Immunology (Lippincott Illustrated Reviews Series) 2nd Edition
Chapter 13: The Well Patient: How Innate and Adaptive Immune Responses Maintain Health
The human body is a fortress. It is always surrounded by organisms that have the potential to enter and do harm. For strategic defense, the perimeter is mined with microcidal molecules, mucous secretions, and neutralizing antibodies. Its walls and borders—the skin and mucosal membranes—comprise tightly packed cells (living and dead) that form a barrier against the entry of invaders. Despite these defenses, the barriers can be breached through cuts, abrasions, injections, and so on. Sentries posted along the borders—phagocytes, natural killer (NK) cells, and complement components—are like watchdogs that attack intruders while also raising an alarm to the rest of the immune system that an invading force has landed and must be repelled.
In the face of this incessant barrage of hostile invaders, how do we remain healthy? Cells and molecules of the immune system must be mobile to communicate with each other, to patrol the body for evidence of invasion, and to congregate in areas where they are needed. When the invading threat has been located, it must be contained and ultimately destroyed. The immune system can unleash a diverse “arsenal” of weaponry at intruders. Depending on the defensive strategies of the enemy and their ability to “return fire,” only some of the host “artillery” will be successful. By unleashing a diverse attack, however, the immune system ensures that a fatal blow is usually dealt to the enemy in one way or another.
Environmental antigens in the air we breathe and the food and liquids we ingest do not necessarily pose threats to us, even though they are nonself. We also live in symbiotic relationships with numerous commensal microbes, as long as they remain outside of our body (the lumenal surfaces of the digestive and respiratory tracts are topologically outside of the body). By necessity, some environmental molecules, such as food and drink, must enter the body through the mucosal tissues. The immune system must distinguish between friend and foe; otherwise, eating would inevitably lead to massive intestinal inflammation. That part of the immune system associated with mucosal surfaces uses various methods to prevent or dampen inflammatory responses except where pathogenic stimuli intrude.
A good defense can be made even better by advance preparation. Vaccination is an attempt to deliberately stimulate a primary immune response prior to subsequent encounter with a microorganism in order to lower the risk of injury or infection. The goal of vaccination is to ensure that subsequent encounters with potentially injurious or lethal microbes or toxins are met with secondary immune responses: neutralizing antibodies, increased antibody levels, and heightened cell-mediated responses to meet and eliminate the threat with far greater vigor and speed than would be possible in an initial exposure. Successful vaccination requires consideration of the structure and lifestyle of the threat (microbe or toxin) as well as strategies to provoke the most beneficial types of immune responses.
II. CELLULAR RECIRCULATION AND HOMING
Microbes may use stealth in an attempt to enter the body undetected. Like sentries, leukocytes continually monitor the body for these unwanted visitors. Immature dendritic cells are strategically located to serve as sentinels of the immune system. Upon perceiving a threat (see Chapter 10), dendritic cells mature and migrate to nearby lymph nodes. There, they act as messengers to convey immunologic intelligence to T and B lymphocytes. When this information is placed into the right “hands” (receptors), the lymphocytes aggressively respond and rush to the site of the threat. Leukocyte mobility is essential to instigating rapid and effective immune
Leukocytes and their products use two circulatory systems (see Chapter 7). A system of lymphatic vessels carries lymphatic fluid composed of cellular debris, live and dead microbes, and leukocytes to lymph nodes, where its contents are scrutinized by leukocytes. Leukocytes also use the cardiovascular system to carry “warrior” leukocytes to sites of invasion. Chemokines and cell adhesion molecules, expressed by endothelial cells that line the blood and lymph vessels, control leukocyte migration.
A. Adhesion molecules: The glue that binds
Adhesion molecules are grouped into several families: selectins, addressins, integrins, and immunoglobulin supergene family molecules (Table 13.1). Their cell surface expression is upregulated or downregulated depending on the nature of the stimulatory signal and serves to bind or glue cells together temporarily. One important role for adhesion molecules is to stabilize the weak interaction of pMHC molecules with TCRs, allowing the cells time to “decide” whether offensive action needs to be taken to ward off a potential threat (Fig. 13.1). Adhesion molecules also determine where and which leukocytes will migrate to a particular organ or tissue.
Adhesion molecules stabilize cell-to-cell interactions. Adhesion molecules expressed by antigen-presenting cells interact with costimulatory (e.g., CD28) or integrin (e.g., LFA-1) molecules expressed by CD4+ T cells to stabilize the otherwise week interaction between pMHC class II and the TCR.
B. Between vasculature and organs/tissues
At sites of microbial invasion, leukocytes and other cells send out distress signals by releasing cytokines or chemokines. These pro-inflammatory signals activate local cardiovascular endothelium (e.g., IL-1 and TNF-α) to express selectin molecules, increase expression of chemotaxic molecules (e.g., IL-1 and IL-8), and activate leukocytes (IL-1, IL-6, IL-8, IL-12, and TNF-α) (Fig. 13.2). All of these activities attract leukocytes to sites of infection and facilitate development of inflammation.
C. To sites of infection and inflammation
Leukocytes migrate out of the blood vessels to underlying sites of inflammation using a four-step process known as extravasation. First, endothelial cells express P-selectin (CD62P) within minutes of receiving proinflammatory signals (e.g., LTB4, C5a, or histamine). Within a few hours, the cells also express TNF-α. In addition, the presence of bacterial lipopolysaccharide (LPS) induces E-selectin (CD62E) expression by the endothelium. These adhesion molecules make contact with molecules on leukocytes, gradually slowing them down until they roll to a stop on the endothelial surface (part 1 of Fig. 13.3). The second step, called tight binding, entails interaction of leukocyte integrins such as LFA-1 (CD11a:CD18) and Mac-1 (CD11b:CD18) with TNF-α-induced ICAM-1 (CD54) expressed by endothelial cells (part 2 of Fig. 13.3). In the third step, the leukocyte crosses through the wall of the blood vessel, a process known as diapedesis (part 3 of Fig. 13.3). Finally, leukocytes migrate to the site of microbial invasion, attracted by chemokines (part 4 of Fig.13.3).
Adhesion molecules: indicators of invasion. Microbes and/or their products that enter through a breach in the dermis induce phagocytes to secrete proinflammatory cytokines, which in turn induce the expression of adhesion molecules by vascular endothelium.
Adhesion molecules: directors of leukocyte migration. Activated leukocytes migrate from the blood vessels by a four-step process known as extravasation. 1. Rolling adhesion. P- (CD62P) then E-selectin (CD62E) expressed by endothelium in response to TNF-α or to lipopolysaccharide (LPS) interacts with sialyl Lewis x on leukocytes causing them to roll along the endothelial surface. 2. Tight binding. Interaction between leukocyte integrins (e.g., LFA-1, Mac1) with endothelial ICAM-1 causes leukocytes to tightly adhere to the endothelium. 3. Diapedesis. A process in which endothelial-bound leukocytes enter tissues underlying the endothelium. 4. Migration. Leukocytes migrate to the site of microbial invasion attracted by chemokines.
III. RESPONSES TO INFECTIOUS AGENTS
The innate and adaptive immune systems provide protection against an array of infectious organisms that vary in size, method of entry into the body, tropisms, reproduction, and pathologies. Many microbes have structural features or lifestyles that enable them to evade or actively subvert the immune responses directed against them. Fortunately, the immune system has a built-in redundancy that activates several different types of responses against a particular invader. As long as at least one of these responses is effective, the infection can be eliminated or controlled.
A. Humoral responses
The innate humoral responses are preexisting and begin acting against infectious agents upon initial contact. Activation of the complement system, through either the mannan-binding lectin pathway or the alternative pathway, provides an almost immediate and highly effective barrier to microbial growth and reproduction. Not only does protection involve the direct lysis of microbial cells via assembly of the membrane attack complex, but also the generation of certain complement fragments serves to heighten the activity of other immune mechanisms. C3b and C4b act as opsonins to accelerate the phagocytic ingestion and destruction of microbes, whereas C3a, C4a, and C5a help to initiate inflammation by attracting and activating leukocytes.
With the subsequent involvement of the adaptive immune response, antibodies augment the role of complement by initiating the classical pathway. Antibodies also tag infectious agents for destruction by phagocytes (opsonization) or by natural killer cells and eosinophils (antibody-dependent cell-mediated cytotoxicity). IgE can trigger the release of inflammatory mediators by mast cells and basophils, an important element in immunologic resistance to parasitic worms. Finally, antibodies can inhibit entry of microbes into the body and into cells by neutralization. The effectiveness of humoral responses against infectious organisms varies, depending on the localization and specific structural features of each organism.
Cytosolic and endosomal localization of intracellular microbes determines the way in which microbes are processed and presented to the immune system.
B. Cell-mediated responses
Many infectious agents not only enter the body, but once inside, go on to enter individual cells. Some may be taken up by phagocytes using toll-like receptors or Fc receptors and complement receptors. However, many microbes, such as viruses and some bacteria, facilitate their own entry into host cells as part of their natural life cycle. Once inside, they are sheltered from the actions of antibodies and complement, and cell-mediated responses are required to clear the infection.
Within cells, viruses persist and reproduce in the cytosol. Most intracellular bacteria live within endosomes formed during their entry into the cells (Fig. 13.4). The cytosolic and endosomal compartment, however, are not completely isolated from one another. Extracellular viruses (and cellular debris containing viral particles) can be taken up by endosomes via phagocytosis. In addition, some intracellular bacteria can exit endosomes and enter the cytosol, as can some of their products or fragments (Fig. 13.5).
Regardless of the route taken, the localization of the infectious organism/material in the cytosolic or endosomal compartments determines the type of cell-mediated response they elicit. Infectious organisms or products in the cytosol will be processed and presented on MHC class I molecules, eliciting responses by CD8+ T cells. Infectious organisms and fragments present in endosomes (phagolysosomes) will be processed there and presented by MHC class II molecules, generating CD4+ T cell responses. The cytotoxic T-cell responses (CD8+) and delayed (-type) hypersensitivity (CD4+) responses that are generated are then capable of destroying the infected cells, disrupting the reproduction of the invasive organisms, and destroying the remaining microbes.
Some endosomal and cytosolic intracellular bacteria or their products may escape from endosomes.
C. Effective responses to pathogens
As part of the ongoing struggle between pathogen and host, infectious organisms are specialized to take advantage of specific niches in the host environment, intracellular or extracellular. They become “guerrilla fighters” within these niches, taking advantage of the local terrain and adapting their “camouflage,” “defense maneuvers,” and “weaponry” to the conditions in which they find themselves. The host immune system, in turn, must be versatile enough to detect, contain, and attack the invasive organisms wherever they have “set up camp” and to strike through the camouflages and defenses to the heart of the enemy camp. The types of immune responses that will be most effective are determined by the nature of the infectious agents (Tables 13.2 and 13.3).
1. Viruses: Resistance to viral infection begins with the innate immune system (see Chapter 5, especially Figs. 5.4 and 5.14). Virally infected cells can produce type I interferons (IFN-α and IFN-b) that induce resistance in neighboring cells. In addition, natural killer cells detect stress molecules produced by virally infected cells and can bind and kill those cells in which the infection leads to reduced expression of MHC I molecules. The participation of phagocytic cells in the destruction of microbes and infected cells and the ingestion and degradation of the resulting cellular debris lead to activation and participation of the adaptive immune response.
Immune defense against viral infection (and against infectious agents in general) has two aspects: clearance of active infections and inhibition of subsequent infections. Initial infections occur in the absence of virus-specific antibodies that can neutralize free virus and prevent infection. As a result, the body has to rely on cell-mediated responses to clear initial infections. Because viruses are localized in the cytosol, their presence within a cell is “broadcast” to the immune system by the presentation of virally derived peptides on surface MHC I (pMHC I) molecules. In addition, the death of infected cells generates cellular debris containing both host and viral material that is ingested, processed, and presented by MHC II (pMHC II) molecules on antigen-presenting cells (APCs). As a result, both CD4+ and CD8+ T cells can be generated. The CD4+ T cells are important in assisting the activation and proliferation of CD8+ T cells and in the subsequent activation of B cells, but it is the CD8+ T cells that become the primary agents for destroying the infected cells (see Chapters 10 and 11). CD4+ T cells can bind only peptides presented by the limited subset of body cells that express MHC class II molecules. However, because MHC class I molecules are expressed by all nucleated cells of the body, the display of viral peptides by MHC class I (pMHC I) molecules provides a way for CD8+ T cells to identify all virally infected cells—APC and non-APCs—in the body, with a few exceptions that we will discuss later.
Once activated, CD8+ cytotoxic T cells (CTLs) proceed to identify, bind, and kill infected cells throughout the body, destroying the nests within which the viruses are breeding. In addition to causing lysis of the infected cells, the ability of CTLs to induce the apoptotic death of infected cells leads to the destruction of nucleic acids of both host and viral origin within the infected cells. This provides an important means of stemming the spread of infectious particles from the disrupted cells. Together, the destruction of both the infected cells and their viral inhabitants results in the clearance of the initial infection.
Holly R., a 50-year-old female, presents with rhinorrhea and sore throat of 4 days’ duration. She also has malaise, headache, and dry cough associated with sneezing and nasal congestion. On examination, the patient is afebrile. Her nasal mucosa is mildly erythematous and edematous with clear watery nasal discharge. Her pharynx is normal in appearance without any erythema or exudate. Mild, nontender anterior cervical lymph nodes are palpable. Her lungs are clear, and cardiac examination is normal.
This patient has clinical symptoms and signs consistent with the common cold (upper respiratory infection) associated with rhinovirus infection. Rhinovirus binds to ICAM-1 adhesion molecules on respiratory epithelial cells to facilitate entry and infection. Because rhinovirus is an obligate intracellular (cytosolic) parasite, the body must generate cell-mediated innate (NK cells) and adaptive (CTLs) responses that destroy the infected cells to terminate viral replication. Treatments for the common cold are mainly supportive measures that include rest and drinking plenty of fluid. Medications such as decongestants, antitussives, and analgesics may be helpful in lessening the symptoms. Antibiotics are not useful in eliminating rhinovirus, although they may be useful against bacterial infections secondary to the viral infection.
Clearance of the initial infection provides the basis for protection against future infection as well. In addition to the generation of increased numbers of virus-specific CD4+ and CD8+ T cells, generation of virus-specific antibodies also occurs, although usually too late to participate in clearance of the original infection. However, the generation of neutralizing antibodies to inhibit viral infectivity is the primary means of limiting or preventing reinfection (see Chapter 11). During reexposure to a particular virus, the number of viral particles able to enter host cells is drastically reduced by neutralizing antibodies, and viruses that do succeed in entering host cells are rapidly dealt with by heightened secondary cell-mediated responses. Resistance to reinfection can be so effective that no noticeable signs or symptoms develop.
2. Bacteria: Most bacteria spend their entire existence in a fluid extracellular environment. Others spend much of their time within host cells (intracellular), although they must spend some time in an extracellular environment as they establish an initial infection or move on to infect additional cells.
a. Extracellular bacteria: Many extracellular pathogenic bacteria, including Staphylococcus, Streptococcus, Neisseria, Bordetella, and Yersinia, infect humans. These organisms, once they are within the host, are constantly exposed to humoral host defenses (complement and antibodies) as well as becoming prey for phagocytes (Fig. 13.6). These responses are usually adequate for clearance. Sometimes, however, bacteria that are normally extracellular may generate substrains that gain the ability to invade host cells. When this occurs, additional immunologic responses are needed for clearance—the same responses that are involved in the clearance of bacteria that normally enter host cells.
Extracellular bacteria. Extracellular bacteria are exposed to the actions of complement, antibodies, and phagocytes.
b. Intracellular bacteria: Pathogenic bacteria that normally invade human cells include Mycobacteria, Shigella, Salmonella, Listeria, and Rickettsia. In addition, pathogenic strains of normally extracellular bacteria such as Escherichia coli occasionally gain the ability to become intracellular pathogens. During infection, these organisms spend much of their time within host cells (usually phagocytes), where antibodies and complement can no longer have access to them. Some enter the host cell via phagocytosis but have mechanisms that allow them to escape destruction and persist within the host phagocyte (Fig. 13.7). In some cases (e.g., Legionella), fusion of the endosome with lysosomes is inhibited. In others (e.g., Mycobacterium), the microcidal environment of the phagolysosome can be inhibited by microbial actions such as modifying the pH. Other bacteria (e.g., Brucella) can direct their own entry into host cells by inducing the formation of vacuoles that are distinct from the usual phagolysosome formation pathway. Whatever the route of entry and persistence, their clearance, like that of viruses, requires adaptive cell-mediated responses. Because most intracellular bacteria live, at least initially, within intracellular endosomes, the earliest adaptive responses for clearance are often delayed (-type) hypersensitivity (DTH) responses generated by CD4+ T cells. Activation of infected macrophages by CD4+ T cells, mediated by CD40/CD154 engagement and IFN-γ, boosts their capacity to destroy internalized microbes and promotes more active and destructive phagocytic activity. The activation of macrophages carrying intracellular bacteria may also be facilitated by NK cells. IL-12, produced by phagocytes following uptake of bacteria, boosts the activity of NK cells. These activated NK cells, in turn, produce IFN-γ that can activate the infected macrophages.
Subsequently, some intracellular bacteria and/or their products may enter the cytosol. For example, Listeria and Shigella remain within endosomes for a rather short time and then escape into the cytosol. Others (e.g., Chlamydia) modify the endosomal walls to permit an exchange of molecules between the endosomal compartment and the cytosol. The presence of bacteria or bacterial products in the cytosol permits proteasomal degradation and the production of bacterially derived peptide fragments that can be loaded onto MHC class I molecules for surface presentation to CD8+ T cells and the subsequent generation of CTL responses for clearance. The generation of antibodies against intracellular bacteria, although ineffective against bacteria sequestered within host cells, can nevertheless be highly effective in the neutralization and prevention of reinfection.
Erythrocyte infection by Plasmodium falciparum. P. falciparum is visible within erythrocytes on blood smears.
3. Protozoa, fungi, and worms: Like bacteria, infectious protozoa can be either extracellular or intracellular within the host. Extracellular protozoa are susceptible to the actions of antibodies, although unlike bacteria, their antibody-mediated destruction appears to be predominantly based on opsonization and phagocytosis, with a lesser role for complement-mediated lysis.
Intracellular protozoa (e.g., Plasmodium, Toxoplasma) are cleared by the same methods that are effective for intracellular bacteria. They enter host cells by the same methods (erythrocytes and liver cells for Plasmodium and several cell types by Toxoplasma) and use a similar array of methods to persist once inside. Some of them modify the endosomes or vesicles around them to exchange materials with the cytosol or, as with Trypanosoma cruzi, to escape into the cytosol. As a result, cell-mediated immune responses by both CD4+ and CD8+ T cells can become involved in clearance.
Fungi (e.g., Candida, Histoplasma, Aspergillus) can trigger various immune responses, including the production of high levels of specific antifungal antibodies. However, antibodies appear to be ineffective in clearing fungal infections, although they can become the basis for hypersensitivity responses triggered by fungal infection. Instead, inflammatory cell-mediated DTH responses are the primary means for clearing fungal infections.
Rachel D., a 40-year-old female, presents with fever, chills, sweats, headaches, muscle pains, nausea, and vomiting persisting for several days. Physical examination reveals elevated temperature, perspiration, and tiredness. According to the patient, she had returned to the United States 2 weeks earlier after visiting Nigeria. Prior to her travel, she was prescribed with medication that could be taken to prevent the onset of malaria. However, she misunderstood the instructions and thought that the pills should be used only for treatment after developing malaria, not to prevent infection.
In addition to ordering routine blood tests, her physician examines her blood smear on a microscopic slide. It reveals several red blood cells infected with Plasmodium falciparum (Fig. 13.8). Her physician confirms that she has malaria and promptly treats her with antimalarial drugs. Active infection by P. falciparum causes a significant destruction of erythrocytes, accounting for her clinical signs. Several days after initiating treatment, her symptoms resolve and the patient recovers. Malaria causes 500 million infections and 2 million deaths per year worldwide. It is the most common infection causing illness and death in travelers.
Immune evasion. Infectious agents can employ various mechanisms to evade immune responses directed against them.
Inflammatory responses are involved in resistance to infections by flatworms (e.g., tapeworms and flukes) and roundworms (e.g., Ascaris, hookworms, filarial nematodes). IgE-mediated type I hypersensitivities and cell-mediated DTH responses create inflammation at the site of infection that may disrupt or inhibit the anchoring of these worms to tissues such as the intestinal epithelium. The binding of IgG and IgA antibodies to worm surfaces can also attract eosinophils that are capable of binding and killing some types of worms through antibody-dependent cell-mediated cytotoxicity.
D. Microbial evasion of immune responses
Infectious agents do not always meekly succumb to the host immune responses that are sent against them. As part of the spiraling “arms race” between host and pathogen, they develop mechanisms for evading, disrupting, and even destroying host immunity.
1. Evasion: Many infectious agents adopt strategies to slip by the surveillance of the host immune system (Fig. 13.9). Some, such as influenza and HIV, have inefficient DNA repair systems that permit the frequent incorporation of random mutations into their antigenic surface molecules. As a result, by the time a host generates an efficient immune response against the original influenza infection, viral variants with new coat proteins have been produced that are different enough to be unaffected by that response. In time, new responses will be generated against the new variants, but in the meantime, yet more variants will have been produced that are again different enough to escape the newly generated immune responses. This process, termed genetic drift, accounts for the frequent changes that occur in the influenza virus from one “flu season” to the next and for the high antigenic diversity that is found among HIV isolates within a single infected individual (Fig. 13.10A). Genetic drift is distinct from a second process called genetic shift, also seen in the influenza virus (Fig. 13.10B). Genetic shift occurs when influenza viruses from different species (e.g., pig and duck) infect the same cell. Under these circumstances, genetic exchange between the two types of viruses can generate new hybrid viruses with characteristics that are considerably different from those of either of the two original types. Genetic shift is usually the source of the occasional highly virulent strains of influenza that arise and cause severe illness or death in large numbers of infected hosts. Genetic drift and genetic shift are not the only means by which infectious organisms change their antigenic molecules to stay ahead of developing host responses. Bacteria such as Neisseria gonorrhoeae and protozoans such as Trypanosoma brucei carry multiple, slightly variant copies of the genes that encode their major surface antigen molecules and periodically change the gene being actively transcribed.
Genetic drift and genetic shift. A. Genetic drift results from the accumulation of small mutations in genes encoding immunogenic molecules of the microbe. B. Genetic shift results from recombination between different strains of a microbe, creating new hybrid forms that may be more virulent than the parental strains involved in the recombination.
Nick W., a 20-year-old male, presents with sore throat, cough, muscle aches, and high fever for several days. According to the patient, he has just returned to the United States after visiting his relatives in China. While in China, he spent some time at a poultry farm. Although Nick might have the typical influenza viral illness, he might have avian influenza (bird flu). Other symptoms of bird flu include pneumonia, acute respiratory distress, respiratory failure, and life-threatening complications. Exposure to and close contact with infected poultry are risk factors for becoming infected with bird flu.
Human infections with avian influenza A (H5N1) have been reported in Asia, Africa, and Europe. This viral infection can be transmitted from direct contact with infected poultry. To date, H5N1 viral infection from human to human is rare. However, there is a concern that the virus could change (e.g., via genetic shift) and that, because the human immune system has yet not been extensively exposed to the virus, a worldwide outbreak of the disease could occur in humans. Scientists around the world are closely monitoring the situation.
Some microbes are able to prevent the immune system from detecting potentially immunogenic molecules on their surfaces. Certain bacteria form polysaccharide capsules that coat other surface molecules such as LPS and peptidoglycan and resist attachment of complement components that trigger opsonization or formation of the membrane attack complex. Two additional types of evasion by stealth and camouflage are particularly interesting. Plasmodium, the protozoan that is responsible for malaria, infects erythrocytes. Being enucleated, erythrocytes express neither MHC class I nor II molecules on their surfaces. Thus, once within the erythrocyte, Plasmodium is sheltered not only from antibodies and complement, but also from the surveillance of CD4+ and CD8+ T cells. The larval and adult forms of Schistosoma, a blood fluke, are able to coat themselves with various molecules, including MHC molecules, taken from host cells, disguising themselves as host cells to elude the host immune system.
2. Disruption: Various infectious agents secrete products that interfere with the immune responses generated against them. For example, Mycobacteria can alter phagolysosomal pH levels, and Legionella can inhibit the fusion of endosomes with lysosomes. Numerous viruses (including cytomegalovirus, adenovirus, and HIV) inhibit the development of CD8+ T cell responses by using various methods to disrupt the presentation of cytosolic peptide fragments by MHC class I molecules (Fig. 13.11). In addition, some infectious organisms (e.g., some species of Neisseriae, Haemophilus, and Streptococcus, as well as Schistosoma) secrete enzymes that degrade immunoglobulins or complement components in the local environment, and some (e.g., Epstein-Barr virus) secrete mediators that inhibit the activities of local leukocytes.
3. Destruction: The ultimate act of resistance by an infectious agent against a host immune system is to destroy it. A dramatic example of this approach is HIV/AIDS (see Chapter 15). Initially infecting dendritic cells and macrophages and eventually spreading to T cells as well (especially CD4+ T cells), HIV gradually destroys these leukocytes with a particularly devastating effect on the CD4+ T cell population. As these cells, which are so critical to the initiation and maintenance of a broad range of immune responses, are lost, the affected individual becomes increasingly susceptible to various opportunistic infections that eventually become the predominant cause of death.
Inflammation is not a singular event; instead, it is the composite of multiple immune responses elicited against a particular stimulus (Fig. 13.12, also see Fig. 5.15). In a sense, it is a “battle” in which the immune system uses every weapon in its “arsenal” in the hope that at least one of them will be effective. Inflammation is characterized by four cardinal signs: swelling, redness, warmth, and pain. Each of these results from simultaneous and ongoing multiple responses. Swelling (edema or tumor ) results from changes in local vascular permeability that permits an influx of cells and fluid into the tissues. The redness (rubor ) and heat (calor ) are produced by increased blood flow to the affected area. Pain (dolor ) is the result of the release of multiple chemical mediators by mast cells, basophils, and eosinophils, some of which stimulate pain receptors.
Viral mechanisms for disruption of MHC class I presentation. Numerous viruses have developed mechanisms to evade CTL responses by disrupting the presentation of viral (and other) epitopes by MHC class I molecules. These can include interfering with the transport and loading of peptides (A, B); redirection of pMHC I (or vesicles containing pMHC I) into the cytoplasm, into lysosomes, or back into the endoplasmic reticulum (C, D, E) where they are degraded or lost; redirection of pMHC I from the surface back into lysosomes where they are degraded (F).
Inflammation. Inflammation results from the composite effects of multiple simultaneous responses by the innate and adaptive immune responses.
Among the many immune responses contributing to inflammation are the following:
• Chemoattraction and activation of neutrophils, phagocytes, and lymphocytes
• Complement activation
• Degranulation of mast cells, basophils, and eosinophils to release inflammatory mediators
• Heightened NK cell activity
• Increased body temperature
• Increased vascular permeability
• Infiltration of tissues by fluids (containing antibodies and complement) and cells (particularly phagocytes and T lymphocytes)
• Secretion of acute phase proteins
• Secretion of proinflammatory cytokines and chemokines
• Secretion of type I interferons
The presence of microbial products (e.g., lipopolysaccharide) at a site of injury and infection induces local phagocytes to release various pro-inflammatory cytokines (e.g., IL-1, IL-6, IL-8, IL-12, and TNF) that recruit additional players to the immunologic team (see Fig. 5.15 and Table 5.1 in Chapter 5). Proinflammatory cytokines such as TNF-α and IL-1 from activated phagocytes cause increased vascular permeability and stimulate increased local blood flow to the affected area. IL-6 promotes the synthesis and release of C-reactive protein (CRP) by the liver. Increasing greatly within 24 to 48 hours of infection, CRP readily binds to phosphocholine (a molecule expressed on some microbes) and acts as an opsonin. CRP is one of a set of serum proteins known as acute phase proteins that inhibit the spread of infectious organisms and also include complement components, type I interferons, fibronectin, and protease inhibitors. Some of the acute phase proteins can act on the hypothalamus to increase body temperature and produce fever, an effective means of inhibiting microbial growth. IL-12 stimulates NK cell activity, resulting in increased production of INF-γ. IL-8 is involved in recruitment of neutrophils to sites of inflammation and infection. Neutrophils are drawn to sites of inflammation and infection in large numbers, attracted by chemokines secreted by activated phagocytes (e.g., IL-8) and by anaphylatoxins (e.g., C5a, C4a, C3a). Their numbers increase rapidly during infection, and elevated neutrophil levels in the blood are evidence of infection in the body. They are the most numerous leukocytes infiltrating inflammatory sites and are major contributors to the clearance of infectious organisms and cellular debris.
Inflammation continues until the stimulus is eliminated and healing begins. Sometimes, inflammatory stimuli cannot be eliminated, and the inflammation becomes chronic. Under such circumstances, it can cause permanent damage that is the basis for some immune-mediated diseases (e.g., rheumatoid arthritis and systemic lupus erythematosus) (see Chapters 14 and 16).
Most of the actual destructive actions that occur during inflammation are carried out by elements of the innate immune response such as complement and phagocytic cells (see Chapter 5). Inflammation is an excellent example of how the innate system and adaptive immune system can work together, the adaptive system acting to focus and intensify the innate response. Antibodies, in initiating the classical pathway of complement activation, can target the resulting inflammation at specific microbes, molecules, or sites. Anaphylatoxins (C3a, C4a, C5a) resulting from complement activation can act as chemical signals promoting vascular permeability as well as attracting leukocytes to the site and activating them (see Table 5.2 in Chapter 5).
Lanny N., a 25-year-old female, presents with an erythematous, warm, indurated streak on her left lower leg associated with intermittent fever and mild pain. Several days previously, she had a bike accident and sustained mild trauma to her lower leg. Her examination is remarkable for an elevated temperature of 38°C and a warm, erythematous, edematous, and tender streak on her lower extremity consistent with cellulitis. She is treated with an intravenous antibiotic followed by a regimen of an oral antibiotic. The patient recovers without any complications.
Cellulitis is a common inflammation of the skin and subcutaneous tissue associated with bacterial invasion of disrupted skin. In normal healthy individuals, the most common bacteria involved are group A Streptococci and Staphylococcus aureus.
Similarly, elements of the innate and the adaptive systems interact in producing cell-mediated inflammation. CD4+ T cells initiate DTH responses, targeting the wrath of activated macrophages at sites that are selected because of the presence of specific stimuli. However, the innate responses that the adaptive responses unleash do not have the same degree of specificity and can inflict collateral damage on normal cells and tissues that are innocent bystanders. Likewise, antibodies attached to cells can mark them for destruction but may trigger more extensive destruction, for example, by activating complement. Activated phagocytes engage in a frenzy of destruction, killing friend and foe alike, whether activated by CD4+ T cells, by engagement of their Fc receptors with cells tagged by antibody, or by engagement of their complement receptors. In a sense, the T cells and antibody are the “spotters” provided by the adaptive system to direct the “artillery” provided by the innate system, but the “artillery rounds” do not land with absolute precision.
V. MUCOSAL IMMUNITY
Although IgA accounts for only 10% to 20% of serum immunoglobulin, it actually makes up about 60% to 70% of all of the immunoglobulin produced daily by normal, healthy individuals. Most of the IgA is secreted, via specialized epithelial cells, into the external environment at mucosal surfaces (see Chapter 6). Large amounts of IgA are associated with the vast mucosal surfaces of the gastrointestinal (GI), respiratory, lachrymal, and urogenital tracts and are also present in secretions such as tears, saliva, breast milk, and some urogenital fluids.
The part of the immune system associated with the mucosal surfaces is often thought of as a separate and independent part of the overall immune system: the mucosa-associated lymphoid tissue (MALT). The immune system functioning in nonmucosal tissues, in contrast, is sometimes referred to as the parenteral or IFN-γ MALT contains secondary lymphoid structures with lymphoid follicles that are comparable to the spleen and lymph nodes of the parenteral system. These are the tonsils of the pharynx and the Peyer’s patches of the small intestine. Despite some significant differences between the MALT and parenteral systems, they are not completely isolated from one another and can interact and influence one another. We will illustrate the nature of the mucosal immune system by examining the part of it that is associated with the GI tract more closely.
The mucosa of the GI tract contains distinct regions: the intestinal epithelium and the lamina propria (Fig. 13.13). The cells of the intestinal epithelium are not only capable of certain immune functions, but also include specialized M cells that participate in sampling antigens within the intestinal lumen and infiltrating intraepithelial lymphocytes (IELs). The lamina propria, lying below the epithelium, contains Peyer’s patches and a large collection of B and T lymphocytes, dendritic cells, macrophages, and other leukocytes.
Immune environment of the GI tract. The mucosal immune system of the GI tract lies in two zones: (1) the intestinal epithelium layer, including M cells and intraepithelial lymphocytes (IELs), and (2) the underlying lamina propria, containing phagocytes, lymphocytes, Peyer’s patches, and blood and lymphatic vessels. DC, dendritic cells; T, T cells; B, B cells; Mac macrophages; P, plasma cells.
A. Epithelial layer
The intestinal epithelial layer contains the cells that have most of the initial contact with antigens from the intestinal lumen. The epithelial cells express not only MHC class I molecules, but also MHC class II and class Ib molecules (see Chapter 6). They can ingest, process, and present molecular material from the lumen and thus act as antigen-presenting cells to the IELs scattered among them. In addition to antigen presentation, intestinal epithelial cells secrete cytokines including IL-7 that aids in the development of the IELs, and TGF-β and IL-10 that inhibit cellular inflammatory responses.
IELs have a limited variability among their T-cell receptors, and about two-thirds of them express CD8. About 10% of them are γδT cells, and the remainder are αβ T cells that for the most part have unusual phenotypes. Only a minor proportion of the αβ T cells among the IELs are “typical”; most have unusual or atypical characteristics. These include αβ T cells with CD8 molecules composed of two α chains instead of an α and a b (TCRαβ:CD8αα), and NKT cells that express both T-cell receptors (TCRαβ) and NK cell receptors (NKG2D). Each of these atypical types of T cells appears to have a distinct function (Fig. 13.14) but jointly contribute to the removal of infected cells and initiate healing. In many cases, the information comes largely from experimental animal models (usually the mouse). Where known, the equivalent human genes or molecules are given.
• Some T cells (with either αβ or γδTCRs) that express CD8αα recognize TL (human equivalent not yet identified), a stress molecule that appears on various cell types when they are injured or infected. Binding to TL increases their cytokine production but not their cytotoxic activity.
• αβTCR:CD8αα T cells can also recognize Qa-2 stress molecules (the human equivalent is HLA-G) expressed on injured or infected host cells. αβTCR:CD8αα T cells can kill the Qa-2 expressing cells to which they bind.
• βδTCR:CD8αβ cells appear to recognize and bind fragments of glycolipids or lipopolysaccharides presented by CD1d (same terminology in humans and mice), an MHC class Ib molecule involved in presentation of nonpeptide molecular fragments by various APCs, including intestinal epithelium.
• NKT cells use their NKG2D (same terminology in humans and mice) receptors to recognize stress molecules such as MICA and MICB (same terminology in humans and mice) on injured or infected cells and proceed to kill them if they are also expressing subnormal levels of MHC class I molecules. NKT cells among the IELs begin to secrete IL-4 and other cytokines following this activity.
The IELs act at the epithelial border to eliminate injured and infected cells, contributing to the healing of the intestinal epithelium. The IL-4, TGF-β, and IL-10 produced by NKT cells and intestinal epithelial cells create an environment at the epithelial surface that is inhibitory to development of inflammatory cell-mediated immune responses.
The scattered microfold or M cells of the intestinal epithelium are derived from cells that migrate from the crypts of the small intestine. They are located over Peyer’s patches and are irregularly shaped, with tunnels or passageways that allow lymphocytes and dendritic cells from the underlying lamina propria to work their way closer to the luminal surfaces of the M cells (see Fig. 13.13). M cells endocytose material from the intestinal lumen and transport it to their nonlumenal surfaces, where awaiting lymphocytes and dendritic cells can access it. There is some disagreement as to whether M cells can process and present the antigens that they transport, but the dendritic cells that take up the transported antigens from the M cells are highly active in doing so.
Intraepithelial lymphocytes (IELs). The IELs include several types of lymphocytes that recognize various molecules expressed by infected or injured epithelial cells or that recognize nonprotein epitopes presented by MHC class Ib molecules on the epithelial cell surfaces.
B. Lamina propria
In contrast with the epithelial layer, the lamina propria appears to be an oasis of normalcy, containing conventional αβ T cells (mostly CD4+), B cells, plasma cells, and phagocytes (see Fig. 13.13). The antigen-presenting cells, particularly the dendritic cells, ingest material transported by M cells, then process and present it to T cells. Dendritic cells in the lamina propria can also extend branches between epithelial cells into the lumen and directly sample the luminal contents. Also in the lamina propria and beneath the M cells are the Peyer’s patches, where antigen-presenting cells, T cells, and B cells are exposed to antigen and interact with one another (Fig. 13.15).
Dendritic cells migrate from the lamina propria to local lymph nodes (usually mesenteric), where they can activate T cells. Although the mechanisms are not understood, it appears that these antigen-presenting cells instruct the T cells as to where they migrated from and induce a significant number of the newly activated T cells to home back to the lamina propria. Activated T cells, together with antigen carried by antigen-presenting cells, can participate in the activation of B cells in the Peyer’s patches and in the local mesenteric lymph nodes. Like the T cells, the activated B cells and plasma cells can pass through the parenteral circulation before preferentially homing back to the lamina propria. B cells passing through Peyer’s patches become committed primarily to production of IgA, and IgA-expressing plasma cells move to the crypts between villi, where they secrete dimeric IgA that is then transported through the specialized epithelial cells in the crypts into the mucus overlying the intestinal epithelium.
Lamina propria and Peyer’s patches. Peyer’s patches are collections of lymphoid tissues with follicular structures reminiscent of lymph nodes. B cells, T cells, and antigen-presenting cells circulate through and interact with Peyer’s patches. Upon exiting, they may remain in the lamina propria or enter the vascular or lymphatic systems for recirculation. Plasma cells in the lamina propria cluster near the crypt areas between villi, where the antibodies they secrete (mostly secretory IgA) are transported into the mucus coating the lumenal surface of the intestinal epithelium.
C. Mechanisms of mucosal immunity
Like other sites in the body, the mucosal immune system uses adhesion molecules and chemotactic molecules to aid in the movement of cells to the lamina propria and intestinal epithelium. For example, T cells migrate to mucosal tissues by using L-selectin and α4β7 integrin (LPAM-1) to detect MadCam-1 on vascular endothelium within MALT. The binding to MadCam-1 facilitates extravasation of the T cells into the mucosal tissues. Once in the mucosal tissues of the GI tract, the T cells use CCR9 and CCR10 chemokine receptors to detect chemotactic molecules CCL25 and CCL28 produced by the epithelium of the small and large intestine, respectively, and then use αEβ7 integrin (HML-1) to detect and bind E-cadherin on the vascular epithelium of the small intestine. T and B cells activated within the mucosal environment, even though they may recirculate through the body, tend to eventually return to mucosal tissues.
Immunologic comparison of the intestinal mucosal environment and the parenteral or peripheral environment. The peripheral immune system initially makes contact with nonself via phagocytic cells that secrete cytokines promoting a Th1-like environment. The mucosal (in this case, the GI tract) immune system initially makes contact with nonself via intestinal epithelial cells and IELs that secrete cytokines promoting a Th2-like environment.
The mucosal environment is normally a noninflammatory one. Mechanisms have evolved to prevent the eruption of inflammatory responses, particularly cell-mediated ones. Inflammatory responses would be counterproductive in, for example, the intestinal environment, where the mucosal immune system is continually exposed to massive amounts of foreign antigens derived from food and drink. To respond vigorously to all of these nonself-materials on a constant basis would create an essentially permanent state of intense chronic inflammation that would likely damage and destroy the intestinal linings. Thus, the presence of a noninflammatory “Th2-like” environment, as evidenced by the predominance of IgA over IgG and the preferential secretion of cytokines such as IL-4, IL-10, and TGF-β, contrasts with the parenteral (or peripheral) immune system by creating a setting in which tolerance to foreign antigens is the norm rather than the exception (Fig. 13.16).
Although the mucosal and parenteral systems appear to operate somewhat separately, they are not isolated from one another. Cells circulate from one into the other and back again. It has been thought that the tendency to induce tolerance within the mucosal tissues could be exploited to induce a similar tolerance in the parenteral tissue. Thus, for example, an antigen that would normally be antigenic in the parenteral tissues could be administered orally so that the initial introduction to the body’s immune system is via the mucosal route, an approach termed induction of oral tolerance. The tolerance that is induced initially in the mucosal tissues might then influence the parenteral system to become tolerant as well. This approach has frequently been successful in experimental models, but its clinical application is still limited.
It was recognized long ago that individuals who survived smallpox, plague, and cholera rarely contracted the disease again, even when surrounded by others suffering from that particular disease. Early forms of vaccinations developed as attempts to confer protection from these fortunate survivors to those who still faced the risk of severe illness or death. Among ancient cultures, the Egyptians and Chinese exposed individuals to powders formed from the crusts and scales of pockmarks taken from individuals recovering from smallpox (Variola major virus). Sometimes individuals who were treated in this way developed mild forms of the disease; on many occasions, they developed no apparent disease at all. Edward Jenner demonstrated in 1794 that intentional inoculation with material from individuals with cowpox (Variola minor, a related virus that normally infects cattle, but only causes mild disease in humans) protected against smallpox (caused by a more virulent type of Vaccinia virus). Jenner and his contemporaries, of course, did not know of microbes and their roles in disease. The subsequent work of Robert Koch and Louis Pasteur established that specific microbes caused specific diseases and broadened the development of effective vaccines against epidemic diseases of agricultural animals and eventually of humans. The expanded use of vaccination led to an enormous improvement in human and animal health. For both children and adults, many of the most fearful diseases throughout human history have been practically eliminated in many parts of the world. The ability to vaccinate early in life has dramatically reduced the burden of illness, crippling, and death that was once a routine part of childhood, resulting from diseases such as diphtheria, polio, and measles. Figure 13.17 presents the standard vaccination schedule in the United States recommended by the Centers for Disease Control and Prevention (CDC) at the time of writing. (These recommendations are updated regularly, and the CDC’s web site should be consulted to obtain the most recent recommendations.)
Childhood immunization schedule. The chart indicates the childhood vaccination schedule recommended by the Centers for Disease Control and Prevention (CDC). The arrows indicate the time points or time ranges when initial vaccinations and boosters should be administered. These recommendations are periodically reviewed and updated, and readers should consult the CDC’s web site to see the most up-to-date recommendations. DPT 5 diphtheria pertussis tetanus.
Vaccination can provide excellent protection to a population, even if not every individual in a population is vaccinated, because of a phenomenon known as herd immunity. As the fraction of the population that is vaccinated increases, the chances of an infectious agent “finding” an unprotected individual becomes increasingly smaller, leaving the population resistant as a whole. There are limits to herd immunity, however. If a significant number of unprotected individuals become infected, the infection could spread rapidly through the unprotected members of the population. In the course of that rapid replication, new mutant forms might arise that could evade the immune response and produce disease in vaccinated individuals as well.
A. Characteristics of vaccines
Vaccines must fulfill several criteria to be effective in protecting large numbers of individuals:
• Effective protection against the intended pathogen must occur without significant danger of actually causing the disease or of producing severe side effects.
• The protection that is provided must be long lasting.
• The vaccine must induce the immune responses (e.g., CTLs) that are most effective against the intended pathogen across a broad range of individuals.
• Neutralizing antibodies must be stimulated in order to minimize reinfection.
• The vaccine must be economically feasible to produce.
• The vaccine must be suitably stable for storage, transport, and use.
B. Types of vaccines
Vaccines can be prepared from various materials derived from pathogenic organisms.
• Live vaccines are based on living organisms capable of normal infection and replication. Such vaccines are not appropriate for pathogens that are capable of causing severe or life-threatening diseases.
• Attenuated vaccines are based on organisms that are living but have had their virulence and ability to replicate reduced by treatment with heat, chemicals, or other techniques. Attenuated vaccines typically cause only subclinical or mild forms of the disease at worst, but they do carry the possibility that mutation might enable the organisms in the vaccine preparations to revert to wild type.
• Killed vaccines include organisms that are dead because of treatment with physical or chemical agents. In the case of toxins, they will have been inactivated (toxoids). They should be incapable of infection, replication, or function but still able to provoke immunity. It must be understood, however, that it might be difficult to guarantee that every organism in a preparation is dead.
• Extract vaccines do not contain whole organisms but are composed of materials isolated from disrupted and lysed organisms but not whole organisms. These vaccines are most suitable for providing protection against organisms so virulent that even killed vaccines pose a risk because a few organisms may have survived the killing treatment. Anthrax vaccine is an example.
• Recombinant vaccines have been made possible by molecular biology techniques that allow creation of organisms from which the removal of certain genes impairs their virulence and/or reproduction. Such organisms can infect host cells and perhaps even proliferate but cannot induce disease.
• DNA vaccines are those in which the host is injected with naked DNA extracted from a pathogen. The DNA is also often engineered to remove some of the genes that are critical to development of the disease. The objective is for host cells to take up the naked DNA and express the gene products from the pathogen. DNA vaccine stimulus typically lasts longer than other methods in which the vaccine is rapidly eliminated from the host.
As a rule, live vaccines are best at generating immune responses, followed by attenuated vaccines, and then by killed vaccines and extracts. Replicating organisms produce the molecules that stimulate the immune responses, but killed and extract vaccines might contain few or none of those molecules. Thus, paradoxically, the safety of a vaccine may be inversely proportional to its effectiveness. The coadministration of adjuvants can heighten the effectiveness of many vaccines.
Although vaccination now provides protection against many dangerous infectious diseases, many diseases still lack effective vaccines (e.g., HIV/AIDS and malaria). The ability to hide within cells, to camouflage themselves, to rapidly change their antigenic makeup, or to disrupt the generation of effective responses allows some of these organisms to defeat attempts to develop effective vaccines.
Poliomyelitis is an acute illness involving destruction of the lower motor neurons of the spinal cord and brain stem by poliovirus, an enteric pathogen. In countries with low immunization rates, poliomyelitis continues to occur. In the United States, no case of paralytic poliomyelitis caused by wild-type poliovirus has occurred in over 20 years. There are, however, a few reported cases of polio that occur (fewer than 10 per year) because of reversion to wild-type virulence of virus in the live-attenuated Sabin polio vaccine.
Vaccination is an effective method of preventing poliomyelitis. Both killed poliovirus (Salk) vaccine and attenuated live oral poliovirus (Sabin) vaccine have shown efficacy in preventing poliomyelitis.
Both vaccines have advantages and disadvantages. The advantage of the vaccine is that it can be safely used in immunocompromised individuals; the primary disadvantage is that it is administrated by injection only, and therefore less immunity occurs in the gastrointestinal tract. The advantages of the attenuated live poliovirus vaccine include oral administration, lifelong protection, and intestinal immunity. The main disadvantage of the live virus vaccine is the small risk of polio infection because of rare incidences of reversion to normal virulence. Therefore, the current recommendation is exclusive use of inactivated poliovirus vaccine.
Adjuvants are bacterial components or other substances, typically suspended in a medium such as oil that prolongs their dispersal into the tissues, administered together with vaccines to heighten the effectiveness of the vaccination. The bacterial (or other) material provokes a mild inflammation that attracts phagocytes and accelerates their activation and antigen presentation to T cells for development of specific adaptive immune responses. Some vaccine components themselves can serve as adjuvants. The pertussis component (from Bordetella pertussis) in DTP (Diphtheria-Tetanus-Pertussis) vaccine is also an effective adjuvant. Other adjuvants include alum and BCG (Bacillus Calmette-Guérin). BCG includes material derived from Mycobacterium and is in wide use around the world as a vaccine against tuberculosis, particularly in areas of high incidence. Its use has declined in some areas where the incidence of tuberculosis has significantly declined. In the United States (and several other countries), BCG is not used routinely for human vaccinations because it interferes with the use of skin testing (creating false positives) in tuberculosis studies and because of adverse reactions (e.g., disseminated BCG infection). However, BCG is still used in the United States for certain high-risk individuals or populations.
• The innate and adaptive immune systems provide protection against an array of infectious organisms that vary in size, method of entry into the body, tropisms, reproduction, and pathologies.
• Complement is part of the innate immune system and begins resisting infectious agents upon initial contact. With the subsequent involvement of the adaptive immune response, antibodies augment the role of complement by initiating the classical pathway.
• Leukocyte mobility is the key to the immune system’s ability to monitor the body for infection and to mount responses where necessary.
• Adhesion molecules stabilize cellular interactions and facilitate interactions between more specialized binding structures (e.g., TCR with pMHC).
• The expression of certain molecules on activated vascular endothelium in areas of inflammation serves to attract leukocytes to the sites of infection.
• At inflammatory sites, leukocytes can leave the vasculature and enter the tissues through a process called extravasation.
• Immune defense against infectious agents has two aspects: clearance of active infections and inhibition of subsequent infections. The most effective method of clearance depends on the localization of the agent within the body or cells. Most resistance to reinfection is provided by neutralizing antibodies.
• Many infectious agents (e.g., Mycobacteria, Shigella, Salmonella, Listeria, and Rickettsia) enter the body and then enter individual cells. Some microbes initiate their entry into host cells as part of their natural life cycle. Microbes are also taken up by phagocytes using toll-like receptors or Fc receptors and complement receptors.
• Intracellular microbes (or their products) that are in the cytosol generate CTL responses that are effective in clearing infections. Intracellular microbes within endosomes generate DTH responses responsible for clearance. Some microbes (or their products) can exist in both intracellular sites and trigger both CTL and DTH responses.
• Many extracellular pathogenic bacteria (e.g., Staphylococcus, Streptococcus, Neisseria, Bordetella, and Yersinia) infect humans but do not enter host cells. They remain in the body fluids, where they are available to antibodies, complements, and phagocytes.
• Like bacteria, infectious protozoa can be either extracellular or intracellular within the host. Immune responses responsible for clearance of each type are similar to those for extracellular and intracellular bacteria.
• Fungi (e.g., Candida, Histoplasma, Aspergillus) can trigger various immune responses, including the production of high levels of specific antifungal antibodies. However, DTH is the response that is generally responsible for clearance of fungal infections.
• Inflammatory responses are involved in resistance to infections by flatworms (e.g., tapeworms, flukes) and roundworms (e.g., Ascaris, hookworms, filarial nematodes).
• Genetic drift occurs when random mutations in genes encoding microbial antigens create new minor variants that are sufficiently different to escape previously generated immune responses. Genetic shift occurs when microbes (e.g., influenza virus) from different species (e.g., pig, duck) infect the same cell, recombine, and produce large changes in antigenic molecules.
• Some microbes are able to prevent the immune system from detecting potentially immunogenic molecules on their surfaces. Various infectious agents secrete products that interfere with the immune responses generated against them.
• Inflammation is characterized by four cardinal signs: swelling, redness, warmth, and pain.
• Mucosa-associated lymphoid tissue, which is part of the immune system associated with the mucosal surfaces, is often thought of as partly separate and independent from the remainder of the immune system.
• The ability to vaccinate early in life has dramatically reduced the burden of illness, crippling, and death that was once a routine part of childhood, resulting from diseases such as diphtheria, polio, and measles.
• Adjuvants are bacterial components or other substances, typically suspended in a medium such as oil that prolongs their dispersal into the tissues, administered together with vaccines to heighten the effectiveness of the vaccination.
13.1. A previously healthy 8-month-old girl with fever and wheezing is diagnosed with respiratory syncytial virus (RSV) infection. Assuming that this is the child’s first exposure to RSV, which of the following mechanisms will most likely operate to clear the infection?
A. CD4+ T cell-mediated necrosis of infected cells
B. Complement-mediated lysis of infected cells
C. Cytotoxic T cell–induced apoptosis of infected cells
D. MHC I presentation of viral peptides on CD8+ T cells
E. Virus-specific antibodies that neutralize free virus
The answer is C. Clearance of viral infections involves destruction of infected cells by cytotoxic T cells to prevent viral replication. CD4+ T cell responses against infected cells are typically effective when the infectious agent is residing within intracellular endosomes. Complement is not effective against intracellular microbes, and sufficient levels of antibodies against the microbes are usually not yet present during primary infections. MHC presentation of viral peptides occurs on APCs, not on CD8+ T cells.
13.2. In a patient with a Salmonella infection, which of the following mechanisms will most likely be the earliest adaptive response for clearing the infection while bacteria are present within intracellular endosomes?
A. Antibody-mediated neutralization of free bacteria
B. Complement-mediated lysis of infected host cells
C. CTL recognition of bacterial peptides presented by MHC II
D. DTH responses generated by CD4+ T cells
E. Type I hypersensitivity mediated by IgE antibodies
The correct answer is D. DTH responses are generally the first effective responses involved in clearance of intraendosomal microbes. Later in such infections, the microbes or their molecules may escape into the cytoplasm, making it possible for CTL responses to develop. Complement does not clear active intracellular infections. Antibodies may be effective in inhibiting reinfection but do not clear active intracellular infections.
13.3. A 25-year-old man is exposed to the roundworm Ascaris but does not develop clinical signs of infection. Which of the following mechanisms is likely to be responsible for his resistance to infection?
A. Antibody-mediated destruction of worm-infected host cells
B. CTL-induced apoptosis of worm-infected host cells
C. Complement-mediated lysis of worm attached to host tissues
D. IgE-mediated type I hypersensitivity disrupting worm attachment
E. Phagocytosis of worms followed by necrosis of phagocytes
The correct answer is D. Local inflammatory responses, such as that induced by IgE, can inhibit attachment of roundworms to the intestinal wall. Ascaris is a large worm (adults reach 12 to 20 inches in length) and is not damaged by antibodies directed at it or by complement, CTLs, or phagocytes.
13.4. Despite having recovered fully from influenza the previous winter, a 56-year-old man becomes ill after being exposed to a colleague with influenza virus. Which of the following mechanisms permits his reinfection despite previous exposure to influenza virus?
A. Neutralizing antibodies against influenza disappear rapidly.
B. Insufficient time has passed for CD4+ T cells to develop memory.
C. Intracellular viral particles escape immune surveillance.
D. Type 1 hypersensitivity responses occur on second exposure to influenza.
E. Viral variants evade the immune response against the original virus.
The correct answer is E. The immunogenic antigens on the surface of influenza virus can change as a result of mutation or recombination so that new influenza viruses arise that might not be recognized by the immune responses generated against previous exposures. Neutralizing antibody levels (especially IgG) remain elevated for a long period. The time interval described is also certainly sufficient for the development of immunologic memory. Intracellular viruses do not escape notice by the immune system, as fragments of their proteins are presented by MHC class I molecules on the surface of the infected cell. IgE-mediated type I (immediate) hypersensitivity responses are not generally associated with viral responses.
13.5. A 35-year-old woman left the United States for the first time and traveled to Brazil, where she contracted malaria, a protozoan infection of erythrocytes. Which of the following describes the state of immunity resulting from this infection?
A. Antibody-mediated neutralization of the protozoa clears the infection.
B. CTL-induced apoptosis of infected erythrocytes clears the infection.
C. Complement-mediated lysis of infected erythrocytes clears the infection.
D. DTH mediated by CD4+ T cells clears the infection.
E. Host immunity is evaded by protozoa reproducing within erythrocytes.
The correct answer is E. Plasmodium, the protozoan causing malaria, evades the host immune system by living and reproducing within erythrocytes. Once inside the cell, the protozoa are sheltered from antibodies and complement. In addition, the absence of surface MHC I and II on the enucleated erythrocytes prevents presentation of microbial peptides, so the infected erythrocytes are not recognized by T cells. Neutralizing antibodies may reduce future infections, but are not responsible for clearance. Clearance by CTLs, complement, or DTH does not occur, for the reasons stated previously.
13.6. In response to the lipopolysaccharide from a gram-negative bacterial infection, local host phagocytes release proinflammatory cytokines, including IL-6, which then stimulates hepatic synthesis and release of
A. C-reactive protein.
The correct answer is A. IL-6 induces production of C-reactive protein by the liver. It does not induce the liver to produce chemokines, complement, immunoglobulins, or interleukins.
13.7. Which of the following is the predominant immunoglobulin isotype secreted in the human MALT?
The correct answer is A. Most of the antibody generated in the human MALT (mucosa-associated lymphoid tissues) is of the IgA isotype. IgE, IgG, and IgM are present, but at far lower levels, and IgD is essentially absent.
13.8. Which of the following is characteristic of the mucosal immune system?
A. A vigorous response is made to all nonself-antigens encountered.
B. Chronic inflammation makes an inhospitable environment for microbes.
C. IL-2 and IFN-γ contribute to a Th1-like environment.
D. Secretion of IgG predominates over secretion of IgA.
E. Tolerance to foreign antigens is the norm rather than the exception.
The correct answer is E. Because the mucosal immune system is constantly exposed to so many nonself-epitopes that are essentially harmless, it is tolerant to most of them. Although it can respond to microbes that pose a pathogenic threat, the mucosal system generally avoids the development of chronic inflammation because of the damage that could be inflicted on the delicate mucosal linings. The immunologic environment is generally described as more Th2-like than Th1-like. IgG is present at far lower levels than is IgA.
13.9. A 14-month-old boy who has not received any recommended vaccines remains healthy despite his daily association with several other children for the past year at a home day care facility. Which of the following mechanisms best explains why he has not contracted diphtheria, measles, pertussis, or polio?
A. Herd immunity
B. Genetic drift
C. Genetic shift
D. Immune evasion
The correct answer is A. It is likely that most or all of the other children at the day care facility have been vaccinated; thus the infant in question is less likely to be exposed to diphtheria, measles, pertussis, or polio. The remaining choices are all mechanisms by which microbes evade immune responses and would be more likely to increase the risk of infection in both the unvaccinated and vaccinated children.
13.10. Which of the following types of vaccines would most likely evoke the best and most long-lasting protective immune response against rubeola (measles)?
A. Attenuated vaccine
B. DNA vaccine
C. Extract vaccine
D. Killed vaccine
E. Recombinant vaccine
The correct answer is A. The attenuated vaccine, in which the organism is still capable of some degree of infection and reproduction, is likely to produce a stronger immune response than are the other types of vaccines, in which the virus is incapable of doing so. In general, the safer the vaccine (in terms of risk of reversion to a virulent wild type), the less effective it is (in terms of offering protection).