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Opportunities in Biology (1989)

Chapter: 7. The Immune System and Infectious Diseases

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Suggested Citation:"7. The Immune System and Infectious Diseases." National Research Council. 1989. Opportunities in Biology. Washington, DC: The National Academies Press. doi: 10.17226/742.
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Suggested Citation:"7. The Immune System and Infectious Diseases." National Research Council. 1989. Opportunities in Biology. Washington, DC: The National Academies Press. doi: 10.17226/742.
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Suggested Citation:"7. The Immune System and Infectious Diseases." National Research Council. 1989. Opportunities in Biology. Washington, DC: The National Academies Press. doi: 10.17226/742.
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Suggested Citation:"7. The Immune System and Infectious Diseases." National Research Council. 1989. Opportunities in Biology. Washington, DC: The National Academies Press. doi: 10.17226/742.
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Suggested Citation:"7. The Immune System and Infectious Diseases." National Research Council. 1989. Opportunities in Biology. Washington, DC: The National Academies Press. doi: 10.17226/742.
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Suggested Citation:"7. The Immune System and Infectious Diseases." National Research Council. 1989. Opportunities in Biology. Washington, DC: The National Academies Press. doi: 10.17226/742.
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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

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

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]

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]

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

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

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

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

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,

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

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.

THE IMMUNE SYSTEM AND INFECTIOUS D SEASES 235 The recent determination of the crystal structure of a class I molecule is a major achievement that should be followed up and extended to class II molecules. When this is done, the structure of these molecules in noncovalent association with antigenic peptides and in the ternary complex consisting of a T-cell receptor with antigen and class I or class II molecules should be better understood. This ambitious undertaking should provide critical information for the understanding of the structural basis of immunogenicity and of the mechanisms through which MHC molecules mediate their potential to determine the immunogenicity of virtually all antigenic substances. An equally important goal of such structural determinations is to develop methods to predict which peptides in a protein will prove capable of forming immunogenic complexes with distinct polymorphic forms of class I or class II molecules. The capacity to make such predictions would be of great value in the design of vaccines, particularly for agents that have displayed low levels of · . ~ mmunogen~c~ty. T-Cell Development Can Be Studied by Tracking the Expression of Developmentally Regulated Surface Markers Like B cells, the stem cells that give rise to T cells are found within hemato- poietic tissues. However, T-cell development takes place in a central lymphoid organ, the thymus. It has been possible to follow the development of T cells from their immature thymic precursors into fully mature cells since the expression of a series of surface markers (CD4, CD8, CD2, and CD3) and of antigen-binding receptors on these cells is developmentally regulated. This expression of surface markers allows the analysis of the molecular basis of T-cell development, of the mechanisms by which T-cell specificity is acquired, and of the germ-line T-cell repertoire from which the T-cell repertoire of mature animals is generated. Matu- ration of T cells in the thymus represents one of the most powerful model systems available for the study of the developmental biology of a highly differentiated set of mammalian cells. Equally important is the opportunity that the study of T-cell development allows for the understanding of the establishment of immunological tolerance in the T-cell pool. It has been suggested that tolerance induction in T cells is more important than tolerance induction in B cells. Tolerance induction in T cells would prevent cellular (T-cell mediated) immune responses against self-antigens and would also markedly diminish antibody responses against self-antigens since most antibody responses require some form of T-cell help. Furthermore, somatic hypermutation does not seem to operate on T-cell receptor genes in peripheral T cells. Thus, the T-cell receptor repertoire would be fixed after cells leave the thymus, which suggests that T-cell tolerance would not be lost through the development of mutants capable of binding to self-antigens. By contrast, some

236 OPPORTUNITIES IN BIOLOGY ~:~ORGAN~:~TRANSPLANT:~I ION:: :~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ .~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~: :~ ~ :~ ~ :~ ~ ~ ~ ~ ~ ~ ~ :::::: :~:~Transpl:antation~ of keys: for then t:reatm:e~nt~:~of :~chron~ ~:~renal disease ~ ~: ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ :~ ~: ~ ~ ~ :~ ~: ~,~ ~ If: :~ ~ ~ :~:~has~b~com~:~an almost~rotrtine therapy.: TI ransplantation~1s~:~:~bein~g:~:~lncre~s-~:~ ~:inq9 Frigid for fur: fu~nition~of~:bone~ Go: Heart liver ~a~:~:~lung. 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Won ~no:nor~ anvil rec~p~e~nt::: are relate: :~:nowever : ~tissu:e ~m~atc~n~ng :preo~cts : Ha b6her~.~:~is~ s~ug~ests ~at:~unrecognized ~HLA:~Qr other different ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ . ~ ~ ~ ~ ~ ~: ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ : ~ ~ ~ : ~ : : : ~ ~ ~ o u n ~ ~ ~ ~ ~ ~ ~ ~ i ~ ~ n ~ ~ ~ ~ i u ~ n r e l a t ~ d ~ : ~ : ~ ~ p a i ~ r s : ~ ~ : p t a y ~ ~ ~ ~ : a n ~ ~ ~ ~ i m p o r t a ~ n t : ~ * l e ~ i n : ~ ~ g r a f t ~ ~ ~ ~ ~ i 0 n . : : : ~ : : ~ ~ : : T h u : s ~ ~ : : : : ~ ~ :~ ~ ~ ~ ~ ~ - ~ ~ ~ ~ ~ ~ ~ ~ :: ~ ~ ~ ~ ~ :~ ~ ~ ~ :~ ~furth~e:r:~improve:me~nts~in::typri~ng~techni:ques~:m~ay:~:be pro - uisites~:~:to~g:reater ~ ::~: ~ ~ ~ ~ ~ ~: ~ ~ ~ ~ . ~ ~ ~ ~ ~ ~ ~ . ~ ~ ~ ~ ~ :: ~ ~ ~ ~ ~ ~ ~: ~ ~ :~:~::~s~ecass l~n:transpla~ntat:lon Loft cad:av:er~erived organs ~but~th~e:~::oontin~u:ed use:: ~ ~ ~ , : I: ~ : ~ ~ ~ . ::: ~ ~ I: ::: ~ ::: : : ~ ~ ~ : : .: ::: .: ~ .~: ~ ~ :~ If: :~ :~: : : :: : ~ : : ::: ~:~ano~l~m~pro - ~m~e~nt~otl:m~m~unosupprQsswe:~tIQcnn~lqu~es~:msos:a:em~:Qssentlal.:~::~: : ::: : :: :: : : : ~ :: ~ ::: :: :: ~ :~ : :~ ~:1~ ~:~::::~1~Thb~d~lop~m~Q~nt~of: :~ivs ~ im~m:u~nosuppre~ssn,~:ld:rulgs~: Such: as: cy-~:~:~:: :~£1bsporin~: A Has been Of: great ~value: in imp~rovingl~t:ransplant acceptances and i: ~ ::: ~:~success.~:~Nonetheless ~:~onspec~fic~and~i:often~ c:h~ro::nic~:::im:m~u~nosuppr~ssion i: :: has t~he~:~maJor~ ~awback~:of~d~ecreasing:~the:ove~raD:~state~loff~:imm~une~:~function::~ :: If: ~ ':n ~tn~B~::rec~lplQ~:: ~:~ :: I: : :: :~::: : ~: : ::: :: ~:~:~:~:~:;~ :~:::Effo~rts~ar~e~:now~::~unde:r way to ~tempt::~to~::develop :mea:n:s~:~to induce i:mmu-:~::: :~::~:~nological:~:toleran~ce~:~in Ether ::rec~pie~n:t~ off th:e::~transplant~ation ~antigens:~of: the ~ : ~ donor. ~in~::~th:e ::~hoDe:: that this s~ecitic :unr~sDonsiveness ~will::~:~:allow:~ :lonokterm i: i: ~gr~su:rv~va:l ~wh':le~in: no ~way~d:iminish~ing::the overall:im~:m~u~ne:::reactivity of the :::: i:: ~:~recipient.~:lf a: successful ::: clinically applicable Istrategy~:~:kor~:the :~induction~:of , . ~ ~ . ;~ Unspecific ~tole:rance:~:~becomes available: ::the possibly at: using organs ~from: : ~ ~ . ~ . ~ ~ , ~ ~ ~ . , ~ ~ ~:~ ~ ether specles~xenogra~ts' win neea:to ~ :co:nslaerea. ':ne:success~ul use of ~:~:~xenog:r:;kits~would:~largely~::~ameliorato the curr~:~severe~shortage:~:~of~s~uitable:~ :: ~:~:~:o~ans~for~transpla~abon.~: ~: ~::~::~ ~:::~:: :~::~:~::~::~:~ :~::~:~:~ :::: :: :: ~;~ ~ :::: i: ~:~:~::::~: ::::::: :~::~ ::: i:: :: ~ I: ::

TlIE IMMUNE SYSTEM A]VD INFECTIOUS DISEASES 237 evidence suggests that one mechanism through which autoantibodies emerge is somatic mutation in immunoglobulin genes in mature B cells. This process may be a major factor in the development of pathogenic autoantibodies. T Cells Are Activated by Signals from a Receptor Complex and the Expression of IL-2 Receptors The membrane receptors through which T cells recognize antigen associated with class I or class II MHC molecules are composed of two distinct chains, which are Ig-like in that they bear sequence homology to Ig and have a generally Ig-like structural organization. Most T cells express a receptor composed of a and ~ chains, both of which are glycosylated peptides with molecular weights of about 45,000. The antigen-recognizing polypeptide chains of the T-cell receptor are part of a complex of polypeptides, designated Ti-T3. The generation of intracellular signals as a result of the binding of the antigen and MHC molecular complex to the T-cell receptor is believed to be mediated through the associated polypeptide chains. Intracellular signaling events in T cells are similar to those in B cells. Two activation events of particular importance have been identified: the expres- sion of membrane receptors for IL-2, which is a potent T-cell growth factor, and, in a subset of T cells, the production of IL-2. These events imply that T cells are capable of autologous stimulation of growth since they both make and respond to IL-2. Activated T Cells Produce Many Distinct Lymphokines Having Important Functions in the Immune and Hernatopoietic Systems Lymphokines are generally made in small amounts and in many cases seem to act locally by binding to target cells having receptors for the lymphokine. Indeed, those lymphokines that assist in the interactions of T cells with antigen- presenting cells, such as macrophages, B cells, and related cell types, are likely to be directionally secreted and seem to act almost exclusively on the cell with which the T cell is engaged. This exclusivity provides a mechanism through which antigen-specific responses may be mediated by the action of factors that are not specific for antigen. In interactions with specific T cells, these lymphokines would be concentrated only in the immediate vicinity of the cells that participate with the T cells in specific immune responses. Other factors important in the immune response may act more like endocrine hormones. Interleukin-1 (IL-1), a factor made by activated macrophages as well as by many other cell types, has a broad range of functions in inflammatory responses, including the activation of T cells and the elevation of body temperature by its action upon hypothalmic cells. These functions suggest that some of the actions of IL-1 are mediated by action at a distance from the cell that secreted it.

238 OPPORTUNITIES IN BIOLOGY The Action of Lymphokines on Their Target Cells Is Mediated by Their Binding to Cell-Surface Receptor Molecules The interaction between lymphokines and receptor molecules results in the creation of intracellular biochemical signals through which the action of the lymphokine on the target cell is achieved. The most intensively studied lymphok- ine receptor is the IL-2 receptor, which exists in both high- and low-affinity forms; the bulk of current evidence suggests that the high-affinity form is largely responsible for the biological actions of IL-2. Since adult T-cell leukemia cells have large numbers of IL-2 receptors, antibodies to the receptor may provide an important tool for the therapy of this highly aggressive lymphoid malignancy. Immunotoxins based on antibodies to the IL-2 receptor are now being tested as therapeutic agents. If successful, such a therapy would suggest that other malignancies displaying heightened numbers of lymphokine receptors would be candidates for a similar antibody-receptor-immu- notoxin therapeutic approach. Killer T Cells and Natural Killer Cells Destroy Cells That Cause Disease Lymphokine production is one mechanism through which T-cell responses are mediated. Although lymphokines can function as effecters, most of their actions are regulatory. Killer T cells, by contrast, have as their principal role the destruction of antigen-bearing target cells, such as cells infected with viruses and those bearing on their membranes viral proteins. These antigens form complexes with class I (in some cases class II) MHC molecules, which are recognized by the receptors of the killer T cell. The recognition of the antigenic complex on the surface of the target cell activates the killer cell, which in turn sets in motion the process that destroys the target cells. Although controversy still exists on this subject, T-cell-mediated cytotoxicity seems to involve killer-cell production of substances called porins, which polymerize, integrate into the target-cell mem- brane, and cause cell lysis. Activated killer T cells may also produce esterases, which may also play a critical role in the destruction of the target cell by specific killer T cells or may help the killer cell detach from targets. Cellular cytotoxicity is also mediated by a second cell type, designated natural killer (NK) cells. These cells are large granular cells resembling lympho- cytes. The molecular mechanisms of killing by NK cells and killer T cells seem to be the same, but the means through which the cells identify their targets differ. NK cells lack T-cell receptor molecules and do not display the type of specificity generally seen in B or T lymphocytes. Nonetheless, they seem to distinguish and to preferentially lyse certain types of tumor cells. The identification of the molecular nature and specificity of the NK cell receptor is a goal of considerable importance. NK cells seem to mediate an important element of nonspecific

THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 239 ~ ~PoTENTlALCLlNlOAL~APPLICATIONSOF~INM:P:H~OKI:NES: :: :~ Tbe Went actors: ~ y:mpho dines on ~ a Aloe ~ vanety Ot ICE FLU ar targets anc ~ t Heir ro ins In t Nolan t ro To it::: many asps of be Immune n sponse ant OT ; ~ ~irdl~amm~tion~ have~suggestdd that these agents may~:~bb~ Of ~great::impo~nce : : ~ i:n~ therapy: ~ diseases in ~ which: the :~i:m~m:une:~ :respon~se~ :or :~the :hem~to:poi~etic hi: system Abnormally plays a moors role.::: Schist possibly: has: lad: many biot~h~- ,nology add p:harma£eut;~1~co~mpanies:to:~:undettake~::sub~tantial reseat . . ~ ~ · · · . . ~ ain't ~ deve opt prams: alma" at: a - ~ offing ~ ymp ~ flings ant ~ Uremia i - : I: ~ ~ biological :res:ponse::~modifiers for clinical purposes.: fonts: to tmat various : :::: : :ma:lignancias:: wild Interferon have :aUra~e£ :=ns~uer~a ~ ~ Fenton.: to Snow ::~ clear that ~interfem:n~ is Ma useful tool in :the treatment of a~:limited ~:nu~mber of ~ ma~li~nanciQs-most~ not~blv~hai~<ell:~leuKemia:. ~iL~has recently been used ~: ~ ::: : to:~treat ~a~wide:~range Of Imetastatic malignancies. ~ ~mphocytes~ from the : ~ blood: a::cance~r patient are grown in tissue culture to gene~te~ly~m~phokin~Q-: :~: : : - iced killer (YAK) cells~and are: then ::returned to: then patients, :who is next: treated with large amounts of lL-2. This:the~rapy causes regression:in :some mastitic ma:lignanc'es, but it has Serious: side Affects :thdt:~l~imit Rs~ use. ~ i: :~ Other pote~ntial:~:u~se~s Elf: ~:l~m~phok':n:es~ arm :not limited to:t~he treatment of: ~ . ~ ~ . . . ma ign~ancles~. :~: -or~exa~m~ple, treatn~en~:ot :'n~ectious As eases ana line re ~ ~ ~ · · · . Inoculation of the: Immune and hen~atopo~et~c: systems bind ~mmu~nosuppressed : pati~ents:~may::be:~aided by the use:~:tcell-derived hematopo:'et~c and Iympho~id growth and differentiation :factors :pr~duced~::~by recombinant DNA techniques. ~ Ine use of tness: agents~to: hasting cellular :repopulation In Individuals who nays receive cancer GnemotnerapQutlC agents and In re ::~ cipients~ Of ~ne-marrow grafts may be particularly important. : :H~ With prov:es :poss~ble to find methods to~;treat AIDS patients by pr~venti:ng cellito cell transfer~of Virus' T<ell~erived: hemato~ietic gr~wth::f~ctors: may begot great :: impo:rtance~:~:for :the reconstitution :of the immune system of the recovering: :. ~ patient.: immunity, mainly against arising tumor cells, but possibly also against infectious agents. Regulation of the Immune Response Immune Responses Are Subject to Both Positive and Negative Regulatory Control A key example of regulatory control is the action of T lymphocytes as helper cells in antibody responses. The production of antibody by B cells requires either

240 OPPORTUNITIES IN BIOLOGY intimate contact between T and B cells (cognate interactions) or the presence of T-cell-derived soluble products. It is now recognized that helper T cells from mice can be subdivided into two sets, TH] and TH2 cells, on the basis of the lymphokines they produce. The lymphokines produced by TH! cells promote cellular immune responses, such as macrophage activation and delayed hypersen- sitivity, and those produced by TH2 cells promote antibody production. The two forms of helper T cells are also specialized in terms of the relative degree of cellular immunity that emerges in immune responses in which one or the other predominates. One of the most important issues to be resolved is the means through which the relative numbers of TH]. and TH2 cells participating in a given immune response are determined. It is most likely that the TH] and TH2 cells have distinctive activation requirements and that immunogens may differ in their ability to activate cells of the two ~es. For example, antibody responses to many parasitic agents are marked by the production of very large amounts of IgE. It seems most likely that responses to these parasites are dominated by the action of TH2 cells, with some feature of the parasite leading to the selective activation of the TH2 cell. A second major aspect of immunological regulation is the inhibition or suppression of responses. This mechanism is necessary to keep immune re- sponses from overwhelming the system; it may also play a role in the maintenance of immunological tolerance. Suppressor cells seem to be a distinctive subpopula- tion of T cells. Many of them express the CD8 surface marker. Their mode of action has been the subject of intense research interest. In addition, in many autoimmune diseases, a failure of suppressor cell function may account for some of the response to self-antigens. Suppressor mechanisms may also limit immune responses to tumor cells and thus diminish the effectiveness of the immunological control of tumor cell growth. A particularly intriguing mechanism through which immune responses may be regulated involves the "immunological network," which is based on the capac- ity of antibodies and receptors to recognize one another. The variable regions of antibodies and receptors are themselves antigenic determinants, which may thus elicit the production of specific antibodies. The unique antigenic determinants of antibodies and receptors are referred to as idiotopes, and the collection of idi- otopes on an individual antibody is its idiotype. Anti-idiotope antibodies, through their recognition of structures on the variable regions of antibodies and receptors, may be thought of as surrogates for the antigens to which the antibodies and receptors "normally" bind. Thus, such anti-idiotope antibodies may be regarded as "internal images" of conventional antigens, and idiotop~anti-idiotope interac- tions may determine the level of action of the immune system against exogenous antigens. Idiotope-based network interactions may be either stimulatory or inhib- itory, depending on the conditions of the interaction. What remains to be estab

THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 241 fished is the relative importance of network-based regulation in determining the level of activity of the immune system. Complement and Over Effector Molecules The Complement System Can Destroy Antzgen-Bearing Microorganisms or Cells The interaction of antibody molecules with antigens on the surface of a microorganism or a malignant cell may prevent the organism from entering a host cell or may block the normal metabolism of the cell. More often, the antibody by itself has only a limited effect on the infectivity of the microorganism or the behavior of the malignant cell. However, the interaction of antibody with anti- gens locally activates a series of enzymes, the complement system, that may directly or indirectly destroy the antigen-bearing microorganism or cell. In addition to direct destruction of target microorganisms or cells through attack on the cell membrane, the activation of the complement system leads to the forma- tion of several highly active fragments of complement components. Among these are the anaphylatoxins that lead to the release of vasoactive amines from mast cells and basophils, resulting in vasodilatation and striking local inflammation. Finally, macrophages and polymorphonuclear leucocytes bear receptors for the components of complement (complement receptor molecules); the engage- ment of this receptor triggers phagocytosis. In this way, the deposition of complement components on the surface of a microorganism markedly enhances phagocytosis and the destruction of the infectious agent. The complexity of the complement system and its high degree of internal regulation have made it a difficult system to study in detail. Nonetheless, great progress has been made as a result of purification of each major component of the system and cloning many of the complement genes. Efforts to understand the molecular and cellular basis of complement action, the regulation of the level of activity of the complement system, and the means infectious agents use to evade the system are producing exciting results. Hypersensitivity, Inflammation, and Phagocytosis The Study of the Cellular and Chemical Mechanisms of Inflammation and Phagocytosis Is Crucial to the Development of Anti-inflammatory Drugs A common feature of the cellular response to foreign agents is a local inflammatory response. Inflammation that occurs as a result of immune re- sponses is often referred to as hypersensitivity. The immediate type of hypersen- sitivity is mediated by the action of antibodies of the IgE class. IgE interacts with

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THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 243 receptors on the surface of mast cells and basophils (Fc£ receptors) and, when cross-linked by antigen, causes these cells to release histamine and other highly active molecules. These substances cause local vasodilatation and may cause bronchoconstriction as part of systemic reactions that occur in severe cases, termed anaphylactic reactions. The inflammatory response that occurs both in hypersensitivity and in direct irritant responses includes the entry into the tissues of neutrophils, macrophages, and eosinophils. These cells are produced in the bone marrow and are distributed throughout the body by the blood. They arrive at sites of inflammation by migrating between postcapillary endothelial cells. Neutrophils are the first cells to enter inflammatory sites. They are phagocytic cells that also release products that activate complement and recruit monocytes and additional neutrophils to the inflammed site. Monocytes are the predominant cells at wound sites within 24 hours. Over a period of days, they develop into macrophages capable of phagocytosis, microbi- cidal activity, and the release of mediators, such as IL-1 and tumor necrosis factor. Macrophages play a particularly important role in the destruction of intracellular parasites; such organisms can cause tuberculosis, leishmaniasis, and toxoplas- mosis. In response to infection with these microbes, macrophages often fuse to form multinucleated giant cells and granulomas. This process is believed to help contain and destroy pathogens. Eosinophils are normally present in small numbers, but they increase strik- ingly in frequency in parasitic infestations and in allergic diseases. These cells are believed to destroy certain parasitic agents, possibly through the recognition by FC£ receptors of IgE antibodies coating the parasite, leading to the release of cytoplasmic granules that contain enzymes that are highly toxic for the parasite. These inflammatory cells can also phagocytose particles. Phagocytosis is enhanced when the cell binds the particle through its cellular receptors for the Fc portion of IgG (Fc~ receptors) and through its CR1 surface receptors. Thus microorganisms or cells coated with antibodies or complement are much more efficiently taken up by phagocytic cells than are uncoated particles. The function of the Fc~receptors is mediated through their action, when aggregated in the plane of the membrane, as voltage nonselective channels for monovalent cations. Through this mechanism, Fc~ receptor aggregation elevates the concentration of calcium ions, an absolute requirement for the membrane internalization that is a key feature of phagocytosis. Phagocytosis brings microorganisms (or cells) into lysosomes, which are rich in degradative enzymes. If sensitive to these enzymes, the phagocytosed agent is destroyed. Phagocytic cells have other means of destroying ingested microorgan- isms, including a complex enzyme system for generating toxic oxygen products, including hydrogen peroxide and hydroxyl radicals. In addition, these cells produce hypochlorous acid, hypochlorite, and chlorine, which oxidize and halo

244 OPPORTUNITY INBIO=GY genate microorganisms and tumor cells. These metabolites can also damage normal cells and injure tissue as is seen in chronic inflammatory conditions. Since the study of the cellular and chemical mechanisms of inflammation and phagocytosis forms one of the principal arenas for the development of drugs that limit tissue damage in chronic inflammatory diseases such as rheumatoid arthritis, it will continue to require strong emphasis, by both academic and industrial laboratories. INFECTIOUS DISEASES In Recent Years Our Understanding of Mechanisms of Microbial Pathogenicity Has Signif cantly Advanced Microorganisms constitute an extraordinarily diverse group of organisms, which are found in virtually every environmental niche, infect all living creatures, and can cause disease in their hosts. When infection occurs, it may lead to a nonpathogenic outcome, in which the infecting agent does not penetrate the host barriers or is effectively controlled by the host immune system. Many bacteria and viruses coexist with the host, causing disease only rarely and only when the host is compromised by impaired immune defense mechanisms. By contrast, the most virulent pathogens produce disease in almost every infected host. After being infected with a pathogenic microbe, the host organism may recover com- pletely and eliminate the pathogen or may develop a persistent or latent infection, resulting in subsequent illness or relapse after a prolonged interval. Pathogenic microorganisms are a highly heterogeneous group of agents; they include some of the smallest and simplest of all biological life forms, from viroids, which consist solely of nucleic acids, to helminths and protozoa, which are highly complex, sometimes multicellular enlcaryotic organisms. For most pathogenic microorganisms, our understanding of the precise mech- anisms of pathogenesis (the capacity of the microbe to cause disease) are poorly understood. The degree of pathogenicity of a microorganism is termed virulence. Virulence is a multifactorial property determined by the product of more than one gene. For bacteria, virulence factors include such properties as growth, motility, chemotaxis, adherence to host tissues, and resistance to lethal host defense mecha- nisms (for example, phagocytosis and bacterial antibodies), elaboration of toxins, and penetration of host cells. For viruses, virulence factors include the capacity to spread, replication in cells, survival in tissue fluids, interaction with proteases and host-cell receptors, and resistance to host defense (macrophages, T cells, and interferon). The interaction between the invading pathogen and the host's im- mune system, together with the concerted effects of many distinct microbial gene products, is ultimately responsible for inducing disease in the host.

THE IMMUNE SYSTEM AlID INFECTIOUS DISEASES Entry into the Host The Mammalian Host Presents a Number of Barriers to Early Events of Pathogenesis 245 The portals through which pathogens gain entry into a host include the conjunctive, the mouth and gastrointestinal tract, the nose and respiratory tract, and the genito-urinary tract. In addition, the body is covered with skin, a natural barrier that may be broken by a number of means (trauma, insect or animal bites, needles). For each of these sites of entry, different microbial strategies have evolved that allow microbes to infect the host. After entering the host, the microbe undergoes primary multiplication. For viruses and intracellular parasites, multiplication occurs inside cells. For ex- tracellular parasites, adherence of the microbe to cell surfaces is an important event that allows the colonization of specific tissues. Many Colonizing Microorganisms Seem to Prefer Certain Tissue Sites over Others The specificity of the association of particular bacteria with various host tissues was suggested by ecological studies of the indigenous (normal flora) and pathogenic bacteria colonizing oral mucosal surfaces and the various niches of dental tissue. For example, the actinomycete bacteria Streptococcus mutans and S. mitts, both of which promote tooth decay, were found in large numbers in dental plaque but sparsely on the surface of tongue epithelial cells. The reverse was true for S. salivarius, an organism normally found in abundance on the tongue but not at all on the teeth. The contrast between two common pathogenic bacteria reinforces the con- cept of specificity. Escherichia colt, the most frequent cause of urinary tract infections, is abundant in periurethral tissues, but is seldom found in the upper respiratory tract. In contrast, group A streptococci, which are virtually limited to colonization of the upper respiratory tract and skin, are seldom associated with urinary tract infections. The specificity of bacterial adherence and colonization is further supported by the observation that certain bacterial infections are limited to . . One animal species. The Chemical Nature of Some Bacterial Adhesins and Their Corresponding Receptors on Host Tissues Is Known A large number of studies performed during the past decade have established that many bacteria have surface structures that bind to specific macromolecules on host cells in a lock-and-key (or induced-fit) fashion analogous to the combina

246 OPPORTUNITIES IN BIOLOGY lion of an enzyme with its substrate or an antibody with its antigen. The terms adhesin and receptor describe the corresponding molecules on the surfaces of the bacteria and the animal cells, respectively. In general, the bacterial adhesins are composed of proteins in the form of fimbriae or pill (hairlike fibers), whereas the recognized part of the receptor is composed of carbohydrates. Because of their specific interactions with carbohydrate residues, most of the bacterial adhesins can be considered lectins, and like plant lectins, many of them agglutinate red blood cells. Bacterial agglutinins (or lectins) were first reported in 1908, following the observation that cells of E. cold agglutinate erythrocytes. Only recently, however, was it established that carbohydrate-lectin interactions constitute the molecular means by which most bacteria adhere to animal cells. These interactions occur in three ways. 1. Bacterial surface lectins can bind to the carbohydrates on the surface of animal cells. Since the 1950s it has been known that mannose and methyl-a-D- mannoside specifically inhibit the adherence of many gram-negative bacteria to eukaryotic cells. In 1977, bacteria were suggested to have surface lectins, which serve as adhesins that bind the organisms to mannose residues on human cells. Since then, both gram-positive and gram-negative bacteria have been found to express specific lectins on their surfaces. Several different sugars that may serve as sites for attachment for these lectins are characteristic constituents of cell- surface glycolipids or glycoproteins. The lectins are organized on bacterial surfaces in either fimbrial or nonfim- brial structures. Fimbriae, long tubelike projections, are assembled as hollow fibers by the polymerization of the monomeric subunits composed entirely of protein. On the basis of their sugar specificity, several types of fimbrial lectins have been distinguished. Some bacterial strains are genotypically able to turn on and off the expression of fimbriae. The phenotypic expression of these organelles seems to be under the control of an on-off switch in the DNA itself and is minimally affected by en- vironmental influences. This switching results in a relatively constant shift from fimbriate to nonfimbriate (or vice versa) at a frequency of one per thousand bacteria per generation, which is about 10,000 times as frequent as a true muta- tional event. The ability to undergo such rapid phenotypic variation in viva is probably a key determinant of the survival of bacteria on mucosal surfaces and of their pathogenicity once they invade deeper tissues. Evidence for such rapid phase shifts has been reported for Proteus mirabilis (responsible for induced urinary tract infections). 2. Extracellular lectin molecules can form bridges between carbohydrates present on the surface of the bacteria and their host. The bridging type of

THE IMMUNE SYSTEM AND INFECTIOUS DISEASES 247 carbohydrate-lectin interaction was first noticed in the interaction of the plant bacterium Rhizabium trifolii with the root hairs of clover. Clover roots secrete a carbohydrate-binding protein, trifolin A, which recognizes carbohydrate struc- tures on the surfaces that are shared by the bacteria and the root hairs and ligates them by forming a bridge between their common sugar residues. Recent data suggest that a mechanism of adherence similar to that of R. trifolii may occur between bacterial and animal cells. The bridging lectin may have endogenous (produced by the host) or exogenous (acquired mostly from food) origins. For example, the intestinal secretions of guinea pigs is character- ized by lectin activity specific for glucose and fucose. This lectin agglutinates Shigellaflexneri and may mediate its attachment to mucosal surfaces of the gut. Since lectins are abundant in food, the possibility was examined that these exogenously acquired lectins may become associated with mucosal cells as a cell- coat component and thus function as receptors for bacterial adherence. Indeed, buccal epithelial cells scraped from persons shortly after they eat raw wheat germ contain high amounts of wheat germ agglutinin on their surfaces. Because wheat germ agglutinin is an N-acetylglucosamine-specific lectin, the coated cells bind an increased number of Streptococcus sanguis organisms, which contain N- acetylglucosamine residues on their surface. Certain dietary 1echns may also reach the alimentary tract in a functional form and thus may potentially mediate bacterial adherence. 3. Bacterial surface carbohydrates can bind to a lectin contained within the animal cell membrane. Evidence accumulated during the past 10 years indicates that animal cells exhibit lectins on their surfaces. Such lectins have been found on many cell types. Liver-cell lectins have been found to serve as receptors for serum asialoglycoproteins, asialoerythrocytes, and various glycoproteins, and are thus responsible for the clearance of these tissue elements from the blood. Simi- larly, when bacteria were injected into the blood streams of animals, they become lodged in the liver in less than an hour. Recent studies demonstrated that bacteria were trapped in the liver by hepatic receptors (lectins), which recognize corre- sponding sugar residues on the bacterial surfaces. Carbohydrate-Lectin Interactions Play a Central Role in the Mutual Recognition Between Many Bacteria and Host Cells One must be cautious in drawing general conclusions about the significance of lectin-carbohydrate interactions in viva on the basis of in vitro studies alone. It is not unlikely that the physiological environment influences the orientation and relative accessibility of the sugar moieties in the oligosaccharides involved in the interactions in vitro; a change in orientation theoretically would markedly affect not only the affinity but also the specificity of the bacteria-host-cell interaction.

248 OPPORTUNITIES IN BIOLOGY Nevertheless, with this caution in mind, further characterization of an increasing number of unique bacterial and host cell lectins and oligosaccharides should lead to a better understanding of their functional significance and the mechanisms by which their synthesis and expression are controlled. Sugars Are Not the Only Determinants of Recognition Between Bacteria and Epithelial Cells Studies have been aimed at clarifying the molecular basis of the host-cell attachment of streptococci. These organisms inhabit the skin, the mouth, and the throat and may cause a variety of infections and postinfectious complications, such as acute rheumatic fever or acute glomerulonephritis. Transmission electron microscopy of streptococci attached to buccal epithelial cells has revealed the presence of fibrillar structures extending from the bacteria to the surface of the epithelial cells. These fibrillar structures are composed of proteins complexed with lipoteichoic acid, an ampiphathic polymer produced by the bacteria: It consists of repeating units of glycerol phosphate capped at one end with a glycolipid moiety. The latter moiety is responsible for the binding of the strepto- cocci to specific receptors on oral epithelial cells. Indeed, isolated lipoteichoic acid binds to receptors on a wide variety of mammalian cells. Moreover, the purified polymer blocked the adherence of epithelial cells of streptococci, but not of other bacteria, such as E. colt. Since the fatty acid of lipoteichoic acid mediates the epithelial cell attach- ment of streptococci, a protein or glycoprotein with fatty-acid binding sites may serve as the receptor. The receptor now seems to be fibronectin, a ubiquitous glycoprotein present on the surface of many host cells including oral epithelial cells. Binding of lipoteichoic acid to fibronectin occurs at a site on the glycopro- tein that specifically binds fatty acid residues with a binding affinity two orders of magnitude higher than the binding of lipotichoic acid to fatty-acid binding sites of serum albumin. These results indicate that in addition to lectin-carbohydrate interactions, protein-lipid interactions are centrally involved in the specific at- tachment of certain bacteria to host cells. Flagellates, which are unicellular eukaryotes, invade host cells by the specific interaction of parasite and host molecules. Malaria parasites invade erythrocytes by interacting with specific ligands on the red cell membrane. The ligand involved in invasion by Plasrnodium vivax, a human malaria, and P. knowlesi, a simian malaria, is the Duffy blood group antigen; this identification explains the resistance to P. vivax of West Africans who lack the Duffy antigen on their red blood cells. The comparable molecule for P. falciparum, the major human malarial parasite, is sialic acid on glycophorin. The parasite receptors that bind these ligands are now being identified. The value of these receptor molecules as

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).

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.

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

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

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

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

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

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. : ~ ~ - ::: ·:

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.

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

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.

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Biology has entered an era in which interdisciplinary cooperation is at an all-time high, practical applications follow basic discoveries more quickly than ever before, and new technologies—recombinant DNA, scanning tunneling microscopes, and more—are revolutionizing the way science is conducted. The potential for scientific breakthroughs with significant implications for society has never been greater.

Opportunities in Biology reports on the state of the new biology, taking a detailed look at the disciplines of biology; examining the advances made in medicine, agriculture, and other fields; and pointing out promising research opportunities. Authored by an expert panel representing a variety of viewpoints, this volume also offers recommendations on how to meet the infrastructure needs—for funding, effective information systems, and other support—of future biology research.

Exploring what has been accomplished and what is on the horizon, Opportunities in Biology is an indispensable resource for students, teachers, and researchers in all subdisciplines of biology as well as for research administrators and those in funding agencies.

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