8536d_ch01_001-0238/1/02 4: 25 PM Page 1 mac79 Mac 79: 45_BW: Goldsby et al./ Immunology 5e Overview of the chapter 1 Immune system HE IMMUNE SYSTEM IS A REMARKABLY VERSATILE defense system that has evolved to protect animals from invading pathogenic microorganisms and cancer. It is able to generate an enormous variety of cells and molecules capable of specifically recognizing and eliminat ing an apparently limitless variety of foreign invaders. These cells and molecules act together in a dynamic network whose complexity rivals that of the nervous system Functionally, an immune response can be divided into two related activities-recognition and response. Immune Numerous T Lymphocytes Interacting with a Single Macrophage recognition is remarkable for its specificity. The immune system is able to recognize subtle chemical differences that distinguish one foreign pathogen from another. Further- a Historical Perspective more, the system is able to discriminate between foreign molecules and the body's own cells and proteins. Once a for s Innate Immunity ign organism has been recognized, the immune system a Adaptive Immunity recruits a variety of cells and molecules to mount an appro- priate response, called an effector response, to eliminate or s Comparative Immunity neutralize the organism. In this way the system is able to Immune Dysfunction and Its Consequences convert the initial recognition event into a variety of effector responses, each uniquely suited for eliminating a particular type of pathogen. Later exposure to the same foreign organ ism induces a memory response, characterized by a more rapid and heightened immune reaction that serves to elimi Like the later chapters covering basic topics in immu nate the pathogen and prevent disease nology, this one includes a section called"Clinical Focus This chapter introduces the study of immunology from that describes human disease and its relation to immu in historical perspective and presents a broad overview of These sections investigate the causes, consequences,or treat the cells and molecules that compose the immune system, ments of diseases rooted in impaired or hyperactive immune along with the mechanisms they use to protect the body function against foreign invaders. Evidence for the presence of very simple immune systems in certain invertebrate organisms then gives an evolutionary perspective on the mammalian Historical Perspective immune system, which is the major subject of this book. El ements of the primitive immune system persist in verte- The discipline of immunology grew out of the observation brates as innate immunity along with a more highly evolved that individuals who had recovered from certain infectious system of specific responses termed adaptive immunity. diseases were thereafter protected from the disease. The These two systems work in concert to provide a high degree Latin term immunis, meaning"exempt, "is the source of the of protection for vertebrate species. Finally, in some circum- English word immunity, meaning the state of protection stances, the immune system fails to act as protector because from infectious disease of some deficiency in its components; at other times, it be Perhaps the earliest written reference to the phenomenon comes an aggressor and turns its awesome powers against its of immunity can be traced back to Thucydides, the great his- own host. In this introductory chapter, our description of torian of the Peloponnesian War. In describing a plague in immunity is simplified to reveal the essential structures and Athens, he wrote in 430 BC that only those who had recov- function of the immune system. Substantive discussions, ex- ered from the plague could nurse the sick because the perimental approaches, and in-depth definitions are left to would not contract the disease a second time. Although early the chapters that follow societies recognized the phenomenon of immunity, almost
chapter 1 ■ Historical Perspective ■ Innate Immunity ■ Adaptive Immunity ■ Comparative Immunity ■ Immune Dysfunction and Its Consequences Numerous T Lymphocytes Interacting with a Single Macrophage Overview of the Immune System T defense system that has evolved to protect animals from invading pathogenic microorganisms and cancer. It is able to generate an enormous variety of cells and molecules capable of specifically recognizing and eliminating an apparently limitless variety of foreign invaders. These cells and molecules act together in a dynamic network whose complexity rivals that of the nervous system. Functionally, an immune response can be divided into two related activities—recognition and response. Immune recognition is remarkable for its specificity. The immune system is able to recognize subtle chemical differences that distinguish one foreign pathogen from another. Furthermore, the system is able to discriminate between foreign molecules and the body’s own cells and proteins. Once a foreign organism has been recognized, the immune system recruits a variety of cells and molecules to mount an appropriate response, called an effector response, to eliminate or neutralize the organism. In this way the system is able to convert the initial recognition event into a variety of effector responses, each uniquely suited for eliminating a particular type of pathogen. Later exposure to the same foreign organism induces a memory response, characterized by a more rapid and heightened immune reaction that serves to eliminate the pathogen and prevent disease. This chapter introduces the study of immunology from an historical perspective and presents a broad overview of the cells and molecules that compose the immune system, along with the mechanisms they use to protect the body against foreign invaders. Evidence for the presence of very simple immune systems in certain invertebrate organisms then gives an evolutionary perspective on the mammalian immune system, which is the major subject of this book. Elements of the primitive immune system persist in vertebrates as innate immunity along with a more highly evolved system of specific responses termed adaptive immunity. These two systems work in concert to provide a high degree of protection for vertebrate species. Finally, in some circumstances, the immune system fails to act as protector because of some deficiency in its components; at other times, it becomes an aggressor and turns its awesome powers against its own host. In this introductory chapter, our description of immunity is simplified to reveal the essential structures and function of the immune system. Substantive discussions, experimental approaches, and in-depth definitions are left to the chapters that follow. Like the later chapters covering basic topics in immunology, this one includes a section called “Clinical Focus” that describes human disease and its relation to immunity. These sections investigate the causes, consequences, or treatments of diseases rooted in impaired or hyperactive immune function. Historical Perspective The discipline of immunology grew out of the observation that individuals who had recovered from certain infectious diseases were thereafter protected from the disease. The Latin term immunis, meaning “exempt,” is the source of the English word immunity, meaning the state of protection from infectious disease. Perhaps the earliest written reference to the phenomenon of immunity can be traced back to Thucydides, the great historian of the Peloponnesian War. In describing a plague in Athens, he wrote in 430 BC that only those who had recovered from the plague could nurse the sick because they would not contract the disease a second time. Although early societies recognized the phenomenon of immunity, almost 8536d_ch01_001-023 8/1/02 4:25 PM Page 1 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
8536d_ch01_001-0238/1/02 4: 25 PM Page 2 mac79 Mac 79: 45_BW: Goldsby et al./ Immunology 5e two thousand years passed before the concept was success- fully converted into medically effective practice The first recorded attempts to induce immunity deliber- ately were performed by the Chinese and Turks in the fif- teenth century. Various reports suggest that the dried crusts derived from smallpox pustules were either inhaled into the nostrils or inserted into small cuts in the skin(a technique called variolation). In 1718, Lady Mary Wortley Montagu, the wife of the British ambassador to Constantinople, observed the positive effects of variolation on the native population and had the technique performed on her own children. The method was significantly improved by the English physician Edward Jenner, in 1798. Intrigued by the fact that milkmaids who had contracted the mild disease cowpox were subse quently immune to smallpox, which is a disfiguring and of- ten fatal disease, Jenner reasoned that introducing fluid from a cowpox pustule into people(i.e, inoculating them)might protect them from smallpox. To test this idea, he inoculated an eight-year-old boy with fluid from a cowpox pustule and later intentionally infected the child with smallpox. As pre lenner's technique of inoculating with cowpox to protect agal. for n knowledge of their causes, it was nearly a hun- against smallpox spread quickly throughout Europe. How- dred years before this technique was applied to other dis- ppens In sclence, ser ombination with astute observation led to the next major advance in immunology, the induction of immunity FICURE 1-1 Wood engraving of Louis Pasteur watching Joseph cholera. Louis Pasteur had succeeded in growing the bac- Meister receive the rabies vaccine. [From Harper's Weekly 29:836 terium thought to cause fowl cholera in culture and then had courtesy of the National Library of Medicine. J shown that chickens injected with the cultured bacterium de eloped cholera. After returning from a summer vacation, he injected some chickens with an old culture. The chickens be- 1885, Pasteur administered his first vaccine to a human,a came ill, but, to Pasteur's surprise, they recovered. Pasteur young boy who had been bitten repeatedly by a rabid dog then grew a fresh culture of the bacterium with the intention(Figure 1-1). The boy, Joseph Meister, was inoculated with a of injecting it into some fresh chickens. But, as the story goes, series of attenuated rabies virus preparations. He lived and his supply of chickens was limited, and therefore he used the later became a custodian at the Pasteur Institut. previously injected chickens. Again to his surprise, the chick- ens were completely protected from the disease. Pasteur Early Studies Revealed Humoral and Cellular hypothesized and proved that aging had weakened the viru- Components of the Immune System lence of the pathogen and that such an attenuated strain might be administered to protect against the disease. He Although Pasteur proved that vaccination worked, he did not called this attenuated strain a vaccine( from the Latin vacca, understand how. The experimental work of Emil von meaning"cow), in honor of Jenner's work with cowpox Behring and Shibasaburo Kitasato in 1890 gave the first in inoculation sights into the mechanism of immunity, earning von Behring Pasteur extended these findings to other diseases, demon- the Nobel prize in medicine in 1901 (Table 1-1). Von Behring strating that it was possible to attenuate, or weaken, a and Kitasato demonstrated that serum(the liquid, noncell pathogen and administer the attenuated strain as a vaccine. lar component of coagulated blood) from animals prevost In a now classic experiment at Pouilly-le-Fort in 1881, Pas- immunized to diphtheria could transfer the immune state teur first vaccinated one group of sheep with heat-attenuated unimmunized animals. In search of the protective agent, var- anthrax bacillus( Bacillus anthracis); he then challenged the ious researchers during the next decade demonstrated that vaccinated sheep and some unvaccinated sheep with a viru- an active component from imi erum could neutralize lent culture of the bacillus. All the vaccinated sheep lived, and toxins, precipitate toxins, and agglutinate(clump)bacteria all the unvaccinated animals died. These experiments In each case, the active agent was named for the activity it ex- marked the beginnings of the discipline of immunology. In hibited: antitoxin, precipitin, and agglutinin, respectively
two thousand years passed before the concept was successfully converted into medically effective practice. The first recorded attempts to induce immunity deliberately were performed by the Chinese and Turks in the fifteenth century. Various reports suggest that the dried crusts derived from smallpox pustules were either inhaled into the nostrils or inserted into small cuts in the skin (a technique called variolation). In 1718, Lady Mary Wortley Montagu, the wife of the British ambassador to Constantinople, observed the positive effects of variolation on the native population and had the technique performed on her own children. The method was significantly improved by the English physician Edward Jenner, in 1798. Intrigued by the fact that milkmaids who had contracted the mild disease cowpox were subsequently immune to smallpox, which is a disfiguring and often fatal disease, Jenner reasoned that introducing fluid from a cowpox pustule into people (i.e., inoculating them) might protect them from smallpox. To test this idea, he inoculated an eight-year-old boy with fluid from a cowpox pustule and later intentionally infected the child with smallpox. As predicted, the child did not develop smallpox. Jenner’s technique of inoculating with cowpox to protect against smallpox spread quickly throughout Europe. However, for many reasons, including a lack of obvious disease targets and knowledge of their causes, it was nearly a hundred years before this technique was applied to other diseases. As so often happens in science, serendipity in combination with astute observation led to the next major advance in immunology, the induction of immunity to cholera. Louis Pasteur had succeeded in growing the bacterium thought to cause fowl cholera in culture and then had shown that chickens injected with the cultured bacterium developed cholera. After returning from a summer vacation, he injected some chickens with an old culture. The chickens became ill, but, to Pasteur’s surprise, they recovered. Pasteur then grew a fresh culture of the bacterium with the intention of injecting it into some fresh chickens. But, as the story goes, his supply of chickens was limited, and therefore he used the previously injected chickens. Again to his surprise, the chickens were completely protected from the disease. Pasteur hypothesized and proved that aging had weakened the virulence of the pathogen and that such an attenuated strain might be administered to protect against the disease. He called this attenuated strain a vaccine (from the Latin vacca, meaning “cow”), in honor of Jenner’s work with cowpox inoculation. Pasteur extended these findings to other diseases, demonstrating that it was possible to attenuate, or weaken, a pathogen and administer the attenuated strain as a vaccine. In a now classic experiment at Pouilly-le-Fort in 1881, Pasteur first vaccinated one group of sheep with heat-attenuated anthrax bacillus (Bacillus anthracis); he then challenged the vaccinated sheep and some unvaccinated sheep with a virulent culture of the bacillus. All the vaccinated sheep lived, and all the unvaccinated animals died. These experiments marked the beginnings of the discipline of immunology. In 1885, Pasteur administered his first vaccine to a human, a young boy who had been bitten repeatedly by a rabid dog (Figure 1-1). The boy, Joseph Meister, was inoculated with a series of attenuated rabies virus preparations. He lived and later became a custodian at the Pasteur Institute. Early Studies Revealed Humoral and Cellular Components of the Immune System Although Pasteur proved that vaccination worked, he did not understand how. The experimental work of Emil von Behring and Shibasaburo Kitasato in 1890 gave the first insights into the mechanism of immunity, earning von Behring the Nobel prize in medicine in 1901 (Table 1-1). Von Behring and Kitasato demonstrated that serum (the liquid, noncellular component of coagulated blood) from animals previously immunized to diphtheria could transfer the immune state to unimmunized animals. In search of the protective agent, various researchers during the next decade demonstrated that an active component from immune serum could neutralize toxins, precipitate toxins, and agglutinate (clump) bacteria. In each case, the active agent was named for the activity it exhibited: antitoxin, precipitin, and agglutinin, respectively. 2 PART I Introduction FIGURE 1-1 Wood engraving of Louis Pasteur watching Joseph Meister receive the rabies vaccine. [From Harper’s Weekly 29:836; courtesy of the National Library of Medicine.] 8536d_ch01_001-023 8/1/02 4:25 PM Page 2 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
8536d_ch01_001-0238/1/02 4: 25 PM Page 3 mac79 Mac 79: 45_BW: Goldsby et al./ Immunology 5e Overview of the Immune System CHAPTER 1 TABLE 1-1 Nobel Prizes for immunologic research Year Re Country Research Emil von Behring Serum antitoxins Robert Koch ellular immunity to tuberculosis Elie Metchnikoff Russia Role of phagocytosis(Metchnikoff) and antitoxins(Ehrlich) Charles richet Anaphylaxis Jules Border Complement-mediated bacteriolysis 1930 Karl Landsteiner United States Discovery of human blood groups Max Theiler South africa of yellow fever vac Switzerland Antihistamines 1960 F. Macfarlane burnet Australia Discovery of acquired immunological Peter Medawar Great Britain tolerance 19 Rodney R.Porter Great Britain Chemical structure of antibodies Gerald M. Edelman United States 1977 Rosalyn R. Yalow United States Development of radioimmunoassay George Snell United States Major histocompatibility complex Jean Dausset United States Cesar Milstein Great Britain Monoclonal antibody Georges E. Kohler Niels K Jerne Denmark mmune regulatory theories Susumu Tonegawa Japan Gene rearrangement in antibod E Donnall thomas United States T Joseph Murray United States 1996 Peter C. Doherty australia Role of major histocompatibility complex Rolf M. Zinkernag Switzerland in antigen recognition byby t cells Initially, a different serum component was thought to be re- In due course, a controversy developed between those sponsible for each activity, but during the 1930s, mainly who held to the concept of humoral immunity and those through the efforts of Elvin Kabat, a fraction of serum first who agreed with Metchnikoff's concept of cell-mediated im- called gamma-globulin(now immunoglobulin)was shown munity. It was later shown that both are correct--immunity to be responsible for all these activities. The active molecules requires both cellular and humoral responses. It was difficult in the immunoglobulin fraction are called antibodies. Be- to study the activities of immune cells before the develop- cause immunity was mediated by antibodies contained in ment of modern tissue culture techniques, whereas studies body fluids(known at the time as humors), it was called hu- with serum took advantage of the ready availability of blood oral immunity and established biochemical techniques. Because of these In 1883, even before the discovery that a serum compo- technical problems, information about cellular immunity ent could transfer immunity, Elie Metchnikoff demon- lagged behind findings that concerned humoral immunity. strated that cells also contribute to the immune state of an In a key experiment in the 1940s, Merrill Chase succeeded animal. He observed that certain white blood cells, which he in transferring immunity against the tuberculosis organism termed phagocytes, were able to ingest(phagocytose)mi- by transferring white blood cells between guinea pigs. This croorganisms and other foreign material. Noting that these demonstration helped to rekindle interest in cellular immu- phagocytic cells were more active in animals that had been nity. With the emergence of improved cell culture techniques immunized, Metchnikoff hypothesized that cells, rather than in the 1950s, the lymphocyte was identified as the cell re- serum components, were the major effector of immunity. sponsible for both cellular and humoral immunity. Soon The active phagocytic cells identified by Metchnikoff were thereafter, experiments with chickens pioneered by Bruce likely blood monocytes and neutrophils(see Chapter 2) Glick at Mississippi State University indicated that there were
Initially, a different serum component was thought to be responsible for each activity, but during the 1930s, mainly through the efforts of Elvin Kabat, a fraction of serum first called gamma-globulin (now immunoglobulin) was shown to be responsible for all these activities. The active molecules in the immunoglobulin fraction are called antibodies. Because immunity was mediated by antibodies contained in body fluids (known at the time as humors), it was called humoral immunity. In 1883, even before the discovery that a serum component could transfer immunity, Elie Metchnikoff demonstrated that cells also contribute to the immune state of an animal. He observed that certain white blood cells, which he termed phagocytes, were able to ingest (phagocytose) microorganisms and other foreign material. Noting that these phagocytic cells were more active in animals that had been immunized, Metchnikoff hypothesized that cells, rather than serum components, were the major effector of immunity. The active phagocytic cells identified by Metchnikoff were likely blood monocytes and neutrophils (see Chapter 2). In due course, a controversy developed between those who held to the concept of humoral immunity and those who agreed with Metchnikoff’s concept of cell-mediated immunity. It was later shown that both are correct—immunity requires both cellular and humoral responses. It was difficult to study the activities of immune cells before the development of modern tissue culture techniques, whereas studies with serum took advantage of the ready availability of blood and established biochemical techniques. Because of these technical problems, information about cellular immunity lagged behind findings that concerned humoral immunity. In a key experiment in the 1940s, Merrill Chase succeeded in transferring immunity against the tuberculosis organism by transferring white blood cells between guinea pigs. This demonstration helped to rekindle interest in cellular immunity. With the emergence of improved cell culture techniques in the 1950s, the lymphocyte was identified as the cell responsible for both cellular and humoral immunity. Soon thereafter, experiments with chickens pioneered by Bruce Glick at Mississippi State University indicated that there were Overview of the Immune System CHAPTER 1 3 TABLE 1-1 Nobel Prizes for immunologic research Year Recipient Country Research 1901 Emil von Behring Germany Serum antitoxins 1905 Robert Koch Germany Cellular immunity to tuberculosis 1908 Elie Metchnikoff Russia Role of phagocytosis (Metchnikoff) and Paul Ehrlich Germany antitoxins (Ehrlich) in immunity 1913 Charles Richet France Anaphylaxis 1919 Jules Border Belgium Complement-mediated bacteriolysis 1930 Karl Landsteiner United States Discovery of human blood groups 1951 Max Theiler South Africa Development of yellow fever vaccine 1957 Daniel Bovet Switzerland Antihistamines 1960 F. Macfarlane Burnet Australia Discovery of acquired immunological Peter Medawar Great Britain tolerance 1972 Rodney R. Porter Great Britain Chemical structure of antibodies Gerald M. Edelman United States 1977 Rosalyn R. Yalow United States Development of radioimmunoassay 1980 George Snell United States Major histocompatibility complex Jean Daussct France Baruj Benacerraf United States 1984 Cesar Milstein Great Britain Monoclonal antibody Georges E. Köhler Germany Niels K. Jerne Denmark Immune regulatory theories 1987 Susumu Tonegawa Japan Gene rearrangement in antibody production 1991 E. Donnall Thomas United States Transplantation immunology Joseph Murray United States 1996 Peter C. Doherty Australia Role of major histocompatibility complex Rolf M. Zinkernagel Switzerland in antigen recognition by by T cells 8536d_ch01_001-023 8/1/02 4:25 PM Page 3 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
8536d_ch01_001-0238/1/02 4: 25 PM Page 4 mac79 Mac 79: 45_BW: Goldsby et al./ Immunology 5e two types of lymphocytes: T lymphocytes derived from the In the 1930s and 1940s, the selective theory was chal thymus mediated cellular immunity, and B lymphocytes lenged by various instructional theories, in which antigen from the bursa of Fabricius(an outgrowth of the cloaca in played a central role in determining the specificity of the an- birds)were involved in humoral immunity. The controversy tibody molecule. According to the instructional theories, a about the roles of humoral and cellular immunity was re- particular antigen would serve as a template around which solved when the two systems were shown to be intertwined, antibody would fold. The antibody molecule would thereby and that both systems were necessary for the immune assume a configuration complementary to that of the antigen template. This concept was first postulated by Friedrich Breinl and felix haurowitz about 1930 and redefined in the Early Theories Attempted to Explain 1940s in terms of protein folding by Linus Pauling. The in the Specificity of the Antibody structional theories were formally disproved in the 1960s, by Antigen Interaction which time information was emerging about the structure of DNA, RNA, and protein that would offer new insights into One of the greatest enigmas facing early immunologists was the vexing problem of how an individual could make anti the specificity of the antibody molecule for foreign material, bodies against almost anything or antigen(the general term for a substance that binds with In the 1950s, selective theories resurfaced as a result of a specific antibody). Around 1900, Jules Bordet at the Pasteur new experimental data and, through the insights of Niels Institute expanded the concept of immunity by demonstrat- Jerne, David Talmadge, and E. Macfarlane Burnet, were re- ing specific immune reactivity to nonpathogenic substances, fined into a theory that came to be known as the clonal such as red blood cells from other species. Serum from an an- selection theory. According to this theory, an individu imal inoculated previously with material that did not cause lymphocyte expresses membrane receptors that are specific infection would react with this material in a specific manner, for a distinct antigen. This unique receptor specificity is de- and this reactivity could be passed to other animals by trans- termined before the lymphocyte is exposed to the antigen ferring serum from the first. The work of Karl Landsteiner Binding of antigen to its specific receptor activates the cell, nd those who followed him showed that injecting an animal causing it to proliferate into a clone of cells that have the with almost any organic chemical could induce production same immunologic specificity as the parent cell. The clonal- of antibodies that would bind specifically to the chemical. selection theory has been further refined and is now accepted These studies demonstrated that antibodies have a capacity as the underlying paradigm of modern immunology. for an almost unlimited range of reactivity, including re- sponses to compounds that had only recently been synthe- The Immune System Includes Innate and sized in the laboratory and had not previously existed in Adaptive components nature. In addition, it was shown that molecules differing in the smallest detail could be distinguished by their reactivity Immunity-the state of protection from infectious disease with different antibodies. Two major theories were proposed -has both a less specific and more specific component. The to account for this specificity: the selective theory and the in- less specific component, innate immunity, provides the first structional theory line of defense against infection. Most components of innat The earliest conception of the selective theory dates to Paul immunity are present before the onset of infection and con Ehrlich in 1900. In an attempt to explain the origin of serum stitute a set of disease-resistance mechanisms that are not antibody, Ehrlich proposed that cells in the blood expressed a specific to a particular pathogen but that include cellular and variety of receptors, which he called"side-chain receptors," molecular components that recognize classes of molecules that could react with infectious agents and inactivate them. peculiar to frequently encountered pathogens. Phagocytic Borrowing a concept used by Emil Fischer in 1894 to explain cells, such as macrophages and neutrophils, barriers such as the interaction between an enzyme and its substrate, Ehrlich skin, and a variety of antimicrobial compounds synthesized proposed that binding of the receptor to an infectious agent by the host all play important roles in innate immunity In was like the fit between a lock and key. Ehrlich suggested that contrast to the broad reactivity of the innate immune sys- teraction between an infectious agent and a cell-bound tem, which is uniform in all members of a species, the spe receptor would induce the cell to produce and release more cific component, adaptive immunity, does not come into ecificity. According to Ehrlich's play until there is an antigenic challenge to the organism. theory, the specificity of the receptor was determined before Adaptive immunity responds to the challenge with a high its exposure to antigen, and the antigen selected the appro- gree of specificity as well as the remarkable property of priate receptor. Ultimately all aspects of Ehrlich's theory"memory. Typically, there is an adaptive immune response would be proven correct with the minor exception that the against an antigen within five or six days after the initial ex receptor exists as both a soluble antibody molecule and as a posure to that antigen. Exposure to the same antigen some cell-bound receptor; it is the soluble form that is secreted time in the future results in a memory response: the immune rather than the bound form released response to the second challenge occurs more quickly than
two types of lymphocytes: T lymphocytes derived from the thymus mediated cellular immunity, and B lymphocytes from the bursa of Fabricius (an outgrowth of the cloaca in birds) were involved in humoral immunity. The controversy about the roles of humoral and cellular immunity was resolved when the two systems were shown to be intertwined, and that both systems were necessary for the immune response. Early Theories Attempted to Explain the Specificity of the Antibody– Antigen Interaction One of the greatest enigmas facing early immunologists was the specificity of the antibody molecule for foreign material, or antigen (the general term for a substance that binds with a specific antibody). Around 1900, Jules Bordet at the Pasteur Institute expanded the concept of immunity by demonstrating specific immune reactivity to nonpathogenic substances, such as red blood cells from other species. Serum from an animal inoculated previously with material that did not cause infection would react with this material in a specific manner, and this reactivity could be passed to other animals by transferring serum from the first. The work of Karl Landsteiner and those who followed him showed that injecting an animal with almost any organic chemical could induce production of antibodies that would bind specifically to the chemical. These studies demonstrated that antibodies have a capacity for an almost unlimited range of reactivity, including responses to compounds that had only recently been synthesized in the laboratory and had not previously existed in nature. In addition, it was shown that molecules differing in the smallest detail could be distinguished by their reactivity with different antibodies. Two major theories were proposed to account for this specificity: the selective theory and the instructional theory. The earliest conception of the selective theory dates to Paul Ehrlich in 1900. In an attempt to explain the origin of serum antibody, Ehrlich proposed that cells in the blood expressed a variety of receptors, which he called “side-chain receptors,” that could react with infectious agents and inactivate them. Borrowing a concept used by Emil Fischer in 1894 to explain the interaction between an enzyme and its substrate, Ehrlich proposed that binding of the receptor to an infectious agent was like the fit between a lock and key. Ehrlich suggested that interaction between an infectious agent and a cell-bound receptor would induce the cell to produce and release more receptors with the same specificity. According to Ehrlich’s theory, the specificity of the receptor was determined before its exposure to antigen, and the antigen selected the appropriate receptor. Ultimately all aspects of Ehrlich’s theory would be proven correct with the minor exception that the “receptor” exists as both a soluble antibody molecule and as a cell-bound receptor; it is the soluble form that is secreted rather than the bound form released. In the 1930s and 1940s, the selective theory was challenged by various instructional theories, in which antigen played a central role in determining the specificity of the antibody molecule. According to the instructional theories, a particular antigen would serve as a template around which antibody would fold. The antibody molecule would thereby assume a configuration complementary to that of the antigen template. This concept was first postulated by Friedrich Breinl and Felix Haurowitz about 1930 and redefined in the 1940s in terms of protein folding by Linus Pauling. The instructional theories were formally disproved in the 1960s, by which time information was emerging about the structure of DNA, RNA, and protein that would offer new insights into the vexing problem of how an individual could make antibodies against almost anything. In the 1950s, selective theories resurfaced as a result of new experimental data and, through the insights of Niels Jerne, David Talmadge, and F. Macfarlane Burnet, were refined into a theory that came to be known as the clonalselection theory. According to this theory, an individual lymphocyte expresses membrane receptors that are specific for a distinct antigen. This unique receptor specificity is determined before the lymphocyte is exposed to the antigen. Binding of antigen to its specific receptor activates the cell, causing it to proliferate into a clone of cells that have the same immunologic specificity as the parent cell. The clonalselection theory has been further refined and is now accepted as the underlying paradigm of modern immunology. The Immune System Includes Innate and Adaptive Components Immunity—the state of protection from infectious disease —has both a less specific and more specific component. The less specific component, innate immunity, provides the first line of defense against infection. Most components of innate immunity are present before the onset of infection and constitute a set of disease-resistance mechanisms that are not specific to a particular pathogen but that include cellular and molecular components that recognize classes of molecules peculiar to frequently encountered pathogens. Phagocytic cells, such as macrophages and neutrophils, barriers such as skin, and a variety of antimicrobial compounds synthesized by the host all play important roles in innate immunity. In contrast to the broad reactivity of the innate immune system, which is uniform in all members of a species, the specific component, adaptive immunity, does not come into play until there is an antigenic challenge to the organism. Adaptive immunity responds to the challenge with a high degree of specificity as well as the remarkable property of “memory.” Typically, there is an adaptive immune response against an antigen within five or six days after the initial exposure to that antigen. Exposure to the same antigen some time in the future results in a memory response: the immune response to the second challenge occurs more quickly than 4 PART I Introduction 8536d_ch01_001-023 8/1/02 4:25 PM Page 4 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
8536d_ch01_001-0238/1/02 4: 25 PM Page 5 mac79 Mac 79: 45_BW: Goldsby et al./ Immunology 5e Overview of the Immune System CHAPTER 1 the first, is stronger, and is often more effective in neutraliz- distinct layers: a thinner outer layer-the epidermis--and a ing and clearing the pathogen. The major agents of adaptive thicker layer-the dermis. The epidermis contains several immunity are lymphocytes and the antibodies and other layers of tightly packed epithelial cells. The outer epidermal molecules they produce layer consists of dead cells and is filled with a waterproofing Because adaptive immune responses require some time to protein called keratin. The dermis, which is composed of arshal, innate immunity provides the first line of defense connective tissue, contains blood vessels, hair follicles, seba during the critical period just after the hosts exposure to a ceous glands, and sweat glands. The sebaceous glands are as- pathogen. In general, most of the microorganisms encoun- sociated with the hair follicles and produce an oily secretion tered by a healthy individual are readily cleared within a few called sebum. Sebum consists of lactic acid and fatty acids, days by defense mechanisms of the innate immune system which maintain the pH of the skin between 3 and 5; this pH before they activate the adaptive immune system. inhibits the growth of most microorganisms. A few bacteria that metabolize sebum live as commensals on the skin and sometimes cause a severe form of acne. One acne drug, Innate Immunity isotretinoin(Accutane), is a vitamin A derivative that pre vents the formation of sebum Innate immunity can be seen to comprise four types of de- Breaks in the skin resulting from scratches, wounds, or fensive barriers: anatomic, physiologic, phagocytic, and in- abrasion are obvious routes of infection. The skin may also flammatory(Table 1-2) be penetrated by biting insects(e.g, mosquitoes, mites, ticks, fleas, and sandflies ) if these harbor pathogenic organisms, The Skin and the Mucosal Surfaces provide they can introduce the pathogen into the body as they feed Protective Barriers Against Infection The protozoan that causes malaria, for example, is deposited in humans by mosquitoes when they take a blood meal. Sim- Physical and anatomic barriers that tend to prevent the entry ilarly, bubonic plague is spread by the bite of fleas, and Ly of pathogens are an organisms first line of defense against in- disease is spread by the bite of ticks fection. The skin and the surface of mucous membranes are The conjunctivae and the alimentary, respiratory, and included in this category because they are effective barriers to urogenital tracts are lined by mucous membranes, not by the the entry of most microorganisms. The skin consists of two dry, protective skin that covers the exterior of the body. These TABLE 1-2 Summary of nonspecific host defenses Type Mechanism Anatomic barriers Mechanical barrier retards entry of microbes. Acidic environment(pH 3-5)retards growth of microbes. Mucous membranes Normal flora compete with microbes for attachment sites and nutrients Mucus entraps foreign microorganisms. Cilia propel microorganisms out of body Physiologic barriers Temperature Normal body temperature inhibits growth of some pathogens Fever response inhibits growth of some pathoge Low pH Acidity of stomach contents kills most ingested microorganism Chemical mediators Lysozyme cleaves bacterial cell wall Interferon induces antiviral state in uninfected cells omplement lyses microorganisms or facilitates phagocytosis Toll-like receptors recognize microbial molecules, signal cell to secrete immunostimulatory cytokines Collectins disrupt cell wall of pathogen Phagocytic/endocytic barriers Various cells internalize(endocytose)and break down foreign macromolecules Specialized cells(blood monocytes, neutrophils, tissue macrophages)internalize (phagocytose), kill, and digest whole microorganisms flammatory barriers mage and infection induce leakage of vascular fluid, containing serum proteins with antibacterial activity, and influx of phagocytic cells into the affected area
the first, is stronger, and is often more effective in neutralizing and clearing the pathogen. The major agents of adaptive immunity are lymphocytes and the antibodies and other molecules they produce. Because adaptive immune responses require some time to marshal, innate immunity provides the first line of defense during the critical period just after the host’s exposure to a pathogen. In general, most of the microorganisms encountered by a healthy individual are readily cleared within a few days by defense mechanisms of the innate immune system before they activate the adaptive immune system. Innate Immunity Innate immunity can be seen to comprise four types of defensive barriers: anatomic, physiologic, phagocytic, and inflammatory (Table 1-2). The Skin and the Mucosal Surfaces Provide Protective Barriers Against Infection Physical and anatomic barriers that tend to prevent the entry of pathogens are an organism’s first line of defense against infection. The skin and the surface of mucous membranes are included in this category because they are effective barriers to the entry of most microorganisms. The skin consists of two distinct layers: a thinner outer layer—the epidermis—and a thicker layer—the dermis. The epidermis contains several layers of tightly packed epithelial cells. The outer epidermal layer consists of dead cells and is filled with a waterproofing protein called keratin. The dermis, which is composed of connective tissue, contains blood vessels, hair follicles, sebaceous glands, and sweat glands. The sebaceous glands are associated with the hair follicles and produce an oily secretion called sebum. Sebum consists of lactic acid and fatty acids, which maintain the pH of the skin between 3 and 5; this pH inhibits the growth of most microorganisms. A few bacteria that metabolize sebum live as commensals on the skin and sometimes cause a severe form of acne. One acne drug, isotretinoin (Accutane), is a vitamin A derivative that prevents the formation of sebum. Breaks in the skin resulting from scratches, wounds, or abrasion are obvious routes of infection. The skin may also be penetrated by biting insects (e.g., mosquitoes, mites, ticks, fleas, and sandflies); if these harbor pathogenic organisms, they can introduce the pathogen into the body as they feed. The protozoan that causes malaria, for example, is deposited in humans by mosquitoes when they take a blood meal. Similarly, bubonic plague is spread by the bite of fleas, and Lyme disease is spread by the bite of ticks. The conjunctivae and the alimentary, respiratory, and urogenital tracts are lined by mucous membranes, not by the dry, protective skin that covers the exterior of the body. These Overview of the Immune System CHAPTER 1 5 TABLE 1-2 Summary of nonspecific host defenses Type Mechanism Anatomic barriers Skin Mechanical barrier retards entry of microbes. Acidic environment (pH 3–5) retards growth of microbes. Mucous membranes Normal flora compete with microbes for attachment sites and nutrients. Mucus entraps foreign microorganisms. Cilia propel microorganisms out of body. Physiologic barriers Temperature Normal body temperature inhibits growth of some pathogens. Fever response inhibits growth of some pathogens. Low pH Acidity of stomach contents kills most ingested microorganisms. Chemical mediators Lysozyme cleaves bacterial cell wall. Interferon induces antiviral state in uninfected cells. Complement lyses microorganisms or facilitates phagocytosis. Toll-like receptors recognize microbial molecules, signal cell to secrete immunostimulatory cytokines. Collectins disrupt cell wall of pathogen. Phagocytic/endocytic barriers Various cells internalize (endocytose) and break down foreign macromolecules. Specialized cells (blood monocytes, neutrophils, tissue macrophages) internalize (phagocytose), kill, and digest whole microorganisms. Inflammatory barriers Tissue damage and infection induce leakage of vascular fluid, containing serum proteins with antibacterial activity, and influx of phagocytic cells into the affected area. 8536d_ch01_001-023 8/1/02 4:25 PM Page 5 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
8536d_ch01_001-0238/1/02 4: 25 PM Page 6 mac79 Mac 79: 45_BW: Goldsby et al./ Immunology 5e membranes consist of an outer epithelial layer and an under- tissues are susceptible to bacterial invasion, whereas others lying layer of connective tissue. Although many pathogens are not. enter the body by binding to and penetrating mucous mem- branes, a number of nonspecific defense mechanisms tend to Physiologic Barriers to Infection Include prevent this entry. For example, saliva, tears, and mucous se- General Conditions and Specific molecules antibacterial or antiviral substances. The viscous fluid called The physiologic barriers that contribute to innate immu- mucus,which is secreted by epithelial cells of mucous mem- nity include temperature, PH, and various soluble and cell- branes, entraps foreign microorganisms. In the lower respi- associated molecules. Many species are not susceptible to cer- ratory tract, the mucous membrane is covered by cilia, tain diseases simply because their normal body temperature hairlike protrusions of the epithelial-cell membranes. The inhibits growth of the pathogens. Chickens, for example, synchronous movement of cilia propels mucus-entrapped have innate immunity to anthrax because their high body microorganisms from these tracts. In addition, nonpath- temperature inhibits the growth of the bacteria. Gastric acid genic organisms tend to colonize the epithelial cells of mu- ity is an innate physiologic barrier to infection because very sal surfaces. These normal flora generally outcompete few ingested microorganisms can survive the low pH of the Some organisms have evolved ways of escaping these de- contents are less acid than those of adul re susceptible to pathogens for attachment sites on the epithelial cell surface stomach contents. One reason newborns and for necessary nutrients. some diseases that do not afflict adults is that their stomach ense mechanisms and thus are able to invade the body A variety of soluble factors contribute to innate immu through mucous membranes. For example, influenza virus nity, among them the soluble proteins lysozyme, interferon, ( the agent that causes flu) has a surface molecule that enables and complement. Lysozyme, a hydrolytic enzyme found in it to attach firmly to cells in mucous membranes of the respi- mucous secretions and in tears, is able to cleave the peptide ratory tract, preventing the virus from being swept out by the glycan layer of the bacterial cell wall. Interferon comprises a ciliated epithelial cells. Similarly, the organism that causes group of proteins produced by virus-infected cells. Among gonorrhea has surface projections that allow it to bind to ep- the many functions of the interferons is the ability to bind to thelial cells in the mucous membrane of the urogenital tract. nearby cells and induce a generalized antiviral state Comple Adherence of bacteria to mucous membranes is due to inter- ment, examined in detail in Chapter 13, is a group of serum actions between hairlike protrusions on a bacterium, called proteins that circulate in an inactive state. A variety of spe- fimbriae or pili, and certain glycoproteins or glycolipids that cific and nonspecific immunologic mechanisms can convert are expressed only by epithelial cells of the mucous mem- the inactive forms of complement proteins into an active brane of particular tissues(Figure 1-2). For this reason, some state with the ability to damage the membranes of pathe genic organisms, either destroying the pathogens or facilitat ing their clearance Complement may function as an effector system that is triggered by binding of antibodies to certain cell surfaces, or it may be activated by reactions between complement molecules and certain components of microbial cell walls. Reactions between complement molecules or frag- ments of complement molecules and cellular receptors trig- ger activation of cells of the innate or adaptive immune systems. Recent studies on collectins indicate that these sur factant proteins may kill certain bacteria directly by disrupt- ing their lipid membranes or, alternatively, by aggregating the bacteria to enhance their susceptibility to phagocytosis Many of the molecules involved in innate immunity have the property of pattern recognition, the ability to recognize a given class of molecules. Because there are certain types of mol ecules that are unique to microbes and never found in multi cellular organisms, the ability to immediately recognize and combat invaders displaying such molecules is a strong feature of innate immunity. Molecules with pattern recognition ability may be soluble, like lysozyme and the complement compo FIGURE1-2Electron micrograph of rod-shaped Escherichia coli nents described above, or they may be cell-associated receptors bacteria adhering to surface of epithelial cells of the urinary tract. (TLRS), TLR2 recognizes the lipopolysaccharide(LPS)found Among the class of receptors designated the toll-like receptors [From N. Sharon and H. Lis, 1993, Sci. Am. 268(: 85: photograph courtesy of k. Fujita. J on Gram-negative bacteria. It has long been recognized that
membranes consist of an outer epithelial layer and an underlying layer of connective tissue. Although many pathogens enter the body by binding to and penetrating mucous membranes, a number of nonspecific defense mechanisms tend to prevent this entry. For example, saliva, tears, and mucous secretions act to wash away potential invaders and also contain antibacterial or antiviral substances. The viscous fluid called mucus, which is secreted by epithelial cells of mucous membranes, entraps foreign microorganisms. In the lower respiratory tract, the mucous membrane is covered by cilia, hairlike protrusions of the epithelial-cell membranes. The synchronous movement of cilia propels mucus-entrapped microorganisms from these tracts. In addition, nonpathogenic organisms tend to colonize the epithelial cells of mucosal surfaces. These normal flora generally outcompete pathogens for attachment sites on the epithelial cell surface and for necessary nutrients. Some organisms have evolved ways of escaping these defense mechanisms and thus are able to invade the body through mucous membranes. For example, influenza virus (the agent that causes flu) has a surface molecule that enables it to attach firmly to cells in mucous membranes of the respiratory tract, preventing the virus from being swept out by the ciliated epithelial cells. Similarly, the organism that causes gonorrhea has surface projections that allow it to bind to epithelial cells in the mucous membrane of the urogenital tract. Adherence of bacteria to mucous membranes is due to interactions between hairlike protrusions on a bacterium, called fimbriae or pili, and certain glycoproteins or glycolipids that are expressed only by epithelial cells of the mucous membrane of particular tissues (Figure 1-2). For this reason, some tissues are susceptible to bacterial invasion, whereas others are not. Physiologic Barriers to Infection Include General Conditions and Specific Molecules The physiologic barriers that contribute to innate immunity include temperature, pH, and various soluble and cellassociated molecules. Many species are not susceptible to certain diseases simply because their normal body temperature inhibits growth of the pathogens. Chickens, for example, have innate immunity to anthrax because their high body temperature inhibits the growth of the bacteria. Gastric acidity is an innate physiologic barrier to infection because very few ingested microorganisms can survive the low pH of the stomach contents. One reason newborns are susceptible to some diseases that do not afflict adults is that their stomach contents are less acid than those of adults. A variety of soluble factors contribute to innate immunity, among them the soluble proteins lysozyme, interferon, and complement. Lysozyme, a hydrolytic enzyme found in mucous secretions and in tears, is able to cleave the peptidoglycan layer of the bacterial cell wall. Interferon comprises a group of proteins produced by virus-infected cells. Among the many functions of the interferons is the ability to bind to nearby cells and induce a generalized antiviral state.Complement, examined in detail in Chapter 13, is a group of serum proteins that circulate in an inactive state. A variety of specific and nonspecific immunologic mechanisms can convert the inactive forms of complement proteins into an active state with the ability to damage the membranes of pathogenic organisms, either destroying the pathogens or facilitating their clearance. Complement may function as an effector system that is triggered by binding of antibodies to certain cell surfaces, or it may be activated by reactions between complement molecules and certain components of microbial cell walls. Reactions between complement molecules or fragments of complement molecules and cellular receptors trigger activation of cells of the innate or adaptive immune systems. Recent studies on collectins indicate that these surfactant proteins may kill certain bacteria directly by disrupting their lipid membranes or, alternatively, by aggregating the bacteria to enhance their susceptibility to phagocytosis. Many of the molecules involved in innate immunity have the property of pattern recognition, the ability to recognize a given class of molecules. Because there are certain types of molecules that are unique to microbes and never found in multicellular organisms, the ability to immediately recognize and combat invaders displaying such molecules is a strong feature of innate immunity. Molecules with pattern recognition ability may be soluble, like lysozyme and the complement components described above, or they may be cell-associated receptors. Among the class of receptors designated the toll-like receptors (TLRs), TLR2 recognizes the lipopolysaccharide (LPS) found on Gram-negative bacteria. It has long been recognized that 6 PART I Introduction FIGURE 1-2 Electron micrograph of rod-shaped Escherichia coli bacteria adhering to surface of epithelial cells of the urinary tract. [From N. Sharon and H. Lis, 1993, Sci. Am. 268(1):85; photograph courtesy of K. Fujita.] 8536d_ch01_001-023 8/1/02 4:25 PM Page 6 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
8536dch010079/5/0211:47 AM Page7mac46mac46:385reb: Overview of the Immune System cHAP ph of macrophage(pink) attack gocytized as scribed in part b and breakdown products secreted. The monocyte sle)has been recruited to the vicinity of the encounter by solubl factors secreted by the macrophage. The red sphere is an erythrocyte Schematic diagram of the steps in phagocytosis of a bacterium purified LPS leads to an acute inflammatory response(see be- low). The mechanism for this response is via a TLR on macrophages that recognizes LPS and elicits a variety of mole cules in the inflammatory response upon exposure. When the TLR is exposed to the LpS upon local invasion by a Gram-neg ative bacterium, the contained response results in elimination of the bacterial challenge Cells That Ingest and Destroy Pathogens Make Up a Phagocytic Barrier to Infection Another important innate defense mechanism is the inges- to membrane evaginations tion of extracellular particulate material by phagocytosis. called pseudopodia Phagocytosis is one type of ende the general term for the uptake by a cell of material from its environment. In 31 phagocytosis, a cell,'s plasma membrane expands around the forming phag 20 ate material, which may include whole pathogen microorganisms, to form large vesicles called phagosor (Figure 1-3). Most phagocytosis is conducted by specialized Phagosome fuses with cells, such as blood monocytes, neutrophils, and tissue macrophages(see Chapter 2). Most cell types are capable of 0(83 other forms of endocytosis, such as receptor-mediated endo- ysosomal enzymes digest cytosis, in which extracellular molecules are internalized after captured material binding by specific cellular receptors, and pinocytosis, the process by which cells take up fluid from the surrounding medium along with any molecules contained in it. Digestion products are released from cell Inflammation Represents a Complex Sequence of Events That Stimulates Immune Responses Tissue damage caused by a wound or by an invading genic microorganism induces a complex sequence of events or inflammation"as rubor(redness), tumor(swelling) collectively known as the inflammatory response. As de- calor(heat), and dolor(pain). In the second century AD,an- scribed above, a molecular component of a microbe, such other physician, Galen, added a fifth sign: functio laesa(loss of function). The cardinal signs of inflammation reflect the LPS,may trigger an inflammatory response via interaction three major events of an inflammatory response( Figure 1-4) with cell surface receptors. The end result of inflammation may be the marshalling of a specific immune response to the 1. VasodilationH-an increase in the diameter of blood invasion or clearance of the invader by components of the vessels--of nearby capillaries occurs as the vessels that innate immune system. Many of the classic features of the arry blood away from the affected area constrict, inflammatory response were described as early as 1600 BC, in resulting in engorgement of the capillary network. The Roman physician Celsus described the"four cardinal signs (erythema)and an increase in tissue temperature Egyptian papyrus writings. In the first century AD, the engorged capillaries are responsible for tissue redne
systemic exposure of mammals to relatively small quantities of purified LPS leads to an acute inflammatory response (see below). The mechanism for this response is via a TLR on macrophages that recognizes LPS and elicits a variety of molecules in the inflammatory response upon exposure. When the TLR is exposed to the LPS upon local invasion by a Gram-negative bacterium, the contained response results in elimination of the bacterial challenge. Cells That Ingest and Destroy Pathogens Make Up a Phagocytic Barrier to Infection Another important innate defense mechanism is the ingestion of extracellular particulate material by phagocytosis. Phagocytosis is one type of endocytosis, the general term for the uptake by a cell of material from its environment. In phagocytosis, a cell’s plasma membrane expands around the particulate material, which may include whole pathogenic microorganisms, to form large vesicles called phagosomes (Figure 1-3). Most phagocytosis is conducted by specialized cells, such as blood monocytes, neutrophils, and tissue macrophages (see Chapter 2). Most cell types are capable of other forms of endocytosis, such as receptor-mediated endocytosis, in which extracellular molecules are internalized after binding by specific cellular receptors, and pinocytosis, the process by which cells take up fluid from the surrounding medium along with any molecules contained in it. Inflammation Represents a Complex Sequence of Events That Stimulates Immune Responses Tissue damage caused by a wound or by an invading pathogenic microorganism induces a complex sequence of events collectively known as the inflammatory response. As described above, a molecular component of a microbe, such as LPS, may trigger an inflammatory response via interaction with cell surface receptors. The end result of inflammation may be the marshalling of a specific immune response to the invasion or clearance of the invader by components of the innate immune system. Many of the classic features of the inflammatory response were described as early as 1600 BC, in Egyptian papyrus writings. In the first century AD, the Roman physician Celsus described the “four cardinal signs Overview of the Immune System CHAPTER 1 7 FIGURE 1-3 (a) Electronmicrograph of macrophage (pink) attacking Escherichia coli (green). The bacteria are phagocytized as described in part b and breakdown products secreted. The monocyte (purple) has been recruited to the vicinity of the encounter by soluble factors secreted by the macrophage. The red sphere is an erythrocyte. (b) Schematic diagram of the steps in phagocytosis of a bacterium. [Part a, Dennis Kunkel Microscopy, Inc./Dennis Kunkel.] Bacterium becomes attached to membrane evaginations called pseudopodia Bacterium is ingested, forming phagosome Phagosome fuses with lysosome Lysosomal enzymes digest captured material Digestion products are released from cell 3 2 4 5 1 (a) (b) of inflammation” as rubor (redness), tumor (swelling), calor (heat), and dolor (pain). In the second century AD, another physician, Galen, added a fifth sign: functio laesa (loss of function). The cardinal signs of inflammation reflect the three major events of an inflammatory response (Figure 1-4): 1. Vasodilation—an increase in the diameter of blood vessels—of nearby capillaries occurs as the vessels that carry blood away from the affected area constrict, resulting in engorgement of the capillary network. The engorged capillaries are responsible for tissue redness (erythema) and an increase in tissue temperature. 8536d_ch01_007 9/5/02 11:47 AM Page 7 mac46 mac46:385_reb:
8536d_ch01_001-0238/1/02 4: 25 PM Page 8 mac79 Mac 79: 45_BW: Goldsby et al./ Immunology 5e Bacteria MMU MMf 4/A Tissue damage causes release of Phagocytes and antibacterial I vasoactive and chemotactic factors exudate destroy bacteria that trigger a local increase in blood flow and capillary permeability (complement, antibody, grate to site of Permeable capillaries allow Creactive protein) amation(chemotaxis) influx of fluid (exudate) an Extravasation Capillary FIGURE 1-4 Major events in the inflammatory response. A bacte. blood cells, including phagocytes and lymphocytes, from the blood rial infection causes tissue damage with release of various vasoactive into the tissues. The serum proteins contained in the exudate have and chemotactic factors. These factors induce increased blood flow antibacterial properties, and the phagocytes begin to engulf the bac- to the area, increased capillary permeability, and an influx of white teria, as illustrated in Figure 1-3 2. An increase in capillary permeability facilitates an influx isms, some are released from damaged cells in response to tis- of fluid and cells from the engorged capillaries into the sue injury, some are generated by several plasma enzyme sys- tissue. The fluid that accumulates (exudate)has a mue tems,and some are products of various white blood cells higher protein content than fluid normally released from participating in the inflammatory response the vasculature. Accumulation of exudate contributes to Among the chemical mediators released in response to tis tissue swelling(edema). sue damage are various serum proteins called acute-phase 3. Influx of phagocytes from the capillaries into the tissues is proteins. The concentrations of these proteins increase dra- facilitated by the increased permeability of the capil matically in tissue-damaging infections. C-reactive protein is laries. The emigration of phagocytes is a multistep a major acute-phase protein produced by the liver in re- process that includes adherence of the cells to the sponse to tissue damage. Its name derives from its pattern endothelial wall of the blood vessels(margination) recognition activity: C-reactive protein binds to the followed by their emigration between the capillary C-polysaccharide cell-wall component found on a variety of endothelial cells into the tissue( diapedesis or extrava- bacteria and fungi. This binding activates the complement sation), and, finally, their migration through the tissue to system, resulting in increased clearance of the pathogen ei- the site of the invasion(chemotaxis ). As phagocytic cells ther by complement-mediated lysis or by a complement- accumulate at the site and begin to phagocytose bacteria mediated increase in phagocytosis. One of the principal mediators of the inflammatory re- healthy cells. The accumulation of dead cells, digested sponse is histamine, a chemical released by a variety of cells material, and fluid forms a substance called pus in response to tissue injury. Histamine binds to receptors on nearby capillaries and venules, causing vasodilation and in The events in the inflammatory response are initiated by a creased permeability. Another important group of inflam complex series of events involving a variety of chemical me- matory mediators, small peptides called kinins, are normally diators whose interactions are only partly understood. Some present in blood plasma in an inactive form. Tissue injury ac of these mediators are derived from invading microorgan- tivates these peptides, which then cause vasodilation and in
2. An increase in capillary permeability facilitates an influx of fluid and cells from the engorged capillaries into the tissue. The fluid that accumulates (exudate) has a much higher protein content than fluid normally released from the vasculature. Accumulation of exudate contributes to tissue swelling (edema). 3. Influx of phagocytes from the capillaries into the tissues is facilitated by the increased permeability of the capillaries. The emigration of phagocytes is a multistep process that includes adherence of the cells to the endothelial wall of the blood vessels (margination), followed by their emigration between the capillaryendothelial cells into the tissue (diapedesis or extravasation), and, finally, their migration through the tissue to the site of the invasion (chemotaxis). As phagocytic cells accumulate at the site and begin to phagocytose bacteria, they release lytic enzymes, which can damage nearby healthy cells. The accumulation of dead cells, digested material, and fluid forms a substance called pus. The events in the inflammatory response are initiated by a complex series of events involving a variety of chemical mediators whose interactions are only partly understood. Some of these mediators are derived from invading microorganisms, some are released from damaged cells in response to tissue injury, some are generated by several plasma enzyme systems, and some are products of various white blood cells participating in the inflammatory response. Among the chemical mediators released in response to tissue damage are various serum proteins called acute-phase proteins. The concentrations of these proteins increase dramatically in tissue-damaging infections. C-reactive protein is a major acute-phase protein produced by the liver in response to tissue damage. Its name derives from its patternrecognition activity: C-reactive protein binds to the C-polysaccharide cell-wall component found on a variety of bacteria and fungi. This binding activates the complement system, resulting in increased clearance of the pathogen either by complement-mediated lysis or by a complementmediated increase in phagocytosis. One of the principal mediators of the inflammatory response is histamine, a chemical released by a variety of cells in response to tissue injury. Histamine binds to receptors on nearby capillaries and venules, causing vasodilation and increased permeability. Another important group of inflammatory mediators, small peptides called kinins, are normally present in blood plasma in an inactive form. Tissue injury activates these peptides, which then cause vasodilation and in- 8 PART I Introduction Tissue damage causes release of vasoactive and chemotactic factors that trigger a local increase in blood flow and capillary permeability Permeable capillaries allow an influx of fluid (exudate) and cells Phagocytes and antibacterial exudate destroy bacteria Phagocytes migrate to site of inflammation (chemotaxis) 2 1 3 4 Exudate (complement, antibody, C-reactive protein) Capillary Margination Extravasation Tissue damage Bacteria FIGURE 1-4 Major events in the inflammatory response. A bacterial infection causes tissue damage with release of various vasoactive and chemotactic factors. These factors induce increased blood flow to the area, increased capillary permeability, and an influx of white blood cells, including phagocytes and lymphocytes, from the blood into the tissues. The serum proteins contained in the exudate have antibacterial properties, and the phagocytes begin to engulf the bacteria, as illustrated in Figure 1-3. 8536d_ch01_001-023 8/1/02 4:25 PM Page 8 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
8536d_ch01_001-0238/1/02 4: 25 PM Page 9 mac79 Mac 79: 45_BW: Goldsby et al./ Immunology 5e Overview of the Immune System CHAPTER 1 creased permeability of capillaries. A particular kinin, called sponses are intimately involved in activating the specific im bradykinin, also stimulates pain receptors in the skin. This mune response. Conversely, various soluble factors produced ffect probably serves a protective role, because pain ne y a specific immune response have been shown to augment mally causes an individual to protect the injured area the activity of these phagocytic cells. As an inflammatory re- an injured tissue also enable enzymes of the blood-clotting duced that attract cells of the soluble mediators are pro- Vasodilation and the increase in capillary permeability in sponse develops, for examp mmune system. The immune system to enter the tissue. These enzymes activate an enzyme response will, in turn, serve to regulate the intensity of the in cascade that results in the deposition of insoluble strands of flammatory response. Through the carefully regulated inter fibrin, which is the main component of a blood clot. The fib- play of adaptive and innate immunity, the two systems work rin strands wall off the injured area from the rest of the body together to eliminate a foreign invader. and serve t the spread of infection. Once the infammatory response has subsided and most The Adaptive Immune System Requires repair and regeneration of new tissue begins. Capillaries Cooperation Between Lymphocytes and grow into the fibrin of a blood clot. New connective tissue Antigen-Presenting Cells cells, called fibroblasts, replace the fibrin as the clot dissolves. An effective immune response involves two major groups of As fibroblasts and capillaries accumulate, scar tissue forms. cells: T lymphocytes and antigen-presenting cells. Lympho The inflammatory response is described in more detail in cytes are one of many types of white blood cells produced in Chapter 15. the bone marrow by the process of hematopoiesis(see Chap- ter 2) Lymphocytes leave the bone marrow, circulate in the blood and lymphatic systems, and reside in various lym Adaptive Immunity phoid organs. Because they produce and display antigen binding cell-surface receptors, lymphocytes mediate the Adaptive immunity is capable of recognizing and selectively defining immunologic attributes of specificity, diversity, eliminating specific foreign microorganisms and molecules memory, and self/nonself recognition. The two major popu (i.e, foreign antigens). Unlike innate immune responses, lations of lymphocytes--Blymphocytes(B cells)and Tlym- adaptive immune responses are not the same in all members phocytes(T cells)-are described briefly here and in greater of a species but are reactions to specific antigenic challenges. detail in later chapters Adaptive immunity displays four characteristic attributes: B LYMPHOCYTES n Diversity B lymphocytes mature within the bone marrow; when they ave it, each expresses a unique antigen-binding receptor on a Immunologic memory its membrane(Figure 1-5a). This antigen-binding or B-cell n Self/nonself recognition receptor is a membrane-bound antibody molecule. Anti bodies are glycoproteins that consist of two identical heavy The antigenic specificity of the immune system permits it to polypeptide chains and two identical light polypeptic distinguish subtle differences among antigens. Antibodies chains. Each heavy chain is joined with a light chain by disul can distinguish between two protein molecules that differ in fide bonds, and additional disulfide bonds hold the two pairs only a single amino acid. The immune system is capable of together. The amino-terminal ends of the pairs of heavy and generating tremendous diversity in its recognition molecules, light chains form a cleft within which antigen binds. When a llowing it to recognize billions of unique structures on for- naive B cell (one that has not previously encountered anti- eign antigens. Once the immune system has recognized and gen)first encounters the antigen that matches its membrane- responded to an antigen, it exhibits immunologic memory; bound antibody, the binding of the antigen to the antibody that is, a second encounter with the same antigen induces a causes the cell to divide rapidly; its progeny differentiate into heightened state of immune reactivity. Because of this memory B cells and effector B cells called plasma cells tribute, the immune system can confer life-long immunity to Memory B cells have a longer life span than naive cells, and many infectious agents after an initial encounter. Finally, the they express the same membrane-bound antibody as their immune system normally responds only to foreign antigens, parent B cell. Plasma cells produce the antibody in a form indicating that it is capable of self/nonself recognition. The that can be secreted and have little or no membrane-bound ability of the immune system to distinguish self from nonself antibody. Although plasma cells live for only a few days, they d respond only to nonself molecules is essential, for, as de- secrete enormous amounts of antibody during this time scribed below, the outcome of an inappropriate response to It has been estimated that a single plasma cell can secrete self molecules can be fatal more than 2000 molecules of antibody per second. Secreted o Adaptive immunity is not independent of innate immu- antibodies are the major effector molecules of humoral ity. The phagocytic cells crucial to nonspecific immune re- immunity
creased permeability of capillaries. A particular kinin, called bradykinin, also stimulates pain receptors in the skin. This effect probably serves a protective role, because pain normally causes an individual to protect the injured area. Vasodilation and the increase in capillary permeability in an injured tissue also enable enzymes of the blood-clotting system to enter the tissue. These enzymes activate an enzyme cascade that results in the deposition of insoluble strands of fibrin, which is the main component of a blood clot. The fibrin strands wall off the injured area from the rest of the body and serve to prevent the spread of infection. Once the inflammatory response has subsided and most of the debris has been cleared away by phagocytic cells, tissue repair and regeneration of new tissue begins. Capillaries grow into the fibrin of a blood clot. New connective tissue cells, called fibroblasts, replace the fibrin as the clot dissolves. As fibroblasts and capillaries accumulate, scar tissue forms. The inflammatory response is described in more detail in Chapter 15. Adaptive Immunity Adaptive immunity is capable of recognizing and selectively eliminating specific foreign microorganisms and molecules (i.e., foreign antigens). Unlike innate immune responses, adaptive immune responses are not the same in all members of a species but are reactions to specific antigenic challenges. Adaptive immunity displays four characteristic attributes: ■ Antigenic specificity ■ Diversity ■ Immunologic memory ■ Self/nonself recognition The antigenic specificity of the immune system permits it to distinguish subtle differences among antigens. Antibodies can distinguish between two protein molecules that differ in only a single amino acid. The immune system is capable of generating tremendous diversity in its recognition molecules, allowing it to recognize billions of unique structures on foreign antigens. Once the immune system has recognized and responded to an antigen, it exhibits immunologic memory; that is, a second encounter with the same antigen induces a heightened state of immune reactivity. Because of this attribute, the immune system can confer life-long immunity to many infectious agents after an initial encounter. Finally, the immune system normally responds only to foreign antigens, indicating that it is capable of self/nonself recognition. The ability of the immune system to distinguish self from nonself and respond only to nonself molecules is essential, for, as described below, the outcome of an inappropriate response to self molecules can be fatal. Adaptive immunity is not independent of innate immunity. The phagocytic cells crucial to nonspecific immune responses are intimately involved in activating the specific immune response. Conversely, various soluble factors produced by a specific immune response have been shown to augment the activity of these phagocytic cells. As an inflammatory response develops, for example, soluble mediators are produced that attract cells of the immune system. The immune response will, in turn, serve to regulate the intensity of the inflammatory response. Through the carefully regulated interplay of adaptive and innate immunity, the two systems work together to eliminate a foreign invader. The Adaptive Immune System Requires Cooperation Between Lymphocytes and Antigen-Presenting Cells An effective immune response involves two major groups of cells: T lymphocytes and antigen-presenting cells. Lymphocytes are one of many types of white blood cells produced in the bone marrow by the process of hematopoiesis (see Chapter 2). Lymphocytes leave the bone marrow, circulate in the blood and lymphatic systems, and reside in various lymphoid organs. Because they produce and display antigenbinding cell-surface receptors, lymphocytes mediate the defining immunologic attributes of specificity, diversity, memory, and self/nonself recognition. The two major populations of lymphocytes—B lymphocytes (B cells) and T lymphocytes (T cells)—are described briefly here and in greater detail in later chapters. B LYMPHOCYTES B lymphocytes mature within the bone marrow; when they leave it, each expresses a unique antigen-binding receptor on its membrane (Figure 1-5a). This antigen-binding or B-cell receptor is a membrane-bound antibody molecule. Antibodies are glycoproteins that consist of two identical heavy polypeptide chains and two identical light polypeptide chains. Each heavy chain is joined with a light chain by disulfide bonds, and additional disulfide bonds hold the two pairs together. The amino-terminal ends of the pairs of heavy and light chains form a cleft within which antigen binds. When a naive B cell (one that has not previously encountered antigen) first encounters the antigen that matches its membranebound antibody, the binding of the antigen to the antibody causes the cell to divide rapidly; its progeny differentiate into memory B cells and effector B cells called plasma cells. Memory B cells have a longer life span than naive cells, and they express the same membrane-bound antibody as their parent B cell. Plasma cells produce the antibody in a form that can be secreted and have little or no membrane-bound antibody. Although plasma cells live for only a few days, they secrete enormous amounts of antibody during this time. It has been estimated that a single plasma cell can secrete more than 2000 molecules of antibody per second. Secreted antibodies are the major effector molecules of humoral immunity. Overview of the Immune System CHAPTER 1 9 8536d_ch01_001-023 8/1/02 4:25 PM Page 9 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
8536d_ch01_001-0238/1/02 4: 25 PM Page 10 mac79 Mac 79: 45_BW: Godsby et al. / Immunology 5e (a)B cell (b)TH cell (c)Tc cell TCR FIGURE 1-5 Distinctive membrane molecules on lymphocytes. (a) antigen associated with class I MHC molecules. In general, CD4* B cells have about 105 molecules of membrane-bound antibody per cells act as helper cells and CD8* cells act as cytotoxic cells.Both cell. All the antibody molecules on a given B cell have the same anti. types of T cells express about 105 identical molecules of the antigen- genic specificity and can interact directly with antigen.()T cells binding T-cell receptor(TCR) per cell, all with the same antigenic bearing CD4(CD4* cells)recognize only antigen bound to class ll specificity. MHC molecules. (c)T cells bearing CD8 (CD8 cells) recognize only LYMPHOCYTES an important role in activating B cells, Tc cells, macrophages, Tlymphocytes also arise in the bone marrow. Unlike B cells, and various other cells that participate in the immune re- which mature within the bone marrow, T cells migrate to the sponse. Differences in the pattern of cytokines produced by thymus gland to matt uring its maturation within the activated TH cells result in different types of immune thymus, the T cell comes to express a unique antigen-binding esp Inder the influence of TH-derived cytokines, a Tc cell membrane-bound antibodies on B cells, which can recognize that recognizes an antigen-MHC class I molecule complex antigen alone, T-cell receptors can recognize only antigen proliferates and differentiates into an effector cell called a cy- that is bound to cell-membrane proteins called major histo- totoxic T lymphocyte( CTL). In contrast to the Tccell,the compatibility complex(MHC)molecules. MHC molecules CTL generally does not secrete many cytokines and instead that function in this recognition event, which is termed "anti- exhibits cell-killing or cytotoxic activity. The Ctl has a vital gen presentation,"are polymorphic (genetically diverse)gly- function in monitoring the cells of the body and eliminating coproteins found on cell membranes(see Chapter 7). There any that display antigen, such as virus-infected cells,tumor are two major types of MHC molecules: Class I MHC mole- lls, and cells of a foreign tissue graft. Cells that display for cules, which are expressed by nearly all nucleated cells of ver- eign antigen complexed with a class I MHC molecule are tebrate species, consist of a heavy chain linked to a small called altered self-cells these are targets of CTls. invariant protein called B2-microglobulin. Class II MHC olecules, which consist of an alpha and a beta glycoprote ANTIGEN-PRESENTING CELLS chain, are expressed only by antigen-presenting cells. When a Activation of both the humoral and cell-mediated branches naive T cell encounters antigen combined with a MHC mol- of the immune system requires cytokines produced by Th ecule on a cell, the T cell proliferates and differentiates into cells. It is essential that activation of TH cells themselves be memory T cells and various effector T cells carefully regulated, because an inappropriate T-cell response There are two well-defined subpopulations of T cells: t to self-components can have fatal autoimmune conse- helper(TH)and T cytotoxic(Tc)cells. Although a third type quences. To ensure carefully regulated activation of TH cells, of T cell, called a T suppressor(Ts)cell, has been postulated, they can recognize only antigen that is displayed together recent evidence suggests that it may not be distinct from TH with class MHC II molecules on the surface of antigen-pre nd Tc subpopulations. T helper and T cytotoxic cells can be senting cells(APCs). These specialized cells, which include distinguished from one another by the presence of either macrophages, B lymphocytes, and dendritic cells, are distin- CD4 or CD8 membrane glycoproteins on their surfaces (Fig- guished by two properties: (1) they express class II MHC ure 1-5b, c). T cells displaying CD4 generally function as TH molecules on their membranes, and(2) they are able to lls, whereas those displaying CD8 generally function as Tc deliver a co-stimulatory signal that is necessary for TH-cell cells(see Chapter 2) ctIvation After a TH cell recognizes and interacts with an anti Antigen-presenting cells first internalize antigen, either by gen-MHC class II molecule complex, the cell is activated -it phagocytosis or by endocytosis, and then display a part of becomes an effector cell that secretes various growth factors that antigen on their membrane bound to a class II mHC known collectively as cytokines. The secreted cytokines play molecule. The TH cell recognizes and interacts with the
T LYMPHOCYTES T lymphocytes also arise in the bone marrow. Unlike B cells, which mature within the bone marrow, T cells migrate to the thymus gland to mature. During its maturation within the thymus, the T cell comes to express a unique antigen-binding molecule, called the T-cell receptor, on its membrane. Unlike membrane-bound antibodies on B cells, which can recognize antigen alone, T-cell receptors can recognize only antigen that is bound to cell-membrane proteins called major histocompatibility complex (MHC) molecules. MHC molecules that function in this recognition event, which is termed “antigen presentation,” are polymorphic (genetically diverse) glycoproteins found on cell membranes (see Chapter 7). There are two major types of MHC molecules: Class I MHC molecules, which are expressed by nearly all nucleated cells of vertebrate species, consist of a heavy chain linked to a small invariant protein called 2-microglobulin. Class II MHC molecules, which consist of an alpha and a beta glycoprotein chain, are expressed only by antigen-presenting cells. When a naive T cell encounters antigen combined with a MHC molecule on a cell, the T cell proliferates and differentiates into memory T cells and various effector T cells. There are two well-defined subpopulations of T cells: T helper (TH) and T cytotoxic (TC) cells.Although a third type of T cell, called a T suppressor (TS) cell, has been postulated, recent evidence suggests that it may not be distinct from TH and TC subpopulations. T helper and T cytotoxic cells can be distinguished from one another by the presence of either CD4 or CD8 membrane glycoproteins on their surfaces (Figure 1-5b,c). T cells displaying CD4 generally function as TH cells, whereas those displaying CD8 generally function as TC cells (see Chapter 2). After a TH cell recognizes and interacts with an antigen–MHC class II molecule complex, the cell is activated—it becomes an effector cell that secretes various growth factors known collectively as cytokines. The secreted cytokines play an important role in activating B cells, TC cells, macrophages, and various other cells that participate in the immune response. Differences in the pattern of cytokines produced by activated TH cells result in different types of immune response. Under the influence of TH-derived cytokines, a TC cell that recognizes an antigen–MHC class I molecule complex proliferates and differentiates into an effector cell called a cytotoxic T lymphocyte (CTL). In contrast to the TC cell, the CTL generally does not secrete many cytokines and instead exhibits cell-killing or cytotoxic activity. The CTL has a vital function in monitoring the cells of the body and eliminating any that display antigen, such as virus-infected cells, tumor cells, and cells of a foreign tissue graft. Cells that display foreign antigen complexed with a class I MHC molecule are called altered self-cells; these are targets of CTLs. ANTIGEN-PRESENTING CELLS Activation of both the humoral and cell-mediated branches of the immune system requires cytokines produced by TH cells. It is essential that activation of TH cells themselves be carefully regulated, because an inappropriate T-cell response to self-components can have fatal autoimmune consequences. To ensure carefully regulated activation of TH cells, they can recognize only antigen that is displayed together with class MHC II molecules on the surface of antigen-presenting cells (APCs). These specialized cells, which include macrophages, B lymphocytes, and dendritic cells, are distinguished by two properties: (1) they express class II MHC molecules on their membranes, and (2) they are able to deliver a co-stimulatory signal that is necessary for TH-cell activation. Antigen-presenting cells first internalize antigen, either by phagocytosis or by endocytosis, and then display a part of that antigen on their membrane bound to a class II MHC molecule. The TH cell recognizes and interacts with the 10 PART I Introduction (a) B cell Antigenbinding receptor (antibody) (b) TH cell (c) TC cell CD4 TCR CD8 TCR FIGURE 1-5 Distinctive membrane molecules on lymphocytes. (a) B cells have about 105 molecules of membrane-bound antibody per cell. All the antibody molecules on a given B cell have the same antigenic specificity and can interact directly with antigen. (b) T cells bearing CD4 (CD4+ cells) recognize only antigen bound to class II MHC molecules. (c) T cells bearing CD8 (CD8+ cells) recognize only antigen associated with class I MHC molecules. In general, CD4+ cells act as helper cells and CD8+ cells act as cytotoxic cells. Both types of T cells express about 105 identical molecules of the antigenbinding T-cell receptor (TCR) per cell, all with the same antigenic specificity. 8536d_ch01_001-023 8/1/02 4:25 PM Page 10 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: