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: