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7 The Immune System and Infectious Diseases THE IMMUNE SYSTEM Vertebrates Developed the Immune System to Deal with Pathogenic Microorganisms, Malignant Cells, and Macromolecules The immune system orchestrates a potent defense that consists of the produc- tion of specific antibody molecules and lymphocytes capable of reacting with and inactivating foreign agents, either directly or indirectly through the involvement of molecular and cellular inflammatory processes. The importance of the immune system to our survival in the face of the wide variety of disease-causing agents is tragically demonstrated by the devastating consequences of the immunological impairment of acquired immune deficiency syndrome (AIDS) and of congenital immunological deficiencies such as severe combined immunodeficiency (SCID) in infants. On the other hand, the enormous power of the immune system as a protection against pathogenic agents carries with it the price that the action of the system may lead to or exacerbate a series of immunological diseases, including systemic lupus erythematosus, rheumatoid arthritis, and type I diabetes (juvenile onset). The immune system is composed mainly of lymphocytes and macrophages. The cells of the immune system are found in the blood and lymph, where they are in a recirculating pool, and in the spleen, lymph nodes, and lymphoid tissues associated with the gastrointestinal tract, the brochopulmonary tree, and mucosal surfaces. Lymphocytes and macrophages develop in the thymus and the bone marrow. Although each cell type in the immune system has a major role to play, it is the lymphocytes that form the unique elements of the system since they display 224
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THE IMMUNE SYSIEM AND INFECTIOUS DISEASES 225 the antigenic specificity that is the hallmark of immunity. Lymphocytes are of two major types, B cells and T cells. B cells are the antecedents of antibody- producing cells, whereas T cells have their major effects in regulating the level of activity of the immune system and in mediating cellular effecter mechanisms of immunity, such as destroying virus-infected cells and tumor cells. The study of the immune system has proven to be of great importance in efforts to understand and to regulate immune responses, both to enhance the system's protective actions against microbes and tumor cells and to control its actions in the development of autoimmune diseases and other disorders with immunological components. In addition, the cells of the immune system are valuable in the study of many aspects of normal biology of mammalian cells since they are easily accessible, have been extensively characterized, and can be easily grown. Specificity of the Immune Response Perhaps the Most Remarkable Aspect of the Immune System Is Its Specificity Each of us has the capacity to make a specific immune response to a vast array of foreign macromolecules: The body develops antibody molecules specific for structures (antigenic determinants called epitopes) on the foreign agent and produces B and T lymphocytes that bear membrane receptors specific for these epitopes. We now recognize that the capacity of the immune system to respond to millions of different foreign antigens depends on the existence of an internal universe of distinct lymphocytes, each capable of mounting an immune response against only one set of structurally related antigens. The capacity of individual lymphocytes to respond to only a single set of molecules is coupled with a rapid and selective increase in the number of these lymphocytes as a result of the introduction of the specific antigen (Figure 7-1~. This increase results in the formation of clones of specific lymphocytes, a prop- erty that led to the designation of the clonal selection theory to describe the concept that the enormous specificity of the immune response is achieved by the antigen-mediated selection of individual cells (or clones of cells), each with but a single specificity. Selected clones not only increase in number, but also differen- tiate into antibody-producing cells (B cells) or into active regulatory cells or killer cells (T cells). Such selection of B cells and the parallel process of T-cell se- lection forms the basis of protective immune responses. The capacity of the immune system to make B-cell and T-cell responses to virtually any foreign substance is based on unique mechanisms that allow the assemblage of genes for the extremely large number of alternative forms of antibodies and receptors. Recent progress in the application of molecular biologi- cal techniques to the study of lymphocytes has led to a solution of this central biological problem. In order to understand the molecular mechanisms respon
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226 OPPORTUNITIES IN BIOLOGY Antigen-independent diversifictaion rl I I I 1 1 1 1 1 ` Antigen of ˘5D Antibody 3 Antigen-dependent proliferation and differentiation Antibody 99 FIGURE 7-1 Lymphocytes undergo antigen-independent diversification and antigen-dependent growth and differentiation. Lymphocyte precursors develop into mature lymphocytes through an antigen-independent process that involves rearrangements of genes for the variable regions of im- munoglobulins (for B cells) or for the variable regions of T-cell receptors (for T cells). As a result of this antigen-independent diversification, each lymphocyte expresses a distinctive receptor on its surface. In the example shown, a series of different B cells (expressing receptors designated 1, 2, .... n) are exposed to an antigen. Two of these (3 and 99) have receptors that can bind to determinants on the antigen, and, as a result, they are stimulated to divide and to differentiate into cells that secrete antibody. That antibody has the same specificity as the receptor, hence, the antibodies are designated antibodies 3 and 99. A similar situation exists for T-cell responses, except that the T cell recognizes a complex of antigen and a class I or class II major histocompatibility molecule and that the T cell does not secrete antibody. T cells mediate their functions as a result of receptor-mediated activation. [Adapted fran I. ~ Weissman et al., Essential Concepts in Immunology (Benjamin/Cummings, Menlo Park, Calif., 1978), figure 3-1]
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THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 227 sible for the generation of the large number of distinctive antibodies and recep- tors, a review of He salient feature of the structure of these molecules is neces- sary. Furthermore, the consideration of the structure of these antibodies, known as immunoglobulin (Ig), and of the related B- and T-cell receptors is important in its own right since they represent a majority of biological recognition systems. Antibody Molecules and B-Cell Receptors Are Proteins Called Immunoglobulins Although Ig exists in several distinct forms, termed classes, these molecules have a common structural organization consisting of a unit that is a dimer of a heavy (H) chain and a light (L) chain pair Q;igure 7-2~. The H chain contains four or five segments, or domains, each of approximately 110 amino acids, whereas the L chain consists of two such domains. Each H-chain-L-chain pair forms an antigen-binding site, which has elements of both the H- and L-chain amino- terminal domains. Indeed, the amino-terminal domains of the H and L chains from different antibodies differ structurally from one another, an observation that is consistent with the fact that the binding site of each antibody is different. Thus, these domains of the H and L chains are designated the variable (V) regions (VH and Vat ). The variability of the V regions is concentrated into three segments of each chain, designated hypervanable regions, which contain the amino acids that actually make contact with the aniigenic determinant in the binding of antibody to antigen. VARIABLE REGIONS HEAVY CHAIN A/ ~:~:y, i> , LIGHT CHAIN ANTIGEN-BINDING / SITE HYPERVARIABLE REGIONS FIGURE 7-2 A schematic drawing of an antibody molecule. Each molecule is composed of two identical light (L) chains and two identical heavy (H) chains. Me antigen-binding sites are formed by a complex of both H and L chains. [Reproduced, with permission, from P. H. Raven and G. B. Johnson, Biology (Times Mirror/Mosby, St. Louis, 1989), figure 52-18B]
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228 OPPORTUNITIES IN BIOLOGY The remaining (carboxy-terminal) portions of the H and L chains are the constant (C) regions (CH and CL)- The CH portion of the Ig molecule determines its biological function. Indeed, Ig exists in a series of distinct classes (IgM, IgD, IgG, IgA, IgE), each of which has a distinct CH region and distinctive functional properties. The structural basis of antibody-epitope binding has recently been clarified by determining the crystal structure of antigen-antibody complexes. This struc- ture graphically illustrates the areas of contact of antibody with antigen (Plates 4 and 5~. More extensive structural analysis of antibody-antigen interactions may allow the development of a technology to improve the specificity and affinity of monoclonal antibodies. Receptors of B cells are Ig molecules that have combining sites identical to the antibodies that these cells will secrete upon antigenic stimulation. The receptor and the antibodies differ in that the receptor is a membrane protein, with a specialized carboxy-terminal region of its H chain that anchors it in the cell membrane, whereas the antibody (Figure 7-2) is a secreted soluble protein. These alternative forms of the same molecule are produced through alternative RNA splicing, which produces distinct H-chain messenger RNAs (mRNAs) for secre- tory and membrane Ig. T-Cell Receptor Molecules Are Heterodirneric Ig-like Molecules Most T cells express receptors composed of a and ,3 chains; others express receptors composed of ~ and ~ chains. T-cell receptor polypeptide chains have amino acid sequence homologies to Ig H and L chains. The a and ,8 chains, which have been studied most extensively, have amino-terminal variable regions and carboxy-terminal constant regions. The Molecular Genetic Basis of Immunoglobulin and T-Cell Receptor Diversification Relies on DNA Translocation Events Understanding the structure of Ig molecules and B- and T-cell receptors gives us a basis for considering the genetic mechanisms that develop the information necessary for encoding the vast array of distinct antibodies and receptors. The VH domain of Ig molecules is coded for by three independent genes, VH, D, and JH, which are separated from one another in germ-line DNA, but which are brought together in B cells by translocation events to form a VHDJH single gene. The germ line contains a large number (200 to 1,500) of distinct VH genes, 12 D genes, and 4 active JH genes. Since these genes may be chosen randomly for assembly into a VHDJH gene and since products of each may contribute to the combining specificity of the resultant VH domain, the number of functionally different H chains that can be generated by simple combinatorial association may
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THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 229 be in excess of 104. A similar assembly of distinct genetic elements leads to formation of the gene for the V' domain. The process by which the VH and V, genes are assembled and coupled with random pairing of H and L chains, could lead to the development of more than 108 distinct H and L pairs. In addition to these mechanisms for creation of diversity, Ig genes undergo somatic hypermuta- tion in the course of B-cell responses to antigen, leading to a further enlargement in the number of distinct Ig genes that the immune system can generate. Thus, through the use of a substantial (but not enormous) amount of genetic informa- tion, the immune system creates an almost limitless array of distinct Ig molecules. The processes involved in diversifying T-cell receptors resemble those de- scnbed for Ig molecules, except that little or no somatic mutation seems to occur. Although this limits the number of distinct T-cell receptor genes that may form when compared with the number of Ig genes, the number of possible T-cell- receptor genes is still very large. B Lymphocytes B Cells Undergo an Ordered Set of Developmental Processes as They Develop from Hematopoietic Progenitor Cells The B lymphocytes are derived from precursors in hematopoietic tissue. These progenitor cells develop into pre-B cells, which lack membrane receptors and thus are insensitive to antigenic stimulation. It is within the pre-B cells that the translocation events occur through which VRJHCH and the V~J, Cat genes are assembled and in which their products, the H and L chains, pair with one another to form intact Ig molecules. Once this has occurred, Ig is expressed on the membrane; the cell now has a receptor capable of recognizing a foreign (or selfl antigen. The processes through which the individual Ig genes are activated and through which the rearrangements are controlled are currently under intense investigation. The Ig genetic system provides an outstanding opportunity to obtain basic information about the general process of genetic control. Indeed, one of the best-characterized systems of tissue-specific genetic enhancers is that of the Ig H-chain genes. Binding of antigen to membrane Ig receptors on immature B cells may eliminate or desensitize these cells. This would lead to the functional deletion of those B cells that bear receptors specific for endogenous antigens present on the tissues or in the extracellular fluids of the individual (self- or auto-antigens) and thus should prevent the maturation of B cells specific for self-antigens. The elimination of autoreactive B cells would thus lead to a state of immunological tolerance in the B-cell population. However, the elimination of such autoreactive B cells seems to be incomplete. Indeed, the production of antibodies that can bind
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230 OPPORTUNITIM IN BIOLOGY to autoantigens is more common than formerly believed. The study of the biology of tolerance induction and of autoantibody production is important because many human diseases seem to be caused or exacerbated by autoantibodies and related autoimmune processes. For example, antibodies to autologous antigens have a serious effect in systemic lupus erythematosus, in which antibodies to DNA cause severe kidney disease through deposition of antigen-antibody complexes in the glomerulus. The immature state of B cells, in which they appear to be uniquely suscep- tible to induced tolerance, is marked by the expression on their surface of recep- tors of the IgM class only. These B cells mature further and acquire surface IgD in addition to IgM. IgM and IgD have the same VH and Via regions and thus have identical antigenic specificity, although their constant regions differ and presuma- bly mediate distinct functions. However, no convincing explanation of the functional difference in IgM and IgD has yet been brought forth. Nonetheless, coincident with the acquisition of IgD by the maturing B cell are the development of a resistance to the induction of experimental tolerance and the development of a heightened ability to become activated and to become antibody-secreting cells, which suggest that IgD may play an important role in these processes. Receptor Cross-Linkage Mediates B-Cell Activation B-cell activation in response to antigenic stimulation seems to follow one of two activation pathways; these alternatives may reflect the existence of two distinct types of antigenic substances. Many biologically important antigenic molecules (termed type II antigens) have multiple copies of the same epitope; principal among them are the capsular polysaccharides of many pathogenic bacte- ria. The multiple copies of the same epitope cross-link the receptors on the surface of specific B cells. Such receptor cross-linkage causes rapid biochemical changes within the cell, which set in motion the process through which the cell is stimulated to enter the cell cycle and divide. The earliest event that has been detected is the activation of the inositol phospholipid metabolic pathway. Initial progress in delineating the biochemical events that control B-cell activation raises the possibility that drugs may be developed that can selectively control the process of B-cell (and T-cell) activation and which for this reason may be of therapeutic value. B-cell activation through receptor cross-linkage also leads to the activation of the c-fos and c-myc cellular proto-oncogenes. These genes and their products, when properly regulated, play a key role in the cellular activation process. Their deregulated action seems to influence the deregulated growth of malignant cells, with c-myc being implicated in certain B-cell tumors. Among the important tasks that lie ahead are (1) the identification of the membrane molecules through which Ig signals the activation of inositol phospho
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THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 231 ~ ~: ~ I:: ~ HY~B:RIDOMAS~:AN~D:~MONOC~LONAL ANTIBODIES :~ ~ :: aid: ~ . :~ I: . : :~ ~ :~:One ~:the~::~most:~:lm'~ftant developments to:flow from:: efforts to:~:u:nder-: Stand the cellular :~and~molecular~:bas:is~ of ~ anti~d~y~product~n~ i:s~the tec~hnol ~ ~1 ~ogy~ tour t:he~:form~atio:n~of :~st:able :somat~::cell hybrids::between~ no~rm:al: Bells ; ~ :~:i and ~ lines: :of:: ~antibody~-pro~ducing cells. ~e:~f~su: tent:: hybrid~omas~are :capable I: :o ~ p'~auang~:~Q~ssenifa y unlimited quantities of:th~e ant:i~dy de~riv~:from the Norma If: ,~a ~:patt~ner. ,eca:use~:such antibodies~f~pre~sef~tthe~prorfuGt of a ~ ~ ~ . ~ : c one~a:erive:o ro:~m~a Sl n., lyric oma ca :tney are refe:rrQd to as~mo:noolo- i: ~ ~ ~ :: ~ ~ , ~ ~nal~antif~odies.~Monoc~'on~al~anti~0y~technofogy pf'DVid~eS~reage~nts~ To f En- ~ A: : : ): Hi:: :: i: ~pr~cedented s~foec~ificity~f~r use in Yiirtua~iiy~ every crisp - goof :~m~ode~rn biological ~ ~ ~ ~ .~ ~ ~ _ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~: ~ ~ sciences. ~ ~ -urthe~rmore,~ mon~lonal~ ~:antibod~ies~ harm ~excepl~nally valu~abl:e~:: :::~:~diagnostic reagents and~:prom~sing as th;erapeutic:~agents :~ ~ ~ ~::~An~ att~r~adtive~strategy hasten to develop monocional a~ntib~dies~:spe- : :...: ~ ~ .~ : . :~ ~: : ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ::: :: ~:cHic~:~:for~:: antige~nic:~d:et:erminants:~: ~pr~erentially; ~;~expres:s:~:~:~ on: t umor Cells. ~ When:: s~uch~:antib~di:es ~a:~coupl~: to a toxic strudu:re~ such:::as Ethel ricin~:~A: : :~ chain, an:~immunotox~in:: ;;s~creat~.~ ~::lmmu~no~xins:~˘a n Specifically ~destroy::: :~tumor:~cells~:l~n~vivo and my thus ~:p~rove~to bd~hi~g~hl~y:~:~sppcific~:antitumor agents.::: if: :::: One monoclinal :anti:bod~y::: spec4:ic for part of t~he~T cellos antigen receipt: . ~ . ~ . , . ~ . , ::;: ::~:lorcomp ex has a ready::; Jeea Icensea for luman:~use In t ':e~:lmmunosupres-:~;: : sign i: of: transplant ::::recipie:nts.~:~::~::lt; ;is :antici:pated that: monoclanal:~ :~antib~dy me t ho d ology ~wil~l~::grow ~ mortem value b Ie cIin~ica1:Iy;: as a dd itional: r 8 agen to ~ are ~ : ~ ~developedandbro~ug:htintogeneraluse~ :: ~:~; ~:~ :~::: ~ ~:::~::~:~:::~:~ I: lipid metabolic pathways to initiate the intracellular signaling process and (2) the detailed description of the molecular events that occur as a result of the activation of this signaling pathway. Particularly important will be the identification of the proteins that are phosphorylated in the course of B-cell activation and the deline ation of the functions these proteins mediate in the response of the cell. B-Cell Activation Can Also Occur Through Cognate T-Cell-B-Cell Interaction Many of the most important antigenic substances against which the immune system must respond have no more than one copy of any individual epitope. These molecules include proteins having many different epitopes but no repetitive elements. since all the receptors on an individual lymphocyte have the same binding specificity, such antigens cannot cause receptor cross-linkage. Thus, they
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232 OPPOItTUNITIES IN BIOLOGY fail to initiate the set of metabolic activation steps described above. Such antigens can activate B cells only through an indirect mechanism that requires the intimate participation of T cells in cognate T-cell-B-cell interactions. For this reason, such antigens are designated T-dependent antigens. In cognate B-cell activation, the B cell binds antigen through its membrane receptors, but this binding, in and of itself, results in no intracellular signal. A portion of these bound antigenic molecules are taken into the cell by endocytosis, where they are fragmented by proteolytic digestion. Some of the resultant peptides are resumed to the surface of the cell as a complex with a cellular membrane protein, generally a class II major histocompatibility complex (MHC) molecule. The association of antigen-derived peptides and class II molecules is based on the specific binding of the antigen by the class II molecule. Receptors of helper T cells are specific for a complex of peptide and class II molecule, rather than for the peptide alone. Thus, helper T cells that have receptors specific for the particular complex formed on the surface of a B cell will bind to that B cell, an event that activates the T cell. In turn, such T cells locally activate B cells either by signal transduction through B-cell surface molecules involved in the T-cell-B-cell interaction or through the secretion of soluble lymphokines such as interleukin4 alma, interleukin-2 (IL-2), and inter- feron y. The Activation and Proliferation of B Lymphocytes Is a Prelude to Their Dif/7erentiaiion into Antibody-Secreting Cells The T-cell-derived lymphokines, including IL-S and the B-cell differentia- tion factor IL-6, direct the development of B cells into antibody-secreting cells. The recent purification and molecular cloning of both IL-5 and IL-6 should make possible a more precise understanding of control of antibody secretion in the near future. Within the B cell, the differentiation events associated with the develop- ment of a B cell into an antibody-secreting cell include a change in the processing of mRNA for Ig H chains. The resting B cell processes the bulk of its H-chain mRNA to produce a membrane form of Ig, in which the H chain has a hydropho- bic region near the carboxy-terminal portion of the molecule. This hydrophobic region, which spans the cell membrane, and the additional "cytoplasmic tail" of the H chain are encoded in distinct exons in the gene for the H chain. In the antibody-producing cell, an alternative mRNA-processing mechanism leads to the production of an H chain that is identical to that found in the resting B cell except that it lacks the transmembrane and cytoplasmic regions. This H chain interacts with L chains to form a secretory protein rather than a membrane protein. An Important Differentiation Event in the Physiology of Antibody Production Is the "Switch" in Expression of Ig Class by B Cells As has been described, each Ig class seems to play a distinct role in the immune response. Cells producing IgG (there are four subclasses of IgG), IgA,
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THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 233 and IgE derive from precursors that initially express IgM or both IgM and IgD on their membranes. The molecular basis of this switching event seems to involve the translocation of an assembled VHDJH gene from its position proximal to the gene for the constant region of the pH chain (C~) to a comparable position proximal to a Cat, Car, or Ca gene. ILL and otherrT-cell-derived lymphokines direct switching to distinct Ig classes. The clarification of the physiological mechanisms controlling class switching both in vitro and in viva is of great importance because of the different functions of antibodies of different classes. T Cells T Cells Recognize a Noncovalent Complex Consisting of an Antigen-Derived Peptide and a Class I or Class II MHC Molecule In contrast to B cells, whose receptors recognize epitopes on soluble mole- cules, T cells recognize a noncovalent complex consisting of an antigen-derived peptide and an MHC molecule. The noncovalent complexes that T cells recog- nize form in and are displayed on the surface of cells with which the T cells interact. Thus, T-cell recognition of an antigen occurs only in intimate associa- tion with other cell types, which act as antigen-presenting cells. The subset of T cells that are principally involved in the stimulation of antibody synthesis and of cellular immunity (helper T cells) generally recognize antigen-derived peptides associated with class II MHC molecules, and thus can interact only with those antigen-presenting cells that express class II molecules. The expression of class II molecules is largely limited to B cells, macrophages, dendritic cells, and special- ized endothelial cells in the thymus. Under conditions of immunologically induced inflammation, however, class II molecules may be found on other cell types. These cells may thus acquire the capacity to interact with and present antigen to helper T cells. In general, those T cells which co-recognize antigen with class II molecules have a surface molecule designated CD4, which may play an important auxiliary role in the T-cell recognition process. Furthermore, it has recently been established that CD4 is the cell-surface receptor for the human immunodeficiency virus (HIV), the virus that causes AIDS. The entry of HIV into cells depends on its binding to CD4, and those cells that express CD4 are susceptible to infection with HIV. This role of CD4 in cellular infection by HIV suggests that strategies to prevent infection by interrupting the binding of the virus to its receptor should be explored seriously. Structural studies of the interaction of CD4 with both HIV and with its natural ligand, the class II mole- cule, may prove to be of great importance in limiting the spread of HIV. A second subset of T cells is able to lyse antigen-bearing target cells, such as virus-infected or tumor cells. These T cells are generally referred to as killer cells. Killer T cells mainly recognize antigen in association with a different group of MHC molecules, class I molecules. In contrast to the expression of class II molecules, most tissues express class I molecules on the surface of their constitu
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234 OPPORTUNITIES IN BIOLOGY ent cells. Thus, virtually any cell type would be susceptible to the cytotoxic action of a killer T cell if the cell expressed the complex consisting of antigen and the class I MHC molecule recognized by the receptors of the killer cell. T cells that co-recognize antigen with class I molecules express CD8 rather than CD4 on their membrane. CD8 molecules seem to function in a manner generally similar to CD4 molecules, but they are not receptors for HIV. The tendency for CD4 to be expressed on helper T cells and for CD8 to be expressed on killer cells and on T cell that suppress immune responses (suppressor T cells) makes the enumeration of the relative number of CD4- and CD8-positive cells a useful first step in the assessment of the relative state of the immune system in individual patients. The MHC Molecules Play a Key Role in Several Aspects of Immunity and in the Rejection of Organ and Tissue Grafts The MHC is a complex of genes located on the short arm of the sixth chromosome in humans. This gene complex contains genes for both class I and class II MHC molecules. Class I molecules are highly polymorphic membrane- spanning glycoproteins with a molecular weight of approximately 45,000. They exist on the membrane in association with a 12,000-dalton polypeptide, desig- nated ,B2-microglobulin. The genes for both the class I polypeptide and )2- microglobulin are homologous with Ig and are members of the immunoglobulin supergene family. The class I molecules have three extracellular domains, each encoded by an individual exon. The two most external domains display substan- tial structural polymorphism, so that many different allelic forms of each class I gene exist and individual allelic forms have multiple differences from one an- other. These allelic differences are recognized by the immune system, and the responses to the allelic polymorphisms of class I and class II molecules are principally, but not solely, responsible for the rejection of grafts. Class II molecules are heterodimers of two chains, designated a and if, both of which are encoded in the MHC. In the human, there are four sets of these molecules. Helper T cells usually recognize complexes of antigen-derived peptides and class II molecules, whereas killer T cells usually co-recognize antigens and class I MHC molecules. These complexes are formed by noncovalent interaction be- tween the MHC molecule and the antigen-derived peptides. Moreover, distinct polymorphic forms of class I and class II molecules are associated with the capacity to respond to specific antigens; this polymorphism correlates, at least in part, with the capacity of the MHC molecules to bind peptides derived from those antigens. The association of distinct human leukocyte antigen types with suscep- tibility to diseases such as non-insulin-dependent diabetes mellitus may reflect the capacity of complexes of antigen and specific MHC molecules to give rise to immune responses that destroy the tissues upon which such complexes appear.
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THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 249 vaccine targets will depend on their variability in the parasite population and the presence of alternative pathways for invasion. Spread in the Host When microbes enter into tissues beyond the epithelial surfaces, they are transported into the lymphatic system, where they are presented to the immune system. This interaction may limit the infection or may disseminate it to regional lymph nodes and eventually to the blood. Some microorganisms invade blood vessel walls and enter the blood directly. Spread through the blood can be rapid and can result in generalized infection. A Number of Pathogenic Bacterial Species Can Penetrate and Grow Intracellularly Within Host Cells Intracellular bacteria resist host immune mechanisms essentially by hiding within host cells. Vascular circulation of host cells infected in this manner can then disseminate the bacteria further into the lymph and blood, which in turn seed other organs and tissues of the host. Some bacteria and protozoa gain entry into the host cell cytoplasm passively by being phagocytosed by macrophages. Once inside the phagocytic cells, these organisms evade the intracellular killing activity of the macrophage by mecha- nisms that include resistance to lysosomal microbicidal activity, inhibition of phagolysosomal fusion, or simple escape from the confinement of the lysosomal vacuoles and multiplication free in the cytoplasm of the host cell. Other bacteria induce their own uptake by phagocytic cells such as epithelial and endothelial cells. The microbial gene products that mediate the binding to host cells and that trigger the endocytic uptake of bacteria have been partially characterized by genetic methods (gene cloning and mutagenesis). Microbes Can Spread Through Local Extension into Neighboring Tissues and Through Peripheral Nerves For microbes that do not enter the bloodstream or peripheral nerves, spread may occur by extension to adjacent cells or release into fluids on body surfaces. Nonspecific host defenses and local anatomical features may play central roles in limiting infection. The spread of bacteria from local sites is enhanced by spread- ing factors, particularly enzymes. But whether these enzymes play additional roles in the pathogenesis of bacterial disease remains obscure. Viral spread by successive infection of adjacent cells is best illustrated with viral infections of the skin (warts and vaccinia).
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250 OPPORTUNITIES IN BIOLOGY An alternative route of spread is through peripheral nerves. Certain viruses (rabies and herpes simplex) and toxins (tetanus and diphtheria) spread from the periphery of the body to the central nervous system through nerves. The exact neural pathway and the microbial determinants remain undefined. For neuro- tropic reoviruses, the viral attachment protein is responsible for allowing the neurotropic strain to enter peripheral nerves, whereupon subsequent movement takes place in the fast axonal transport system (see Chapter 4~. The specific microbial and host factors that determine the capacity of the microbe to spread and choose one or another pathway in the host are poorly defined. The initial battle between the host and the parasite takes place in lymph nodes and results in either a virulent or nonvirulent outcome. Virulent bacteria entering a lymph node often kill macrophages or resist being taken up by them, produce products that dilate blood vessels and affect inflammatory cells, and produce substances that allow the bacteria to continue to divide and spread. Similarly, some viruses resist macrophage destruction and thus have the capacity to replicate, rather than be destroyed in macrophages or lymphocytes. These viruses can then spread within the host as part of the cells' normal migration. Whereas viruses including those that are relatively avirulent spread with rela- tive ease through the host via the bloodstream, most bacteria, fungi, and protozoa are blocked from spread by lymphatics. Understanding the factors that determine whether a microorganism can evade the filtering action of the lymph nodes is a goal of major importance. After Entering the Blood, Microbes Are Efficiently Transported Through the Body Although most bacteria or fungi do not regularly invade the blood, many viruses, rickettsiae, and protozoa do. These microbes may be carried in several compartments: free in plasma, in leukocytic-associated compartments (mononu- clear phagocytes), and in erythrocytic-associated compartments. Removal of microbes from the blood may be efficient. Since the reticuloendothelial system with its population of fixed macrophages is heavily concentrated in the liver and spleen, most clearance occurs at these sites. Infected leukocytes may also be trapped at these organs, which would help to arrest infection. Transient bacter- emia or viremia are thus usually of little consequence. But, when host resistance is impaired or when especially virulent microbes circulate, a sustained viremia or septicemia may occur. The liver is the main organ responsible for clearing foreign particles, includ- ing bacteria, from the blood. Studies of virulent strains of bacteria may shed light on the mechanisms by which pathogenic organisms escape being recognized by hepatic lectins and hence being cleared from the blood during bacteremia or septicemia.
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THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 251 The blood may also deliver microbes to distant organs. The blood-tissue junction plays a central, albeit poorly defined, role in determining spread into an organ. For a microbe to enter an organ, it must first bind to the surface of the endothelium of the blood vessel, usually in capillaries. It must then reach the tissue by moving through breaks or leaks in the vessel wall, growing through the wall, or being carried passively in association with some structure (or cell) passing through the wall. Our ability to study this phase of the infectious cycle has improved dramatically in recent years with the development of methods to culture blood vessels and to study the interaction of microbes with endothelial cells. Interactions of Viruses with the Host Cell Viruses Exist Either as an Extracellular Virion Particle or as Intracellular Forms Undergoing Replication For inactivation of a virus, the infectious virus particle must be neutralized by antibodies or its replication must be inhibited within the host cell. To be therapeu- tically useful, any agent that inhibits replication must specifically affect a viral replication process and not the host cell. Once a virus has bound to the cell receptor molecule, the virion must cross the plasma membrane to enter the host cell. Nucleocapsids of some lipid- enveloped viruses cross the plasma membrane by direct fusion of the lipid envelope with the cell plasma membrane. Nucleocapsids of other types of viruses cross the membrane into the cytoplasm after being taken into endocytotic ves- icles. Once inside the host cell, the viral genome is transported to its cellular site of replication-often the nucleus for DNA viruses and the cytoplasm for RNA viruses. One of the next events is the synthesis of viral mRNA if the viral genome cannot be used directly for translation. With some DNA viruses, host-cell enzymes produce the viral mRNA. For other viral genomes, such as double- or single-stranded RNA genomes, no cell enzymes exist that can transcribe the genomes into mRNA. Therefore, these viruses encode a transcriptase enzyme, which is often encapsidated in the virion. After viral proteins are translated, the input viral genome is amplified or replicated and progeny virions are assembled. Any of these viral-specific stages of replication are potential targets for antiviral agents. Cellular Molecules or Structures May Be Appropriated by Viruses and Modif ed to a New Form for the Replication of the Virus If the virus utilizes a host-cell component for its own replication or inacti- vates a host-cell function to promote its replication process, injury to the cell can
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252 OPPORTUNITIES IN BIOLOGY result. For example, poliovirus inactivates one of the host-cell translational initiation factors during its replication cycle. This inactivation is believed to favor the translation of viral mRNAs, but it is also one of the factors that eventually leads to cell death and lysis. Similarly, DNA viruses such as herpes simplex utilize parts of the cell's nuclear transcription and DNA replication apparatus for their replication, and they inhibit these cell processes. Herpes simplex virus may even utilize preexisting nuclear sites of cell DNA synthesis as sites for assembly of viral DNA replication complexes. Such perturbations of the host cell may lead to the gross pathological changes in the cell known as cytopathic effect. If the virus stimulates the expression or activity of certain cell gene products and the cell survives infection, the cell may emerge with an oncogenic, or cancerous, phenotype. In this case, pan or all of the viral genome becomes integrated into the cell genome. For example, infection of mouse cells with simian virus 40 (SV40) leads to a low frequency of transformed cells that retain part of the SV40 genome and continue to express the large T antigen that interacts with the host cell to alter its growth controls. Two other possible outcomes of viral infection are the establishment of a latent or a persistent infection. In a latent infection, no infectious virus is found in the cell, but upon reactivation, the viral genome within the cell is replicated and infectious virus is produced. In a persistent infection, the infected cell survives, but the cell continuously produces infectious virus at some detectable level. Cell and Tissue Tropism A Hallmark of Microbial Infection Is the Localization of Infection in Specific Tissues or Cells Localization gives rise to the specific symptom complex of infectious dis- eases and is perhaps the most characteristic feature of microbe-induced diseases. The factors determining the localization of microbes in certain tissues their tropism-have been under intensive investigation. Although we still do not know the details of all the factors involved, certain aspects of major significance in host- parasite interaction are emerging. These factors include the presence of cell- surface receptors recognized by surface structures of microbes, tissue-specific proteases, and tissue-specific enhancer DNA or other regulatory sequences in the viral DNA. Although tissue localization has been studied in all classes of microbes, most of the recent insight into tissue specificity has emerged from studies with bacteria and viruses; the findings concerning bacterial adhesion have already been described. That the specificity of certain viruses (for example, poliovirus) for human cells results from the interaction between the viral capsid and host-cell receptors exposed at the cell exterior has been well known since the late l950s. The
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THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 253 presence or absence of receptors for viruses on the cells' plasma membrane is of central importance in initiating infection. For a number of viruses, the attachment protein on the virus panicle recognizes sugar molecules on host cells as bacterial lectins do, suggesting that many strategies used by bacteria to colonize and adhere to host tissues resemble those used by viruses. The Identification of Receptors for Viruses and Other Microbes Is a Focus of Biological Research In addition to receptors containing static acid, considerable progress has been made in identifying cell-surface proteins that are both physiological receptors and receptors for viruses. These cell-surface proteins include the acetylcholine recep- tor for rabies virus, the p-adrenergic receptor for reovirus 3, the T4 lymphocyte antigen for HIV, and the CR2 receptor for Epstein-Barr virus. Given the central role of receptors in pathogenesis and tropism, one should stress the importance of determining receptor identities and characterizing the molecular interactions in- volved in the binding reactions between virus and host receptor. Although considerable work is being done on the receptor binding of some viruses (such as influenza, polio, and HIV), the role of receptors, especially the question of receptor identity, has been neglected in most other virus systems. In addition to illuminating microbial pathogenesis, the isolation of receptors should provide insights into the structure and function of many normal cell proteins. The possible importance of cell-surface receptors for protozoa is illus- trated by studies with malaria. Malaria sporozoites attach to liver cells, possibly in response to specific receptors. Whereas the merozoite responsible for initiating and perpetuating the erythrocyte stage has a complex surface, the sporozoite has a dense surface coat protein that contains two regions conserved in all malarial. These regions may be conserved for binding to liver cells or to mosquito salivary glands. One of these regions is highly homologous to the soluble human protein thrombospondin, which cross-links host cells. Other Determinants of Tissue Tropisms Include Tissue-Specif id Host Enzymes and Regulatory Factors The cleavage of viral glycoproteins from an inactive precursor form to an active product is an important determinant of pathogenicity for myxovirus and paramyxovirus. The cleavage of viral proteins by tissue-specific proteases is necessary to the production of infectious virus. The nature of this cleavage determines whether there will be high titers of virus. Thus, host proteases probably play a specific role in the organ-specific activation of viral proteins. Increased research on specific steps in viral replication and the factors regu- lating those steps will undoubtedly enhance understanding of the molecular
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254 OPPORTUNITIES IN BIOLOGY biology of viral virulence. In the context of tissue tropism, certain regulatory factors may be cell- or tissue-specif~c. Thus, for example, enhancer sequences active only in certain cells could lead to enhanced replication and high titers of virus in specific cells. Such factors may play an important role in the localization of viral growth and tissue injury. How Is Injury Mediated? Many Infectious Agents Can Multiply in the Host Without Causing Significant Damage Infectious diseases are the most important outcomes of multiplication of microorganisms in the host. Many infectious agents, however, multiply in the host without causing significant damage. For viruses, this is probably the rule rather than the exception, even for viruses that are capable of causing disease. For some viruses, damage at the morphological level may be undetectable, even when effects on aspects of cell function or secretion may be profound. This type of effect on the cell, whereby the cell is capable of replicating without any detectable histological abnormality, but loses a differentiated function, has been termed a loss of "luxury" functions. Cells that secrete important products for host physiol- ogy (such as hormones) are especially important in this regard. Thus, disease production by viruses may not be associated with more than minimal overt pathology. In contrast, when bacteria, fungi, protozoa, or rickettsiae invade tissues, overt tissue injury, slight or profound, is the rule. Microorganisms may damage cells directly by replicating in a particular cell, or, in the case of bacteria and fungi, by exposing cells to toxins that are part of the bacterial cell wall (endotoxin) or that are released from the replicating microbe (exotoxins). In addition to the direct injury by microorganisms or their products, the damage may occur indirectly. The host response itself may lead to pathological outcomes, which may be relatively nonspecific (as when proteases are released from macrophages in an inflammatory response that subsequently results in injury to normal cells) or may result in specific injury from cellular immune responses or the action of antibodies. Direct Damage of Cells by Viruses Can Occur in Different Ways In general, viruses shut down host macromolecular synthesis while modify- ing the cell to synthesize viral proteins. Cytopathic viruses generally cause cell death only after they replicate, suggesting that the primary effects of viral infec- tion involve the cellular synthetic machinery and that later effects on the cell are secondary. The later effects include, depending on the virus, profound effects on the cytoskeleton, injury to membrane and leakage of ions, fusion of membranes
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THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 255 (resulting in multinucleated giant cells), or damage to lysosomes with release of lysosomal enzymes. One of the best-studied viral systems is poliovirus. Poliovirus causes host protein synthesis to decline and ribosomes to dissociate from host mRNA. Polio infection inhibits the host by inhibiting the cellular cap-binding complex required for attachment of "capped" mRNAs to ribosomes. Since polio RNA is uncapped, unlike cellular mRNA, it is unaffected by the loss of the cap-binding protein. Other viruses inhibit the host in different ways. For example, inhibition of host-protein synthesis by mengovirus results from competition between viral and host mRNAs. These studies illustrate the feasibility of gaining insights into details of the molecular basis of viral injury. Undoubtedly, this will be a major focus for the next decade and will aid in identifying new anoroaches for developing antiviral drugs. , ~, ~ Infection Can Result in Indirect Damage from the Response of the Host Inflammatory Response. The host response to microbial infection generates inflammation. This response, clasically resulting in redness, swelling, pain, and loss of function, may damage the host more than the replicating microbe. The early inflammatory response has both cellular components (macrophages and natural killer cells) and humoral components (complement, interferon, and tumor necrosis factor). The release of proteases from macrophages with injury to normal tissue (the so-called innocent bystanders) illustrates one way by which such injury may be mediated. Hypersensitivity. In addition to early inflammatory reactions, the classic reactions of hypersensitivity may be involved in microbial immunopathology. Anaphylactic reactions depend on reactions of antigens with IgE antibodies attached to mast cells that lead to the release of histamine and heparin from mast cell granules, and they may be severe enough to lead to urticaria, bronchospasm, or shock. Helminth parasites induce severe hypereosinophilia, as in tropical (filarial) pulmonary eosinophilia, in which the toxic contents of the eosinophile granules are responsible for tissue destruction and resultant pathology. In the type of hypersensitivity reaction termed antibody-dependent cellular cytotoxicity, antibody combines with antigen on the surface of the cell and results in cell lysis through the action of killer lymphocytes, polymorphonuclear leuko- cytes, or macrophages. This type of reaction may be important in certain viral, parasitic, and bacterial infections. Although cytotoxic reactions can be shown in vitro, they need further study to define their role in vivo. Tissue Damage Mediated by Immune Complex. Circulating immune com- plexes are probably common in most viral infections, but they also occur with
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256 OPPORTUNITIES IN BIOLOGY : ~ ~ ~ ~ SLOW VlRUS~ES, PO<::)RIN tJND~ERSTOOD~, : :~: :: ~ ~: :: :~ ~::~ ::MAY~: :CAUSE SEVE~RAL:~ ~DISEASES~:::::~ ::: : :::: T h e : c a u s a t i v ~ a g e : ~ n t : f o r : : t h e t r a n s m i : s s i ~ b l e § p o n g i f : o r r n ~ : : e n c e p h a l o p a t h i e s ~ : ~ ~ : (~craoiQ::kL'rL, ~:CrQut~faId:- a to ~ lsQasQ and ~erstmann-~trauss er~svn:- ::: :: drom~) r ~:mains~ ~a~ mystery.~: ~ ~Possibly~:associated ~are ~mysterious ~ agents ~: ~calied~ sldw~vi~ruses. ~The:˘auses~ these diseases chailenge~ our concepts: : ~ of ~:~convent~'ona m'˘roo~g:anis~ms s'~nce,~to:~ate, t ~ey~ ,mre~ not ~een~ s ~own~ to :~ ::~:~:::co~ain~ RNA :or~:DNA.~: ~: :Infectivibr~de~dved :~from :~:brai:n:~:~ or;:~:lym:pho;id: :tiss~ue~: ; ~ ~ . ~ : :::~ ~homog~:ndtes ~has:~several~unusu~al~biolog~ical :properti~es,:~s:uch~:as:~ex~ptiQnal: :: ~resistance~ :to i~n:activat~n~ b) :~rmaldehyde~ or~ ty::~ultravio:let~ or~ x-irrad~iation~.~ :: Attempts~ td ~purify~the ~agent~ ~indicate that ~infe˘tivity remains ~associatdd w~h ~ : ~cellular~:me~mbrane fradt~ns~ and thus lacks~homogeneous~ b:~physical~ pro~ Fert'es. ~ ut ,ermore' eve uation ot purn:'catwon~ protoco s 1as~ 3een ~am~pered ~y: t 3e Inamura~ ot assays us: - ~ :o ~quant~: InJ:~'v~7 ~e :recent~ use ot : the incubation~:period~ ass~ay~ to~ qu:an$~ify:~inf~ctivity:~is ~qui~: and requires fewe:r:~ ~ ::~ animals but. if an:~hina. is less or~cise in discriminating ouantitative: d ffQr-: en~s.: ~Thus, Wth~because of ths~inaccura~ ot~the essay:: ano tne nonno-: ~:: ~ mogenous~ ph:ysical nature of ~:~ the:~:~agerit, ~ it ~:re:ma~i:ns::~ extremeIy ~ difficult ~ to i:~: desi:gn ~an :effective ~pu::rif:icat:ion ~::prdto˘ol :~r:~th~el::infedtious age:nt.~::~ ~: ~:: ~: Recent~ly~ several: research:~:~gro~u~ps ~have~:~patti~ally~: ~pu~rified:::::i~fectivity: o~n sucrose~ gradients.: ln intectio:us ~fradtions ~: macromolecular:~fibril-like~:: stru:c-: tures have been visualized with the electron~microscope: ~which raises the ~: :possibilRy tbat ;these: might: be the~ ag~e~nt or :a~ oomponent~ of the: agent. : Prot:ein con,~nents of these fraction:s we:re :fu:rther purif:ied~: :under denaturing conditions. Since infectivity was: destroyed in: t:hese procedures, ~ it was impossible to relate the purified:: prote:ins d~i:rectl~y~ :~to t~he: infectious: agent. Partial amino acid sequence analysis of th~e mayor polypoptide :obtained known as prion ~protein,~:has led~to the cloning and sequencing of the: : com:plementary::DNA~:en:coding the :prioni:prc~tein. Hybridizatio:n experi:ments ~ with these clones: show~d :that ~:prion protei:n: ~mRNA~ was ~ndt :found exclu-~ : sively in::scrapie-inf~ctdd~ animals, but::: occorred to the same~ e~ctent:in t:he : tissues of un:inf~ted animals. :Thus, th~e relationship of:the prion protein: gene and Rs expressed protein to the infectious agents of scrapie and other; : : spongiforrn encephalopathie:s is as yet uncertain. : ~ ~ - ::: ·:
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THE IMMUNE SYSlEM AND INFE=IOUS DISEASES 257 parasites and bacteria. Immune complexes may lead to pathological outcomes, either in the vascular spaces or in tissues. Autoimmune responses have recently been identified for viral and bacterial antigens. In such cases, the host responds not only to the microbial antigen but also to normal host components. A variety of mechanisms for autoimmunity have been proposed. With our increased capacity to study components of the immune system as well as to define the individual microbial proteins or components involved in recognition of the immune system by microbes, we should in the next several years gain striking insights into the etiology of autoimmune reactions to microbes. Bacterial Toxins Are Studied More as Probesfor Specific Cell Functions Than They Are for Their Roles in Pathogenesis Toxic proteins and peptides, which are involved in a wide variety of biologi- cal phenomena (such as bacterial pathogenesis, attack by venomous insects and animals, and the toxicity of certain plants), have classically been of interest from a medical perspective. Microbiologists in the 1880s and 1890s were intrigued by toxins because they provided a potential explanation of bacterial disease. More- over, they soon found that repeated injection of sublethal doses of toxins into animals induced specific resistance to those toxins, a finding that represented the discovery of humoral immunity. They developed methods of immunization, which culminated in the mass inoculations and successful immunizations against diphtheria and tetanus toxoids. From a biological standpoint, toxins represented little more than curiosities until recently. Within the past two decades, interest in these substances and the mechanisms whereby they affect cells of the animal or plant host has revived. Toxins are excellent probes of important biochemical and cell-biolog~cal proc- esses; they are interesting from the point of view of structure and functions of proteins and with respect to the theoretical analysis of microbial host-parasite interactions and their genetic regulation. Moreover, the progress made in under- standing toxin structure and mode of action has stimulated new potential applica- tions in medicine. The coupling of cytotoxic proteins to monoclonal or polyclo- nal antibodies provides a new approach to chemotherapy for cancer and other diseases that call for the elimination of a specific class of cells. Finally, the cumulated knowledge on classical toxins may provide an impor- tant base of information for understanding yet another aspect of the immune system, namely cellular immunity. Evidence is increasing that the killing of cells recognized by the cellular immunity system involves the action of cytotoxic proteins. Similar molecules may also mediate tissue regression and other onto- logical phenomena.
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258 OPPORTUNITIES IN BIOLOGY Persistent Infections Microbial Persistence Is a Common Sequel to a Large Number of Infections Persistent infections may be important in the maintenance of microorganisms in host populations. In certain circumstances they may be activated in immuno- suppressed patients, and they may be associated with neoplasms. Persistent infections include those in which the microbe is latent (as in a noninfectious state in some location in the host) or persistent (as when it multiplies more or less continuously for long periods of time). Parasites Are Able to Remain in the Blood Exposed to the Immune System) for Months to Years Plasmodium malariae, one of the four human malarial parasites, can persist in the bloodstream for the life of the host, reinvading new red cells every Free days. The adult schistosome, a trematode, lives in venules for many years, copulating and laying eggs that spread the infection and trigger the disease. Within days after the schistosome enters the host, its tegument becomes resistant to complement lysis and to cell-mediated killer mechanisms. The African Dypanosome Trypanosoma gambiense, a flagellate that infects animals and hu- mans, undergoes antigenic variation to escape destruction by antibody-dependent complement lysis. Each parasite clone contains multiple genes capable of ex- pressing antigenically unique surface proteins. The control of expression is not fully understood, but gene duplication and translocation to an expression site is one mechanism. The trypanosome continually expresses new surface proteins from its large repertoire of genes, which are funkier expanded by mutation. The American trypanosome Trypanosoma cruzi, uses a different evasive maneuver: It elaborates a molecule similar to a decay-activating factor that speeds the break- down of a critical complement component and thus may prevent complement- dependent lysis by the alternative pathway. Despite the many strategies of parasites, the host does eventually become immune to most parasites. The challenge to immunologists is to develop vaccine strategies that attack parasites in susceptible stages or by mechanisms that they cannot resist. CONCLUSION Studies on the Immune System and Infectious Diseases Have Made Enormous Progress During the Past Decade Because of the Introduction of Powerful New Technologies The applications of molecular biology, monoclonal antibodies, flow cytomet- ric analysis, modern methods of cell culture, and powerful new techniques of
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THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 259 protein chemistry have led to many of the insights described in this chapter. Improvements during the forthcoming decade promise to bring us the solutions to many of the central unresolved problems of immunology and pathology as well as to provide a new level of insight to all aspects of cellular biology. Equally, the central role of the immune system in resistance to infectious diseases, in the elimination of tumor cells, and in the pathogenesis of many chronic disease makes it an obvious target for clinical efforts. During the next decade, substantial emphasis needs to be placed on developing a quantitative understanding of the contribution of the various components of the immune system to the function of that system in humans and other animals, both in normal situations and in various disease states. Such information together with our growing understanding of the basic cellular and molecular mechanisms of immunity should make possible the development of new vaccines for the prevention of many of the still-uncon~olled infectious diseases such as AIDS and malaria and should allow the introduction of rational therapy for a host of immunologically based disorders.
Representative terms from entire chapter: