: FIGHTING THE GOOD FIGHT?

“Wash your hands!” Parents have been telling their children this for generations. Dirty hands can spread disease. But is it possible to get rid of enough pathogens that children will never get sick? Are children who avoid exposure to pathogens better off? The answers to both these questions appears to be no.

Antibacterial wipes, soaps, gels, and even toys with antibacterial substances embedded in their plastic are ubiquitous in our society. Still, these products do not rid the skin and gastrointestinal tract of bacteria, and it would be harmful to our health if they did. We need these nonpathogenic bacteria on and within our bodies to keep the pathogenic ones from growing. The urge to keep children perfectly clean is thus probably misguided. Children will get sick anyway, and the later benefits of immunological memory far outweigh the minor discomforts of most childhood diseases. In fact, getting diseases such as chickenpox or measles later in life is much harder on the adult and are associated with symptoms significantly worse than those seen in the childhood illnesses. Of course, vaccinations help children avoid some illnesses, but there are so many pathogens, we will never be immune to them all.

Could over-cleanliness be the reason that allergies are increasing in more developed countries? Some scientists think so. Allergies are based on an IgE antibody response. Many scientists think the system evolved to help the body rid itself of worm parasites. The hygiene theory is the idea that the immune system is geared to respond to antigens, and if pathogens are not present, it will respond instead to inappropriate antigens such as allergens and self-antigens. This is one explanation for the rising incidence of allergies in developed countries, where the response to nonpathogens like pollen, shrimp, and cat dander cause allergic responses while not serving any protective function.

The Mucosal Immune Response

Mucosal tissues are major barriers to the entry of pathogens into the body. The IgA (and sometimes IgM) antibodies in mucus and other secretions can bind to the pathogen, and in the cases of many viruses and bacteria, neutralize them. Neutralization is the process of coating a pathogen with antibodies, making it physically impossible for the pathogen to bind to receptors. Neutralization, which occurs in the blood, lymph, and other body fluids and secretions, protects the body constantly. Neutralizing antibodies are the basis for the disease protection offered by vaccines. Vaccinations for diseases that commonly enter the body via mucous membranes, such as influenza, are usually formulated to enhance IgA production.

Immune responses in some mucosal tissues such as the Peyer’s patches in the small intestine take up particulate antigens by specialized cells known as microfold or M cells (Figure). These cells allow the body to sample potential pathogens from the intestinal lumen. Dendritic cells then take the antigen to the regional lymph nodes, where an immune response is mounted.

IgA Immunity

The nasal-associated lymphoid tissue and Peyer’s patches of the small intestine generate IgA immunity. Both use M cells to transport antigen inside the body so that immune responses can be mounted.

Defenses against Bacteria and Fungi

The body fights bacterial pathogens with a wide variety of immunological mechanisms, essentially trying to find one that is effective. Bacteria such as Mycobacterium leprae, the cause of leprosy, are resistant to lysosomal enzymes and can persist in macrophage organelles or escape into the cytosol. In such situations, infected macrophages receiving cytokine signals from Th1 cells turn on special metabolic pathways. Macrophage oxidative metabolism is hostile to intracellular bacteria, often relying on the production of nitric oxide to kill the bacteria inside the macrophage.

Fungal infections, such as those from Aspergillus, Candida, and Pneumocystis, are largely opportunistic infections that take advantage of suppressed immune responses. Most of the same immune mechanisms effective against bacteria have similar effects on fungi, both of which have characteristic cell wall structures that protect their cells.

Defenses against Parasites

Worm parasites such as helminths are seen as the primary reason why the mucosal immune response, IgE-mediated allergy and asthma, and eosinophils evolved. These parasites were at one time very common in human society. When infecting a human, often via contaminated food, some worms take up residence in the gastrointestinal tract. Eosinophils are attracted to the site by T cell cytokines, which release their granule contents upon their arrival. Mast cell degranulation also occurs, and the fluid leakage caused by the increase in local vascular permeability is thought to have a flushing action on the parasite, expelling its larvae from the body. Furthermore, if IgE labels the parasite, the eosinophils can bind to it by its Fc receptor.

Defenses against Viruses

The primary mechanisms against viruses are NK cells, interferons, and cytotoxic T cells. Antibodies are effective against viruses mostly during protection, where an immune individual can neutralize them based on a previous exposure. Antibodies have no effect on viruses or other intracellular pathogens once they enter the cell, since antibodies are not able to penetrate the plasma membrane of the cell. Many cells respond to viral infections by downregulating their expression of MHC class I molecules. This is to the advantage of the virus, because without class I expression, cytotoxic T cells have no activity. NK cells, however, can recognize virally infected class I-negative cells and destroy them. Thus, NK and cytotoxic T cells have complementary activities against virally infected cells.

Interferons have activity in slowing viral replication and are used in the treatment of certain viral diseases, such as hepatitis B and C, but their ability to eliminate the virus completely is limited. The cytotoxic T cell response, though, is key, as it eventually overwhelms the virus and kills infected cells before the virus can complete its replicative cycle. Clonal expansion and the ability of cytotoxic T cells to kill more than one target cell make these cells especially effective against viruses. In fact, without cytotoxic T cells, it is likely that humans would all die at some point from a viral infection (if no vaccine were available).

Evasion of the Immune System by Pathogens

It is important to keep in mind that although the immune system has evolved to be able to control many pathogens, pathogens themselves have evolved ways to evade the immune response. An example already mentioned is in Mycobacterium tuberculosis, which has evolved a complex cell wall that is resistant to the digestive enzymes of the macrophages that ingest them, and thus persists in the host, causing the chronic disease tuberculosis. This section briefly summarizes other ways in which pathogens can “outwit” immune responses. But keep in mind, although it seems as if pathogens have a will of their own, they do not. All of these evasive “strategies” arose strictly by evolution, driven by selection.

Bacteria sometimes evade immune responses because they exist in multiple strains, such as different groups of Staphylococcus aureus. S. aureus is commonly found in minor skin infections, such as boils, and some healthy people harbor it in their nose. One small group of strains of this bacterium, however, called methicillin-resistant Staphylococcus aureus, has become resistant to multiple antibiotics and is essentially untreatable. Different bacterial strains differ in the antigens on their surfaces. The immune response against one strain (antigen) does not affect the other; thus, the species survives.

Another method of immune evasion is mutation. Because viruses’ surface molecules mutate continuously, viruses like influenza change enough each year that the flu vaccine for one year may not protect against the flu common to the next. New vaccine formulations must be derived for each flu season.

Genetic recombination—the combining of gene segments from two different pathogens—is an efficient form of immune evasion. For example, the influenza virus contains gene segments that can recombine when two different viruses infect the same cell. Recombination between human and pig influenza viruses led to the 2010 H1N1 swine flu outbreak.

Pathogens can produce immunosuppressive molecules that impair immune function, and there are several different types. Viruses are especially good at evading the immune response in this way, and many types of viruses have been shown to suppress the host immune response in ways much more subtle than the wholesale destruction caused by HIV.

Review

Early childhood is a time when the body develops much of its immunological memory that protects it from diseases in adulthood. The components of the immune response that have the maximum effectiveness against a pathogen are often associated with the class of pathogen involved. Bacteria and fungi are especially susceptible to damage by complement proteins, whereas viruses are taken care of by interferons and cytotoxic T cells. Worms are attacked by eosinophils. Pathogens have shown the ability, however, to evade the body’s immune responses, some leading to chronic infections or even death. The immune system and pathogens are in a slow, evolutionary race to see who stays on top. Modern medicine, hopefully, will keep the results skewed in humans’ favor.

It is important to keep in mind that although the immune system has evolved to be able to control many pathogens, pathogens themselves have evolved ways to evade the immune response. An example already mentioned is in Mycobactrium tuberculosis, which has evolved a complex cell wall that is resistant to the digestive enzymes of the macrophages that ingest them, and thus persists in the host, causing the chronic disease tuberculosis. This section briefly summarizes other ways in which pathogens can “outwit” immune responses. But keep in mind, although it seems as if pathogens have a will of their own, they do not. All of these evasive “strategies” arose strictly by evolution, driven by selection.

Bacteria sometimes evade immune responses because they exist in multiple strains, such as different groups of Staphylococcus aureus. S. aureus is commonly found in minor skin infections, such as boils, and some healthy people harbor it in their nose. One small group of strains of this bacterium, however, called methicillin-resistant Staphylococcus aureus, has become resistant to multiple antibiotics and is essentially untreatable. Different bacterial strains differ in the antigens on their surfaces. The immune response against one strain (antigen) does not affect the other; thus, the species survives.

Another method of immune evasion is mutation. Because viruses’ surface molecules mutate continuously, viruses like influenza change enough each year that the flu vaccine for one year may not protect against the flu common to the next. New vaccine formulations must be derived for each flu season.

Genetic recombination—the combining of gene segments from two different pathogens—is an efficient form of immune evasion. For example, the influenza virus contains gene segments that can recombine when two different viruses infect the same cell. Recombination between human and pig influenza viruses led to the 2010 H1N1 swine flu outbreak.

Pathogens can produce immunosuppressive molecules that impair immune function, and there are several different types. Viruses are especially good at evading the immune response in this way, and many types of viruses have been shown to suppress the host immune response in ways much more subtle than the wholesale destruction caused by HIV.

Innate immune responses (and early induced responses) are in many cases ineffective at completely controlling pathogen growth. However, they slow pathogen growth and allow time for the adaptive immune response to strengthen and either control or eliminate the pathogen. The innate immune system also sends signals to the cells of the adaptive immune system, guiding them in how to attack the pathogen. Thus, these are the two important arms of the immune response.

The Benefits of the Adaptive Immune Response

The specificity of the adaptive immune response—its ability to specifically recognize and make a response against a wide variety of pathogens—is its great strength. Antigens, the small chemical groups often associated with pathogens, are recognized by receptors on the surface of B and T lymphocytes. The adaptive immune response to these antigens is so versatile that it can respond to nearly any pathogen. This increase in specificity comes because the adaptive immune response has a unique way to develop as many as 10, or 100 trillion, different receptors to recognize nearly every conceivable pathogen. How could so many different types of antibodies be encoded? And what about the many specificities of T cells? There is not nearly enough DNA in a cell to have a separate gene for each specificity. The mechanism was finally worked out in the 1970s and 1980s using the new tools of molecular genetics

Primary Disease and Immunological Memory

The immune system’s first exposure to a pathogen is called a primary adaptive response. Symptoms of a first infection, called primary disease, are always relatively severe because it takes time for an initial adaptive immune response to a pathogen to become effective.

Upon re-exposure to the same pathogen, a secondary adaptive immune response is generated, which is stronger and faster that the primary response. The secondary adaptive response often eliminates a pathogen before it can cause significant tissue damage or any symptoms. Without symptoms, there is no disease, and the individual is not even aware of the infection. This secondary response is the basis of immunological memory, which protects us from getting diseases repeatedly from the same pathogen. By this mechanism, an individual’s exposure to pathogens early in life spares the person from these diseases later in life.

Self Recognition

A third important feature of the adaptive immune response is its ability to distinguish between self-antigens, those that are normally present in the body, and foreign antigens, those that might be on a potential pathogen. As T and B cells mature, there are mechanisms in place that prevent them from recognizing self-antigen, preventing a damaging immune response against the body. These mechanisms are not 100 percent effective, however, and their breakdown leads to autoimmune diseases, which will be discussed later in this chapter.

T Cell-Mediated Immune Responses

The primary cells that control the adaptive immune response are the lymphocytes, the T and B cells. T cells are particularly important, as they not only control a multitude of immune responses directly, but also control B cell immune responses in many cases as well. Thus, many of the decisions about how to attack a pathogen are made at the T cell level, and knowledge of their functional types is crucial to understanding the functioning and regulation of adaptive immune responses as a whole.

T lymphocytes recognize antigens based on a two-chain protein receptor. The most common and important of these are the alpha-beta T cell receptors (Figure).

There are two chains in the T cell receptor, and each chain consists of two domains. The variable region domain is furthest away from the T cell membrane and is so named because its amino acid sequence varies between receptors. In contrast, the constant region domain has less variation. The differences in the amino acid sequences of the variable domains are the molecular basis of the diversity of antigens the receptor can recognize. Thus, the antigen-binding site of the receptor consists of the terminal ends of both receptor chains, and the amino acid sequences of those two areas combine to determine its antigenic specificity. Each T cell produces only one type of receptor and thus is specific for a single particular antigen.

Antigens

Antigens on pathogens are usually large and complex, and consist of many antigenic determinants. An antigenic determinant(epitope) is one of the small regions within an antigen to which a receptor can bind, and antigenic determinants are limited by the size of the receptor itself. They usually consist of six or fewer amino acid residues in a protein, or one or two sugar moieties in a carbohydrate antigen. Antigenic determinants on a carbohydrate antigen are usually less diverse than on a protein antigen. Carbohydrate antigens are found on bacterial cell walls and on red blood cells (the ABO blood group antigens). Protein antigens are complex because of the variety of three-dimensional shapes that proteins can assume, and are especially important for the immune responses to viruses and worm parasites. It is the interaction of the shape of the antigen and the complementary shape of the amino acids of the antigen-binding site that accounts for the chemical basis of specificity (Figure).

Antigen Processing and Presentation

Although Figure shows T cell receptors interacting with antigenic determinants directly, the mechanism that T cells use to recognize antigens is, in reality, much more complex. T cells do not recognize free-floating or cell-bound antigens as they appear on the surface of the pathogen. They only recognize antigen on the surface of specialized cells called antigen-presenting cells. Antigens are internalized by these cells. Antigen processing is a mechanism that enzymatically cleaves the antigen into smaller pieces. The antigen fragments are then brought to the cell’s surface and associated with a specialized type of antigen-presenting protein known as a major histocompatibility complex (MHC) molecule. The MHC is the cluster of genes that encode these antigen-presenting molecules. The association of the antigen fragments with an MHC molecule on the surface of a cell is known as antigen presentationand results in the recognition of antigen by a T cell. This association of antigen and MHC occurs inside the cell, and it is the complex of the two that is brought to the surface. The peptide-binding cleft is a small indentation at the end of the MHC molecule that is furthest away from the cell membrane; it is here that the processed fragment of antigen sits. MHC molecules are capable of presenting a variety of antigens, depending on the amino acid sequence, in their peptide-binding clefts. It is the combination of the MHC molecule and the fragment of the original peptide or carbohydrate that is actually physically recognized by the T cell receptor (Figure).

Two distinct types of MHC molecules, MHC class I and MHC class II, play roles in antigen presentation. Although produced from different genes, they both have similar functions. They bring processed antigen to the surface of the cell via a transport vesicle and present the antigen to the T cell and its receptor. Antigens from different classes of pathogens, however, use different MHC classes and take different routes through the cell to get to the surface for presentation. The basic mechanism, though, is the same. Antigens are processed by digestion, are brought into the endomembrane system of the cell, and then are expressed on the surface of the antigen-presenting cell for antigen recognition by a T cell. Intracellular antigens are typical of viruses, which replicate inside the cell, and certain other intracellular parasites and bacteria. These antigens are processed in the cytosol by an enzyme complex known as the proteasome and are then brought into the endoplasmic reticulum by the transporter associated with antigen processing (TAP) system, where they interact with class I MHC molecules and are eventually transported to the cell surface by a transport vesicle.

Extracellular antigens, characteristic of many bacteria, parasites, and fungi that do not replicate inside the cell’s cytoplasm, are brought into the endomembrane system of the cell by receptor-mediated endocytosis. The resulting vesicle fuses with vesicles from the Golgi complex, which contain pre-formed MHC class II molecules. After fusion of these two vesicles and the association of antigen and MHC, the new vesicle makes its way to the cell surface.

Professional Antigen-presenting Cells

Many cell types express class I molecules for the presentation of intracellular antigens. These MHC molecules may then stimulate a cytotoxic T cell immune response, eventually destroying the cell and the pathogen within. This is especially important when it comes to the most common class of intracellular pathogens, the virus. Viruses infect nearly every tissue of the body, so all these tissues must necessarily be able to express class I MHC or no T cell response can be made.

On the other hand, class II MHC molecules are expressed only on the cells of the immune system, specifically cells that affect other arms of the immune response. Thus, these cells are called “professional” antigen-presenting cells to distinguish them from those that bear class I MHC. The three types of professional antigen presenters are macrophages, dendritic cells, and B cells (Table).

Macrophages stimulate T cells to release cytokines that enhance phagocytosis. Dendritic cells also kill pathogens by phagocytosis (see Figure), but their major function is to bring antigens to regional draining lymph nodes. The lymph nodes are the locations in which most T cell responses against pathogens of the interstitial tissues are mounted. Macrophages are found in the skin and in the lining of mucosal surfaces, such as the nasopharynx, stomach, lungs, and intestines. B cells may also present antigens to T cells, which are necessary for certain types of antibody responses, to be covered later in this chapter.

T Cell Development and Differentiation

The process of eliminating T cells that might attack the cells of one’s own body is referred to as T cell tolerance. While thymocytes are in the cortex of the thymus, they are referred to as “double negatives,” meaning that they do not bear the CD4 or CD8 molecules that you can use to follow their pathways of differentiation (Figure). In the cortex of the thymus, they are exposed to cortical epithelial cells. In a process known as positive selection, double-negative thymocytes bind to the MHC molecules they observe on the thymic epithelia, and the MHC molecules of “self” are selected. This mechanism kills many thymocytes during T cell differentiation. In fact, only two percent of the thymocytes that enter the thymus leave it as mature, functional T cells.

Later, the cells become double positives that express both CD4 and CD8 markers and move from the cortex to the junction between the cortex and medulla. It is here that negative selection takes place. In negative selection, self-antigens are brought into the thymus from other parts of the body by professional antigen-presenting cells. The T cells that bind to these self-antigens are selected for negatively and are killed by apoptosis. In summary, the only T cells left are those that can bind to MHC molecules of the body with foreign antigens presented on their binding clefts, preventing an attack on one’s own body tissues, at least under normal circumstances. Tolerance can be broken, however, by the development of an autoimmune response, to be discussed later in this chapter.

The cells that leave the thymus become single positives, expressing either CD4 or CD8, but not both (see Figure). The CD4⁺ T cells will bind to class II MHC and the CD8⁺ cells will bind to class I MHC. The discussion that follows explains the functions of these molecules and how they can be used to differentiate between the different T cell functional types.

Mechanisms of T Cell-mediated Immune Responses

Mature T cells become activated by recognizing processed foreign antigen in association with a self-MHC molecule and begin dividing rapidly by mitosis. This proliferation of T cells is called clonal expansion and is necessary to make the immune response strong enough to effectively control a pathogen. How does the body select only those T cells that are needed against a specific pathogen? Again, the specificity of a T cell is based on the amino acid sequence and the three-dimensional shape of the antigen-binding site formed by the variable regions of the two chains of the T cell receptor (Figure). Clonal selection is the process of antigen binding only to those T cells that have receptors specific to that antigen. Each T cell that is activated has a specific receptor “hard-wired” into its DNA, and all of its progeny will have identical DNA and T cell receptors, forming clones of the original T cell.

Clonal Selection and Expansion

The clonal selection theory was proposed by Frank Burnet in the 1950s. However, the term clonal selection is not a complete description of the theory, as clonal expansion goes hand in glove with the selection process. The main tenet of the theory is that a typical individual has a multitude (10¹¹) of different types of T cell clones based on their receptors. In this use, a clone is a group of lymphocytes that share the same antigen receptor. Each clone is necessarily present in the body in low numbers. Otherwise, the body would not have room for lymphocytes with so many specificities.

Only those clones of lymphocytes whose receptors are activated by the antigen are stimulated to proliferate. Keep in mind that most antigens have multiple antigenic determinants, so a T cell response to a typical antigen involves a polyclonal response. A polyclonal response is the stimulation of multiple T cell clones. Once activated, the selected clones increase in number and make many copies of each cell type, each clone with its unique receptor. By the time this process is complete, the body will have large numbers of specific lymphocytes available to fight the infection (see Figure).

The Cellular Basis of Immunological Memory

As already discussed, one of the major features of an adaptive immune response is the development of immunological memory.

During a primary adaptive immune response, both memory T cells and effector T cells are generated. Memory T cells are long-lived and can even persist for a lifetime. Memory cells are primed to act rapidly. Thus, any subsequent exposure to the pathogen will elicit a very rapid T cell response. This rapid, secondary adaptive response generates large numbers of effector T cells so fast that the pathogen is often overwhelmed before it can cause any symptoms of disease. This is what is meant by immunity to a disease. The same pattern of primary and secondary immune responses occurs in B cells and the antibody response, as will be discussed later in the chapter.

T Cell Types and their Functions

In the discussion of T cell development, you saw that mature T cells express either the CD4 marker or the CD8 marker, but not both. These markers are cell adhesion molecules that keep the T cell in close contact with the antigen-presenting cell by directly binding to the MHC molecule (to a different part of the molecule than does the antigen). Thus, T cells and antigen-presenting cells are held together in two ways: by CD4 or CD8 attaching to MHC and by the T cell receptor binding to antigen (Figure).

Although the correlation is not 100 percent, CD4-bearing T cells are associated with helper functions and CD8-bearing T cells are associated with cytotoxicity. These functional distinctions based on CD4 and CD8 markers are useful in defining the function of each type.

Helper T Cells and their Cytokines

Helper T cells (Th), bearing the CD4 molecule, function by secreting cytokines that act to enhance other immune responses. There are two classes of Th cells, and they act on different components of the immune response. These cells are not distinguished by their surface molecules but by the characteristic set of cytokines they secrete (Table).

Th1 cells are a type of helper T cell that secretes cytokines that regulate the immunological activity and development of a variety of cells, including macrophages and other types of T cells.

Th2 cells, on the other hand, are cytokine-secreting cells that act on B cells to drive their differentiation into plasma cells that make antibody. In fact, T cell help is required for antibody responses to most protein antigens, and these are called T cell-dependent antigens.

Cytotoxic T cells

Cytotoxic T cells (Tc) are T cells that kill target cells by inducing apoptosis using the same mechanism as NK cells. They either express Fas ligand, which binds to the fas molecule on the target cell, or act by using perforins and granzymes contained in their cytoplasmic granules. As was discussed earlier with NK cells, killing a virally infected cell before the virus can complete its replication cycle results in the production of no infectious particles. As more Tc cells are developed during an immune response, they overwhelm the ability of the virus to cause disease. In addition, each Tc cell can kill more than one target cell, making them especially effective. Tc cells are so important in the antiviral immune response that some speculate that this was the main reason the adaptive immune response evolved in the first place.

Regulatory T Cells

Regulatory T cells (Treg), or suppressor T cells, are the most recently discovered of the types listed here, so less is understood about them. In addition to CD4, they bear the molecules CD25 and FOXP3. Exactly how they function is still under investigation, but it is known that they suppress other T cell immune responses. This is an important feature of the immune response, because if clonal expansion during immune responses were allowed to continue uncontrolled, these responses could lead to autoimmune diseases and other medical issues.

Not only do T cells directly destroy pathogens, but they regulate nearly all other types of the adaptive immune response as well, as evidenced by the functions of the T cell types, their surface markers, the cells they work on, and the types of pathogens they work against (see Table).

Nonspecific innate immunity can be characterized as a multifaceted system of defenses that targets invading pathogens in a nonspecific manner. In this chapter, we have divided the numerous defenses that make up this system into three categories: physical defenses, chemical defenses, and cellular defenses. However, it is important to keep in mind that these defenses do not function independently, and the categories often overlap. Table 17.1 provides an overview of the nonspecific defenses discussed in this chapter.

Table 17.1

Physical defenses provide the body’s most basic form of nonspecific defense. They include physical barriers to microbes, such as the skin and mucous membranes, as well as mechanical defenses that physically remove microbes and debris from areas of the body where they might cause harm or infection. In addition, the microbiome provides a measure of physical protection against disease, as microbes of the normal microbiota compete with pathogens for nutrients and cellular binding sites necessary to cause infection.

Physical Barriers

Physical barriers play an important role in preventing microbes from reaching tissues that are susceptible to infection. At the cellular level, barriers consist of cells that are tightly joined to prevent invaders from crossing through to deeper tissue. For example, the endothelial cells that line blood vessels have very tight cell-to-cell junctions, blocking microbes from gaining access to the bloodstream. Cell junctions are generally composed of cell membrane proteins that may connect with the extracellular matrix or with complementary proteins from neighboring cells. Tissues in various parts of the body have different types of cell junctions. These include tight junctions, desmosomes, and gap junctions, as illustrated in Figure 17.2. Invading microorganisms may attempt to break down these substances chemically, using enzymes such as proteases that can cause structural damage to create a point of entry for pathogens.

Figure 17.2 There are multiple types of cell junctions in human tissue, three of which are shown here. Tight junctions rivet two adjacent cells together, preventing or limiting material exchange through the spaces between them. Desmosomes have intermediate fibers that act like shoelaces, tying two cells together, allowing small materials to pass through the resulting spaces. Gap junctions are channels between two cells that permit their communication via signals. (credit: modification of work by Mariana Ruiz Villareal)

The Skin Barrier

One of the body’s most important physical barriers is the skin barrier, which is composed of three layers of closely packed cells. The thin upper layer is called the epidermis. A second, thicker layer, called the dermis, contains hair follicles, sweat glands, nerves, and blood vessels. A layer of fatty tissue called the hypodermis lies beneath the dermis and contains blood and lymph vessels (Figure 17.3).

Figure 17.3 Human skin has three layers, the epidermis, the dermis, and the hypodermis, which provide a thick barrier between microbes outside the body and deeper tissues. Dead skin cells on the surface of the epidermis are continually shed, taking with them microbes on the skin’s surface. (credit: modification of work by National Institutes of Health)

The topmost layer of skin, the epidermis, consists of cells that are packed with keratin. These dead cells remain as a tightly connected, dense layer of protein-filled cell husks on the surface of the skin. The keratin makes the skin’s surface mechanically tough and resistant to degradation by bacterial enzymes. Fatty acids on the skin’s surface create a dry, salty, and acidic environment that inhibits the growth of some microbes and is highly resistant to breakdown by bacterial enzymes. In addition, the dead cells of the epidermis are frequently shed, along with any microbes that may be clinging to them. Shed skin cells are continually replaced with new cells from below, providing a new barrier that will soon be shed in the same way.

Infections can occur when the skin barrier is compromised or broken. A wound can serve as a point of entry for opportunistic pathogens, which can infect the skin tissue surrounding the wound and possibly spread to deeper tissues.

CASE IN POINT

Every Rose Has its Thorn

Mike, a gardener from southern California, recently noticed a small red bump on his left forearm. Initially, he did not think much of it, but soon it grew larger and then ulcerated (opened up), becoming a painful lesion that extended across a large part of his forearm (Figure 17.4). He went to an urgent care facility, where a physician asked about his occupation. When he said he was a landscaper, the physician immediately suspected a case of sporotrichosis, a type of fungal infection known as rose gardener’s disease because it often afflicts landscapers and gardening enthusiasts.

Under most conditions, fungi cannot produce skin infections in healthy individuals. Fungi grow filaments known as hyphae, which are not particularly invasive and can be easily kept at bay by the physical barriers of the skin and mucous membranes. However, small wounds in the skin, such as those caused by thorns, can provide an opening for opportunistic pathogens like Sporothrix schenkii, a soil-dwelling fungus and the causative agent of rose gardener’s disease. Once it breaches the skin barrier, S. schenkii can infect the skin and underlying tissues, producing ulcerated lesions like Mike’s. Compounding matters, other pathogens may enter the infected tissue, causing secondary bacterial infections.

Luckily, rose gardener’s disease is treatable. Mike’s physician wrote him a prescription for some antifungal drugs as well as a course of antibiotics to combat secondary bacterial infections. His lesions eventually healed, and Mike returned to work with a new appreciation for gloves and protective clothing.

Figure 17.4 Rose gardener’s disease can occur when the fungus Sporothrix schenkii breaches the skin through small cuts, such as might be inflicted by thorns. (credit left: modification of work by Elisa Self; credit right: modification of work by Centers for Disease Control and Prevention)

Mucous Membranes

The mucous membranes lining the nose, mouth, lungs, and urinary and digestive tracts provide another nonspecific barrier against potential pathogens. Mucous membranes consist of a layer of epithelial cells bound by tight junctions. The epithelial cells secrete a moist, sticky substance called mucus, which covers and protects the more fragile cell layers beneath it and traps debris and particulate matter, including microbes. Mucus secretions also contain antimicrobial peptides.

In many regions of the body, mechanical actions serve to flush mucus (along with trapped or dead microbes) out of the body or away from potential sites of infection. For example, in the respiratory system, inhalation can bring microbes, dust, mold spores, and other small airborne debris into the body. This debris becomes trapped in the mucus lining the respiratory tract, a layer known as the mucociliary blanket. The epithelial cells lining the upper parts of the respiratory tract are called ciliated epithelial cells because they have hair-like appendages known as cilia. Movement of the cilia propels debris-laden mucus out and away from the lungs. The expelled mucus is then swallowed and destroyed in the stomach, or coughed up, or sneezed out (Figure 17.5). This system of removal is often called the mucociliary escalator.

Figure 17.5 This scanning electron micrograph shows ciliated and nonciliated epithelial cells from the human trachea. The mucociliary escalator pushes mucus away from the lungs, along with any debris or microorganisms that may be trapped in the sticky mucus, and the mucus moves up to the esophagus where it can be removed by swallowing.

The mucociliary escalator is such an effective barrier to microbes that the lungs, the lowermost (and most sensitive) portion of the respiratory tract, were long considered to be a sterile environment in healthy individuals. Only recently has research suggested that healthy lungs may have a small normal microbiota. Disruption of the mucociliary escalator by the damaging effects of smoking or diseases such as cystic fibrosis can lead to increased colonization of bacteria in the lower respiratory tract and frequent infections, which highlights the importance of this physical barrier to host defenses.

Like the respiratory tract, the digestive tract is a portal of entry through which microbes enter the body, and the mucous membranes lining the digestive tract provide a nonspecific physical barrier against ingested microbes. The intestinal tract is lined with epithelial cells, interspersed with mucus-secreting goblet cells (Figure 17.6). This mucus mixes with material received from the stomach, trapping foodborne microbes and debris. The mechanical action of peristalsis, a series of muscular contractions in the digestive tract, moves the sloughed mucus and other material through the intestines, rectum, and anus, excreting the material in feces.

Figure 17.6 Goblet cells produce and secrete mucus. The arrows in this micrograph point to the mucus-secreting goblet cells (magnification 1600⨯) in the intestinal epithelium. (credit micrograph: Micrograph provided by the Regents of University of Michigan Medical School © 2012)

Endothelia

The epithelial cells lining the urogenital tract, blood vessels, lymphatic vessels, and certain other tissues are known as endothelia. These tightly packed cells provide a particularly effective frontline barrier against invaders. The endothelia of the blood-brain barrier, for example, protect the central nervous system (CNS), which consists of the brain and the spinal cord. The CNS is one of the most sensitive and important areas of the body, as microbial infection of the CNS can quickly lead to serious and often fatal inflammation. The cell junctions in the blood vessels traveling through the CNS are some of the tightest and toughest in the body, preventing any transient microbes in the bloodstream from entering the CNS. This keeps the cerebrospinal fluid that surrounds and bathes the brain and spinal cord sterile under normal conditions.

Mechanical Defenses

In addition to physical barriers that keep microbes out, the body has a number of mechanical defenses that physically remove pathogens from the body, preventing them from taking up residence. We have already discussed several examples of mechanical defenses, including the shedding of skin cells, the expulsion of mucus via the mucociliary escalator, and the excretion of feces through intestinal peristalsis. Other important examples of mechanical defenses include the flushing action of urine and tears, which both serve to carry microbes away from the body. The flushing action of urine is largely responsible for the normally sterile environment of the urinary tract, which includes the kidneys, ureters, and urinary bladder. Urine passing out of the body washes out transient microorganisms, preventing them from taking up residence. The eyes also have physical barriers and mechanical mechanisms for preventing infections. The eyelashes and eyelids prevent dust and airborne microorganisms from reaching the surface of the eye. Any microbes or debris that make it past these physical barriers may be flushed out by the mechanical action of blinking, which bathes the eye in tears, washing debris away (Figure 17.7).

Figure 17.7 Tears flush microbes away from the surface of the eye. Urine washes microbes out of the urinary tract as it passes through; as a result, the urinary system is normally sterile.

Microbiome

In various regions of the body, resident microbiota serve as an important first-line defense against invading pathogens. Through their occupation of cellular binding sites and competition for available nutrients, the resident microbiota prevent the critical early steps of pathogen attachment and proliferation required for the establishment of an infection. For example, in the vagina, members of the resident microbiota compete with opportunistic pathogens like the yeast Candida. This competition prevents infections by limiting the availability of nutrients, thus inhibiting the growth of Candida, keeping its population in check. Similar competitions occur between the microbiota and potential pathogens on the skin, in the upper respiratory tract, and in the gastrointestinal tract. As will be discussed later in this chapter, the resident microbiota also contribute to the chemical defenses of the innate nonspecific host defenses.

The importance of the normal microbiota in host defenses is highlighted by the increased susceptibility to infectious diseases when the microbiota is disrupted or eliminated. Treatment with antibiotics can significantly deplete the normal microbiota of the gastrointestinal tract, providing an advantage for pathogenic bacteria to colonize and cause diarrheal infection. In the case of diarrhea caused by Clostridium difficile, the infection can be severe and potentially lethal. One strategy for treating C. difficile infections is fecal transplantation, which involves the transfer of fecal material from a donor (screened for potential pathogens) into the intestines of the recipient patient as a method of restoring the normal microbiota and combating C. difficile infections.

Table 17.2 provides a summary of the physical defenses discussed in this section.

Table 17.2