Edelman United States Rosalyn R.
Doherty Australia Role of major histocompatibility complex Rolf M. It was later shown that both are correct—immunityto be responsible for all these activities. The active molecules requires both cellular and humoral responses. It was difficultin 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 studiesbody fluids known at the time as humors , it was called hu- with serum took advantage of the ready availability of bloodmoral immunity.
Because of these In , even before the discovery that a serum compo- technical problems, information about cellular immunitynent could transfer immunity, Elie Metchnikoff demon- lagged behind findings that concerned humoral immunity.
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He observed that certain white blood cells, which he in transferring immunity against the tuberculosis organismtermed phagocytes, were able to ingest phagocytose mi- by transferring white blood cells between guinea pigs. Thiscroorganisms 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 techniquesimmunized, Metchnikoff hypothesized that cells, rather than in the s, the lymphocyte was identified as the cell re-serum components, were the major effector of immunity.
SoonThe active phagocytic cells identified by Metchnikoff were thereafter, experiments with chickens pioneered by Brucelikely blood monocytes and neutrophils see Chapter 2. Glick at Mississippi State University indicated that there were 4. The controversy tibody molecule. According to the instructional theories, aabout the roles of humoral and cellular immunity was re- particular antigen would serve as a template around whichsolved when the two systems were shown to be intertwined, antibody would fold. The antibody molecule would therebyand that both systems were necessary for the immune assume a configuration complementary to that of the antigenresponse.
This concept was first postulated by Friedrich Breinl and Felix Haurowitz about and redefined in theEarly Theories Attempted to Explain s in terms of protein folding by Linus Pauling. The in-the Specificity of the Antibody— structional theories were formally disproved in the s, by which time information was emerging about the structure ofAntigen Interaction DNA, RNA, and protein that would offer new insights intoOne 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.
Around , Jules Bordet at the Pasteur new experimental data and, through the insights of NielsInstitute expanded the concept of immunity by demonstrat- Jerne, David Talmadge, and F. 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 individualimal inoculated previously with material that did not cause lymphocyte expresses membrane receptors that are specificinfection 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.
The work of Karl Landsteiner Binding of antigen to its specific receptor activates the cell,and those who followed him showed that injecting an animal causing it to proliferate into a clone of cells that have thewith 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. In addition, it was shown that molecules differing in Adaptive Componentsthe smallest detail could be distinguished by their reactivity Immunity—the state of protection from infectious diseasewith different antibodies.
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Two major theories were proposed —has both a less specific and more specific component. Theto account for this specificity: the selective theory and the in- less specific component, innate immunity, provides the firststructional theory. Most components of innate The earliest conception of the selective theory dates to Paul immunity are present before the onset of infection and con-Ehrlich in PhagocyticBorrowing a concept used by Emil Fischer in to explain cells, such as macrophages and neutrophils, barriers such asthe interaction between an enzyme and its substrate, Ehrlich skin, and a variety of antimicrobial compounds synthesizedproposed that binding of the receptor to an infectious agent by the host all play important roles in innate immunity.
Inwas like the fit between a lock and key. Ehrlich suggested that contrast to the broad reactivity of the innate immune sys-interaction 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 intoreceptors with the same specificity.
Exposure to the same antigen somecell-bound receptor; it is the soluble form that is secreted time in the future results in a memory response: the immunerather than the bound form released. Overview of the Immune System CHAPTER 1 5the first, is stronger, and is often more effective in neutraliz- distinct layers: a thinner outer layer—the epidermis—and aing and clearing the pathogen. The major agents of adaptive thicker layer—the dermis. The epidermis contains severalimmunity are lymphocytes and the antibodies and other layers of tightly packed epithelial cells.
The outer epidermalmolecules they produce. The sebaceous glands are as-pathogen. In general, most of the microorganisms encoun- sociated with the hair follicles and produce an oily secretiontered 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 pHbefore they activate the adaptive immune system.
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 pre-Innate Immunity vents the formation of sebum. Innate immunity can be seen to comprise four types of de- Breaks in the skin resulting from scratches, wounds, orfensive barriers: anatomic, physiologic, phagocytic, and in- abrasion are obvious routes of infection. The skin may alsoflammatory Table The protozoan that causes malaria, for example, is depositedProtective Barriers Against Infection in humans by mosquitoes when they take a blood meal.
The skin and the surface of mucous membranes are The conjunctivae and the alimentary, respiratory, andincluded in this category because they are effective barriers to urogenital tracts are lined by mucous membranes, not by thethe entry of most microorganisms. The skin consists of two dry, protective skin that covers the exterior of the body. 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. 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. Although many pathogens are not. For example, saliva, tears, and mucous se-cretions act to wash away potential invaders and also contain General Conditions and Specific Moleculesantibacterial 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 temperaturehairlike 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 bodymicroorganisms from these tracts.
In addition, nonpatho- 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 verycosal surfaces. These normal flora generally outcompete few ingested microorganisms can survive the low pH of thepathogens for attachment sites on the epithelial cell surface stomach contents. One reason newborns are susceptible toand for necessary nutrients.
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 init to attach firmly to cells in mucous membranes of the respi- mucous secretions and in tears, is able to cleave the peptido-ratory tract, preventing the virus from being swept out by the glycan layer of the bacterial cell wall. Interferon comprises aciliated epithelial cells. Similarly, the organism that causes group of proteins produced by virus-infected cells. Amonggonorrhea has surface projections that allow it to bind to ep- the many functions of the interferons is the ability to bind toithelial cells in the mucous membrane of the urogenital tract.
Comple-Adherence of bacteria to mucous membranes is due to inter- ment, examined in detail in Chapter 13, is a group of serumactions 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 convertare expressed only by epithelial cells of the mucous mem- the inactive forms of complement proteins into an activebrane of particular tissues Figure For this reason, some state with the ability to damage the membranes of patho- 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- FIGURE Electron micrograph of rod-shaped Escherichia coli nents described above, or they may be cell-associated receptors.
Among the class of receptors designated the toll-like receptors[From N.
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Sharon and H. Lis, , Sci. It has long been recognized that 7. The bacteria are phagocytized as de-scribed in part b and breakdown products secreted. The monocyte purple has been recruited to the vicinity of the encounter by solublefactors secreted by the macrophage. The red sphere is an erythrocyte.
The mechanism for this response is via a TLR onmacrophages that recognizes LPS and elicits a variety of mole-cules in the inflammatory response upon exposure. When theTLR is exposed to the LPS upon local invasion by a Gram-neg-ative bacterium, the contained response results in eliminationof the bacterial challenge.
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