1、General Properties of Immune Responses The term immunity is derived from the Latin word immunitas, which referred to the protection from legal prosecution offered to Roman senators during their tenures in office. Historically, immunity meant protection from disease and, more specifically, infectious
2、 disease. The cells and molecules responsible for immunity constitute the immune system, and their collective and coordinated response to the introduction of foreign substances is called the immune response. The physiologic function of the immune system is defense against infectious microbes. Howeve
3、r, even noninfectious foreign substances can elicit immune responses. Furthermore, mechanisms that normally protect individuals from infection and eliminate foreign substances are themselves capable of causing tissue injury and disease in some situations. Therefore, a more inclusive definition of im
4、munity is a reaction to foreign substances, including microbes, as well as to macromolecules such as proteins and polysaccharides, regardless of the physiologic or pathologic consequence of such a reaction. Immunology is the study of immunity in this broader sense and of the cellular and molecular e
5、vents that occur after an organism encounters microbes and other foreign macromolecules. Historians often credit Thucydides, in Athens during the fifth century BC, as having first mentioned immunity to an infection that he called “plague” (but that was probably not the bubonic plague we recognize to
6、day). The concept of immunity may have existed long before, as suggested by the ancient Chinese custom of making children resistant to smallpox by having them inhale powders made from the skin lesions of patients recovering from the disease. Immunology, in its modern form, is an experimental science
7、, in which explanations of immunologic phenomena are based on experimental observations and the conclusions drawn from them. The evolution of immunology as an experimental discipline has depended on our ability to manipulate the function of the immune system under controlled conditions. Historically
8、, the first clear example of this manipulation, and one that remains among the most dramatic ever recorded, was Edward Jenners successful vaccination against smallpox. Jenner, an English physician, noticed that milkmaids who had recovered from cowpox never contracted the more serious smallpox. On th
9、e basis of the observation, he injected the material from a cowpox pustule into the arm of an 8-year-old boy. When this boy was later intentionally inoculated with smallpox, the disease did not develop. Jenners landmark treatise on vaccination (Latin vaccines, of or from cows) was published in 1798.
10、 It led to the widespread acceptance of this method for inducing immunity to infectious diseases, and vaccination remains the most effective method for preventing infections. An eloquent testament to the importance of immunology was the announcement by the World Health Organization in 1980 that smal
11、lpox was the first disease that had been eradicated worldwide by a program of vaccination. Since the 1960s, there has been a remarkable transformation in our understanding of the immune system and its functions. Advances in cell culture techniques (including monoclonal antibody production), immunoch
12、emistry, recombinant DNA methodology, x-ray crystallography, and creation of genetically altered animals (especially transgenic and knockout mice) have changed immunology from a largely descriptive science into one in which diverse immune phenomena can be explained in structural and biochemical term
13、s. Innate and Adaptive Immunity Defense against microbes is mediated by the early reactions of innate immunity and the later responses of adaptive immunity. Innate immunity (also called natural or native immunity) consists of cellular and biochemical defense mechanisms that are in place even before
14、infection and poised to respond rapidly to infections. These mechanisms react only to microbes and not to noninfectious substances, and they respond in essentially the same way to repeated infections. The principal components of innate immunity are (1) physical and chemical barriers, such as epithel
15、ia and antimicrobial substances produced at epithelial surfaces; (2) phagocytic cells (neutrophils, macrophages) and NK (natural killer) cells; (3) blood proteins, including members of the complement system and other mediators of inflammation; and (4) proteins called cytokines that regulate and coor
16、dinate many of the activities of the cells of innate immunity. The mechanisms of innate immunity are specific for structures that are common to groups of related microbes and may not distinguish fine differences between foreign substances. Innate immunity provides the early lines of defense against
17、microbes. In contrast to innate immunity, there are other immune responses that are stimulated by exposure to infectious agents and increase in magnitude and defensive capabilities with each successive exposure to a particular microbe. Because this form of immunity develops as a response to infectio
18、n and adapts to the infection, it is called adaptive immunity. The defining characteristics of adaptive immunity are exquisite specificity for distinct molecules and an ability to “remember” and respond more vigorously to repeated exposures to the same microbe. The adaptive immune system is able to
19、recognize and react to a large number of microbial and nonmicrobial substances. In addition, it has an extraordinary capacity to distinguish among different, even closely related, microbes and molecules, and for this reason it is also called specific immunity, to emphasize that potent protective res
20、ponses are “acquired” by experience. The components of adaptive immunity are lymphocytes and their products. Foreign substances that induce specific immune responses or are the targets of such responses are called antigens. By convention, the terms immune responses and immune system refer to adaptiv
21、e immunity, unless stated otherwise. Innate and adaptive immune responses are components of an integrated system of host defense in which numerous cells and molecules function cooperatively. The mechanisms of innate immunity provide effective defense against infections. However, many pathogenic micr
22、obes have evolved to resist innate immunity, and their elimination requires the powerful mechanisms of adaptive immunity. There are two important links between innate immunity and adaptive immunity. First, the innate immune response to microbes stimulates adaptive immune responses and influences the
23、 nature of the adaptive responses. Second, adaptive immune responses use many of the effector mechanisms of innate immunity to eliminate microbes, and they often function by enhancing the antimicrobial activities of the defense mechanisms of innate immunity. Innate immunity is phylogenetically the o
24、ldest system of host defense, and the adaptive immune system evolved later. In invertebrates, host defense against foreign invaders is mediated largely by the mechanisms of innate immunity, including phagocytes and circulating molecules that resemble the plasma proteins of innate immunity in vertebr
25、ates. Adaptive immunity, consisting of lymphocytes and antibodies, first appeared in jawed vertebrates and became increasingly specialized with further evolution. Types of Adaptive Immune Responses There are two types of adaptive immune responses, called humoral immunity and cell-mediated immunity,
26、that are mediated by different components of the immune system and function to eliminate different types of microbes. Humoral immunity is mediated by molecules in the blood and mucosal secretions, called antibodies, that are produced by cells called B lymphocytes (also called B cells). Antibodies re
27、cognize microbial antigens, neutralize the infectivity of the microbes, and target microbes for elimination by various effector mechanisms. Humoral immunity is the principal defense mechanism against extracellular microbes and their toxins because secreted antibodies can bind to these microbes and t
28、oxins and assist in their elimination. Antibodies themselves are specialized, and different types of antibodies may activate different effector mechanisms. For example, some types of antibodies promote phagocytosis, and others trigger the release of inflammatory mediators from leukocytes such as mas
29、t cells. Cell-mediated immunity, also called cellular immunity, is mediated by T lymphocytes (also called T cells). Intracellular microbes, such as viruses and some bacteria, survive and proliferate inside phagocytes and other host cells, where they are inaccessible to circulating antibodies. Defens
30、e against such infections is a function of cell-mediated immunity, which promotes the destruction of microbes residing in phagocytes or the killing of infected cells to eliminate interiors of infection. Protective immunity against a microbe may be induced by the hosts response to the microbe or by t
31、he transfer of antibodies or lymphocytes specific for the microbe. The form of immunity that is induced by exposure to a foreign antigen is called active immunity because the immunized individual plays an active role in responding to the antigen. Individuals and lymphocytes that have not encountered
32、 a particular antigen are said to be naive. Individuals who have responded to a microbial antigen and are protected from subsequent exposures to that microbe are said to line immune. Immunity can also be conferred on an individual by transferring serum or lymphocytes from a specifically immunized in
33、dividual, a process known as adaptive transfer in experimental situations. The recipient of such a transfer becomes immune to the particular antigen without ever having been exposed to or having responded to that antigen. Therefore, this form of immunity is called passive immunity. Passive immunizat
34、ion is a useful method for conferring resistance rapidly, without having to wait for an active immune response to develop. An example of passive immunity is the transfer of maternal antibodies to the fetus, which enables newborns to combat infections before they acquire the ability to produce antibo
35、dies themselves. Passive immunization against bacterial toxins by the administration of antibodies from immunized animals is a lifesaving treatment of potentially lethal infections, such as tetanus. The technique of adoptive transfer has also made it possible to define the various cells and molecule
36、s that are responsible for mediating specific immunity. In fact, humoral immunity was originally defined as the type of immunity that could be transferred to unimmunized, or na ve, individuals by antibody containing cell-free portions of the blood (i.e., plasma or serum once called humors) obtained
37、from previously immunized individuals. Similarly, cell-mediated immunity was defined as the form of immunity that can be transferred to naive individuals with cells (T lymphocytes) from immunized individuals but not with plasma or serum. The first experimental demonstration of humoral immunitv was p
38、rovided by Emil von Behring and Shibasaburo Kitasato in 1890. They showed that if serum from animals who had recovered from diphtheria infection was transferred to naive animals, the recipients became specifically resistant to diphtheria infection. The active components of the serum were called anti
39、toxins because they neutralized the pathologic effects of the diphtheria toxin. In the early 1900s, Karl Landsteiner and other investigators showed that not only toxins but also nonmicrobial substances could induce humoral immune responses. From such studies arose the more general germ antibodies fo
40、r the serum proteins that mediate humoral immunity. Substances that bound antibodies and generated the production of antibodies were then called antigens. In 1900, Pual Ehrlich provided a theoretical framework for the specificity of antigen-antibody reactions, the experimental proof for which came d
41、uring the next 50 years from the work of Land Steiner and others using simple chemicals as antigens. Ehrlichs theories of the physicochemical complementarity of antigens and antibodies are remarkable for their prescience. This early emphasis on antibodies led to the general acceptance of the humoral
42、 theory of immunity, according to which immunity is mediated by substances present in body fluids. The cellular theory of immunity, which stated that host cells were the principal mediators of immunity, was championed initially by Elie Metchnikoff. His demonstration of phagocytes surrounding a thorn
43、 stuck into a translucent starfish larva, published in 1893, was perhaps the first experimental evidence that cells respond to foreign invaders. Sir Almroth Wrights observation in the early 1900s that factors in immune serum enhanced the phagocytosis of bacteria by coating the bacteria, a process kn
44、own as opsonization, lent support to the belief that antibodies prepared microbes for ingestion by phagocytes. These early “cellularists” were unable to prove that specific immunity to microbes could be mediated by cells. The cellular theory of immunity became firmly established in the 1950s, when G
45、eorge Mackaness showed that resistance to an intracellular bacterium, Listeria monocytogenes, could be adoptively transferred with cells but not with serum. We now know that the specificity of cell-mediated immunity is due to lymphocytes, which often function in concert with other cells, such as pha
46、gocytes, to eliminate microbes. In the clinical setting, immunity to a previously encountered microbe is measured indirectly, either by assaying for the presence of products of immune responses (such as serum antibodies specific for microbial antigens) or by administering substances purified from th
47、e microbe and measuring reactions to these substances. A reaction to a microbial antigen is detectable only in individuals who have previously encountered the antigen; these individuals are said to be “sensitized” to the antigen, and the reaction is an indication of “sensitivity”. Although the react
48、ion to the purified antigen has no protective function, it implies that the sensitized individual is capable of mounting a protective immune response to the microbe. Cardinal Features of Adaptive Immune Responses All humoral and cell-mediated immune responses to foreign antigens have a number of fun
49、damental properties that reflect the properties of the lymphocytes that mediate these responses. Specificity and diversity. Immune responses are specific for distinct antigens and, in fact, for different portions of a single complex protein, polysaccharide, or other macromolecule. The parts of such antigens that are specifically recognized by individual lymphocytes are called determinants or epitopes. This fine specificity exists because individual lymphocytes express membrane receptors that are able to distinguish subtle differences in structure between distinct antigens. Clones of ly
