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 thantwo 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 re￾solved 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 demonstrat￾ing specific immune reactivity to nonpathogenic substances, such as red blood cells from other species. Serum from 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 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 re￾sponses to compounds that had only recently been synthe￾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 theory and the in￾structional 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 appro￾priate 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 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 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 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 anti￾bodies 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 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 antigen. 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 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 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 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 sys￾tem, which is uniform in all members of a species, the spe￾cific 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 de￾gree 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 ex￾posure 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: