1、8536d_ch01_001-023 8/1/02 4:25 PM Page 1 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:chapter 1Overview of the Immune SystemTfrom invading pathogenic microorganisms anddefense system that has evolved to protect animalscancer.It is able to generate an enormous variety of cells and molecules capa

2、ble 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 activitiesrecognition

3、 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. Further- more, the system is able to discriminate between foreign molecules and the bodys own cells and proteins

4、. Once a for- eign organism has been recognized, the immune system recruits a variety of cells and molecules to mount an appro- priate 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 variet

5、y 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- nate the pathogen and prevent disease.This chapter

6、introduces the study of immunology froman 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 certai

7、n invertebrate organisms then gives an evolutionary perspective on the mammalian immune system, which is the major subject of this book. El- ements of the primitive immune system persist in verte- brates as innate immunity along with a more highly evolved system of specific responses termed adaptive

8、 immunity. These two systems work in concert to provide a high degree of protection for vertebrate species. Finally, in some circum- stances, the immune system fails to act as protector because of some deficiency in its components; at other times, it be- comes an aggressor and turns its awesome powe

9、rs 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, ex- perimental approaches, and in-depth definitions are left to the chapters that follow.Like the later chap

10、ters covering basic topics in immu- nology, this one includes a section called “Clinical Focus” that describes human disease and its relation to immunity. These sections investigate the causes, consequences, or treat- ments of diseases rooted in impaired or hyperactive immune function.Historical Per

11、spectiveThe 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

12、infectious disease.Perhaps the earliest written reference to the phenomenon of immunity can be traced back to Thucydides, the great his- torian of the Peloponnesian War.In describing a plague in Athens, he wrote in 430 BC that only those who had recov- ered from the plague could nurse the sick becau

13、se they would not contract the disease a second time. Although early societies recognized the phenomenon of immunity, almostNumerous T Lymphocytes Interacting with a Single Macrophage Historical Perspective Innate Immunity Adaptive Immunity Comparative Immunity Immune Dysfunction and Its Consequence

14、s8536d_ch01_001-023 8/1/02 4:25 PM Page 2 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:2PART I Introductiontwo 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

15、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 a

16、mbassador 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 mi

17、ld 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

18、fluid from a cowpox pustule and later intentionally infected the child with smallpox. As pre- dicted, the child did not develop smallpox.Jenners technique of inoculating with cowpox to protectagainst smallpox spread quickly throughout Europe. How- ever, for many reasons, including a lack of obvious

19、disease targets and knowledge of their causes, it was nearly a hun- dred years before this technique was applied to other dis- eases. 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.

20、Louis Pasteur had succeeded in growing the bac- terium thought to cause fowl cholera in culture and then had shownthatchickensinjectedwiththeculturedbacteriumde- veloped cholera. After returning from a summer vacation, he injected some chickens with an old culture. The chickens be- came ill, but, to

21、 Pasteurs 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 previouslyinjectedchickens.Againtohissurprise,thechick- ens were c

22、ompletely protected from the disease. Pasteur hypothesized and proved that aging had weakened the viru- lence 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

23、honor of Jenners work with cowpox inoculation.Pasteur extended these findings to other diseases, demon-strating 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, Pas- teur first vaccinat

24、ed one group of sheep with heat-attenuated anthrax bacillus (Bacillus anthracis); he then challenged the vaccinated sheep and some unvaccinated sheep with a viru- lentculture of the bacillus. All the vaccinated sheep lived,and all the unvaccinated animals died. These experiments marked the beginning

25、s of the discipline of immunology. InFIGURE 1-1 Wood engraving of Louis Pasteur watching JosephMeister receive the rabies vaccine. From Harpers Weekly 29:836;courtesy of the National Library of Medicine.1885, Pasteur administered his first vaccine to a human, a young boy who had been bitten repeated

26、ly 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 SystemAlthough Pasteur proved that vaccin

27、ation worked, he did not understand how. The experimental work of Emil von Behring and Shibasaburo Kitasato in 1890 gave the first in- sights 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 liq

28、uid, noncellu- lar component of coagulated blood) from animals previously immunized to diphtheria could transfer the immune state to unimmunized animals. In search of the protective agent, var- ious researchers during the next decade demonstrated that an active component from immune serum could neut

29、ralize toxins, precipitate toxins, and agglutinate (clump) bacteria. In each case, the active agent was named for the activity it ex- hibited: antitoxin, precipitin, and agglutinin, respectively.8536d_ch01_001-023 8/1/024:25 PM Page 3 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:3Overview of th

30、e Immune System CHAPTER 1YearRecipientCountryResearch190119051908Emil von BehringRobert KochElie Metchnikoff Paul EhrlichCharles Richet Jules Border Karl Landsteiner Max Theiler Daniel BovetF. Macfarlane Burnet Peter MedawarRodney R. Porter Gerald M. EdelmanRosalyn R. YalowGeorge Snell Jean Daussct

31、Baruj BenacerrafCesar Milstein Georges E. KhlerNiels K. Jerne Susumu TonegawaGermanyGermanyRussia GermanyFrance Belgium United States South Africa SwitzerlandAustralia Great BritainGreat Britain United StatesUnited StatesUnited States France United StatesGreat Britain GermanyDenmark JapanSerum antit

32、oxinsCellular immunity to tuberculosisRole of phagocytosis (Metchnikoff) and antitoxins (Ehrlich) in immunityAnaphylaxisComplement-mediated bacteriolysis Discovery of human blood groups Development of yellow fever vaccine AntihistaminesDiscovery of acquired immunological toleranceChemical structure

33、of antibodies191319191930195119571960197219771980Development of radioimmunoassayMajor histocompatibility complex1984Monoclonal antibodyImmune regulatory theoriesGene rearrangement in antibody productionTransplantation immunology19871991E. Donnall Thomas Joseph MurrayPeter C. Doherty Rolf M. Zinkerna

34、gelUnited States United StatesAustralia Switzerland1996Role of major histocompatibility complex in antigen recognition by by T cellsInitially, a different serum component was thought to be re- sponsible for each activity, but during the 1930s, mainly through the efforts of Elvin Kabat, a fraction of

35、 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. Be- cause immunity was mediated by antibodies contained in body fluids (known at the time as humors), it was called

36、 hu- moral immunity.In 1883, even before the discovery that a serum compo- nent could transfer immunity, Elie Metchnikoff demon- strated 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 (phagocyto

37、se) mi- croorganisms and other foreign material. Noting that these phagocytic cells were more active in animals that had been immunized, Metchnikoff hypothesized thatcells,rather than serum components, were the major effector of immunity. The active phagocytic cells identified by Metchnikoff were li

38、kely 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 Metchnikoffs concept of cell-mediated im- munity. It was later shown that both are correctimmunity requires both cellular an

39、d humoral responses. It was difficult to study the activities of immune cells before the develop- ment 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, inform

40、ation 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 inter

41、est in cellular immu- nity. With the emergence of improved cell culture techniques in the 1950s, the lymphocyte was identified as the cell re- sponsible for both cellular and humoral immunity. Soon thereafter, experiments with chickens pioneered by Bruce Glick at Mississippi State University indicat

42、ed that there wereTABLE 1-1 Nobel Prizes for immunologic research8536d_ch01_001-023 8/1/02 4:25 PM Page 4 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:4PART I Introductiontwo types of lymphocytes: T lymphocytes derived from the thymus mediated cellular immunity, and B lymphocytes from the bursa

43、 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 re- solved when the two systems were shown to be intertwined, and that both systems were necessary for the immune response.In the 1930s and 1940

44、s, the selective theory was chal- lenged by various instructional theories, in which antigen played a central role in determining the specificity of the an- tibody molecule. According to the instructional theories, a particular antigen would serve as a template around which antibody would fold. The

45、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 in- structional theories were formal

46、ly 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 anti- bodies against almost anything.In the 1950s, selective theories resurfaced as a result of new exp

47、erimental data and, through the insights of Niels Jerne, David Talmadge, and F. Macfarlane Burnet, were re- fined into a theory that came to be known as the clonal- selection theory. According to this theory, an individual lymphocyte expresses membrane receptors that are specific for a distinct anti

48、gen. This unique receptor specificity is de- termined 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 clonal- selection

49、theory has been further refined and is now accepted asthe underlying paradigm ofmodern immunology.Early Theories Attempted to Explain the Specificity of the Antibody Antigen InteractionOne of the greatest enigmas facing early immunologists was the specificity of the antibody molecule for foreign mat

50、erial, 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 demonstrat- ing specific immune reactivity to nonpathogenic substances, such as red blood cells from other species. Serum f

51、rom an an- imal 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 trans- ferring serum from the first. The work of Karl Landsteiner and those who followed him showed that injec

52、ting 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 re- sponses to compounds that had only recently been s

53、ynthe- sized 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 the

54、ory and the in- structional theory.The earliest conception of the selective theory dates to PaulEhrlich in 1900. In an attempt to explain the origin of serum antibody, Ehrlich proposedthatcells in the blood expresseda variety of receptors, which he called “side-chain receptors,” that could react wit

55、h 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 be

56、tween an infectious agent and a cell-bound receptor would induce the cell to produce and release more receptors with the same specificity. According to Ehrlichs theory, the specificity of the receptor was determined before its exposure to antigen, and the antigen selected the appro- priate receptor.

57、 Ultimately all aspects of Ehrlichs 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.The Immune System Includes Innate and A

58、daptive ComponentsImmunitythe state of protection from infectious diseasehas 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 con- stitute 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