Immunology, Infection, and Immunity

The principal function of the immune system is to protect against infection. The modern appreciation of the physiologic function of the immune system is barely more than 100 years old. Blood is an important component of the immune system. It contains the hematopoietic cells, proteins, and liquid that circulates throughout the body. The major protein found in the blood and on mucosal surfaces, such as the respiratory, gastrointestinal, and urogenital tracts, that mediates immune system function is antibody. Two broad categories of immune system function have been defined: innate immunity and adaptive immunity. Phagocytic cells recognize foreign microorganisms and ingest (or engulf) them. The cell releases into the phagosome toxic compounds that digest and kill the microorganism. Polymorphonuclear neutrophils (PMNs) are principally found in the blood and live only 12 to 24 hours. Therefore, a prodigious amount of new PMNs are made each day by an individual. However, early after an antigenic stimulus is detected, the PMNs leave the blood and travel to the site of infection, ready to ingest antigens and kill those that are living. Adaptive immunity can be subdivided into cell-mediated and humoral immunity labels that can be somewhat confusing, since both types of immunity involve cells—the lymphocytes. It is important that the immune effector mechanisms that are operative during hypersensitive responses are identical to the mechanisms that occur during appropriate and protective immune responses in other circumstances.

The innate defenses are either constitutively active or rapidly mobilized and are effective against many types of microbial agents, whereas the acquired immune response is activated slowly, depends on the entry of an antigenic stimulus into an individual’s tissues, and is specific to a particular foreign material. The acquired and the innate immune responses supplement each other and stimulate and regulate each other’s activity. In terms of innate immunity, there are other differences between the cornea and the skin. Individuals also possess a large battery of enzymes that can damage bacteria, viruses, and other even nonviable foreign antigens. These enzymatic effectors of innate immunity generally function by damaging the structural integrity of the microbial surface, although the different effectors accomplish this in different ways. Many of the enzymatic effectors of innate immunity are present in mucosal secretions such as tears and saliva. Proteases are enzymatic effector molecules that contribute to innate immunity at mucosal surfaces. Most important in innate immunity to viruses are the type I interferons, IFN-α and IFN-β. During viral infection, the cytokines are secreted by lymphocytes, monocytes, and macrophages and bind to a receptor (IFN-α and IFN-β bind to the same receptor) expressed by almost all cell types. When a type I interferon binds to its receptor, the cell enters an "antiviral state" during which viral replication is inhibited by interference with protein synthesis within the infected cell.

The cells of the immune system include the granulocytes (neutrophils, eosinophils, and basophils), mast cells, monocytes, dendritic cells, lymphocytes, and platelets. This chapter covers growth and development of immune cell types; identification of cell types by cell surface markers; morphology and immune function of myeloid cell types; morphology and immune function of lymphoid cell types. In adults, hematopoiesis normally takes place in the bone marrow. Neutrophils are the most numerous leukocytes in the blood and the most important cellular component of the innate immune system for destroying bacteria and fungi via phagocytosis. As such, neutrophils are a major first line of defense against such infections. Lymphoid cells are morphologically the simplest and functionally the most diverse cells of the immune system. In summary, lymphoid cell surface markers can be used to provide not only information about a lymphocyte's lineage but also specific information about a lymphocyte's maturation and activational state. Natural killer (NK) cells are part of the innate immune system and are able to act rapidly, within several hours of challenge.

This chapter talks about organs essential for the generation of immune cells, organs and tissues essential for the function of immune cells, anatomic factors that influence the immune response, trafficking and circulation of immune cells through the body, immune function at the mucosal surfaces of the body and immune function in the skin. The various cell types comprising the immune system and their functions are distributed throughout the body but are concentrated within the organs and tissues that support the development and function of the immune cells. In cattle and sheep, B-cell maturation takes place in a specialized lymphoid organ called the ileal Peyer’s patch. The generative organs are those that produce hematopoietic cells involved in host defense. In most mammals, these organs are the bone marrow and the thymus. The bone marrow is the most important source of hematopoiesis-derived cells in adult mammals. Lymphocytes reside in lymphoid tissues for various periods of time, the duration depending largely on whether the lymphocytes are activated by antigen. Germinal centers are important sites for B-lymphocyte differentiation. The initial activation of B lymphocytes most likely occurs outside the germinal center. The spleen receives blood through a single splenic artery. Lymph nodes are a site for the convergence of two distinct, nonoverlapping circulatory systems. The epithelial linings of various mucosae present different types of barriers to microbial invasion. The mouth, pharynx, esophagus, urethra, and vagina all contain stratified squamous epithelium.

Complement proteins fall into three broad categories, although some complement proteins may actually fit into two of these categories. The first category encompasses the complement serum proteins, which react with foreign bodies in either an antibody-dependent or antibody-independent manner. The second are regulatory proteins present in serum or on the membranes of host cells. The third are cell surface receptors that bind to the products of complement activation and signal host cells to participate in inflammatory and immune reactions. The complement system is designed to mobilize a large number of immune effector mechanisms when it detects infected or injured self tissues. Three pathways of complement activation are now known: the alternative pathway, the classical pathway, and the lectin pathway. A third pathway of complement activation, the lectin pathway, has recently been defined but, like the alternative pathway of complement activation, likely arose during evolution prior to the classical pathway. Serum opsonins include antibody, complement, fibronectin, and C-reactive protein (CRP). Host phagocytes, such as neutrophils and macrophages, have receptor proteins on their cell surfaces that specifically recognize portions of the antibody molecule (Fc receptors), fragments of complement (C3 receptors), and fibronectin. Immune cells attracted to such sites expose cell surface receptor proteins that recognize particular fragments of C3 and fulfill the biologic function of phagocytosis. Thus, complement constitutes the fundamental proinflammatory response system that can trigger and regulate the remainder of the immune response.

An understanding of how antibodies carry out their effector functions through interactions with other cells and soluble proteins not only has identified key features of the biology of the adaptive immune system but also has provided important and novel insights into the interactions between the innate and adaptive immune systems. Antibodies are glycoproteins and, as such, contain one or more types of carbohydrate modifications. Immunoglobulins are glycoproteins and, as such, are potent immunogens when introduced into different species, where they are recognized as ‘’foreign’’. Therefore, antibodies can be used to induce other antibodies by appropriate immunizations. The elimination of antigens is initiated by the biologic activities of antibodies, which are properties of the H-chain constant regions. Immunoglobulin G (IgG) is the most abundant Ig in serum, accounting for approximately 80% of the total of serum antibodies, with normal serum concentrations being 10 mg/ml or higher. The study of humoral immunity usually focuses on antibodies of mice and humans, and with good reason. The study of humoral immunity in cartilaginous fish has revealed the presence in the species of three classes of immunoglobulin and immunoglobulin-like proteins: IgW, nurse shark antigen receptor or new antigen receptor (NAR), and IgNARC. That IgG isotype immunoglobulins exist in nature (and that they are functional in antigen binding) suggests that, for certain species, single-chain antibodies such as NARs are sufficient to mediate protective immunity against infection.

The vast diversity of the antibodies generated by B cells derives largely from the fact that the variable portion of these molecules is assembled differently in each individual lymphocyte using a large number of individual genes. Three types of genes known as the variable (V), diversity (D), and joining (J) genes need to be rearranged for the H-chain variable region to be complete, while only two of them, V and J, are used for the L-chain variable region. Preceding each V gene is a small exon encoding a hydrophobic leader sequence (Ls) that is responsible for guiding the nascent H-chain or L-chain protein into the lumen of the endoplasmic reticulum for processing and assembly. The Immunoglobulin H-Chain variable (IGHV) genes have been divided into 14 to 15 subgroups labeled IGHV1 to IGHV15. Subgroups are formed from closely related IGHV genes, but the related genes are not necessarily grouped together on the chromosome. It should be noted, however, that this total change in nucleotide number is ultimately affected not only by P-nucleotide addition but also by the processes of junctional flexibility and N-nucleotide addition that further contribute to antibody diversity. One of the most perplexing puzzles in the molecular genetics of antibody production was the ability of an animal to produce different isotype antibodies of identical antigenic specificity. There are numerous regulatory processes that control B-cell development, including transcriptional regulation of the immunoglobulin genes, allelic exclusion, and sequential rearrangement of L-chain variable-region genes.

The initiation of an immune response requires the interaction between T cells, B cells, and antigen-presenting cells (APCs), which form central components of almost all immune responses, and antigens, substances recognized as foreign by the immune system. The ability of an antigen to combine with antibody reflects the property of antigenicity. The distinction between antigenicity and immunogenicity can be seen by examining antigen-antibody reactions; a substance that is antigenic but not immunogenic would likely bind to a B-cell membrane immunoglobulin receptor but fail to provoke subsequent antibody production by that B cell. Researchers have determined the three-dimensional structure of major histocompatibility complex (MHC) class I and class II proteins bound to peptide. This work provided important insights into the nature of T-cell epitopes. To elucidate the differences between antigenicity and immunogenicity, K. Landsteiner, in the 1920s, synthesized numerous small organic compounds that, by themselves, could not induce antibodies but, after coupling or conjugation to a larger molecule, could induce antibodies capable of binding the free compound. Adjuvants enhance immunity, usually by provoking a more intense and prolonged immune response. Common T-cell mitogens include concanavalin A, phytohemagglutinin, and pokeweed mitogen. These mitogens bind surface carbohydrates on cells and may also promote cellular agglutination. Although mitogens are an experimentally useful surrogate for measuring lymphocyte responses to antigens, the results of such experiments must be interpreted with caution since the responses may deviate considerably from the true in vivo situation.

Antibody-antigen interactions are in many respects comparable to enzyme-substrate interactions (immunologic reactions), in that both are highly specific, reversible, and based on noncovalent intermolecular interactions. The lock-and-key model describes antibody-antigen binding as the perfect fit of two rigid, complementary shapes. An important implication of the induced-fit model is a reduction in antibody-antigen specificity, since the ability of an antibody to subtly change the shape of its antigen-binding site might allow the site to bind multiple antigens. This could explain the frequently observed phenomenon of cross-reactivity, in which an antibody originally generated to one antigen is also capable of binding other, unrelated antigens. Affinity is one of the most important concepts that define the antibody-antigen interaction. The reversibility of antibody-antigen interactions implies that the binding conferred by the noncovalent forces generally is very weak and highly dependent on the distance between the partners. Electrostatic forces are the strongest of all noncovalent bonds but are relatively uncommon in naturally occurring antibody-antigen interactions. Tests based on antigen-antibody interactions are used widely in many fields because of their sensitivity, simplicity, and universal application of the concept that antibodies bind tightly and specifically to antigens. Large variety of laboratory techniques for determining antigen-antibody reactions and cellular responses to antigens have been developed, and sensitive analyses of single cell responses of immunologic relevance are now routinely made.

Antibodies are essential mediators of immunity to pathogens that survive and multiply in extracellular spaces and utilize the extracellular milieu to spread within host tissues. B lymphocytes are the primary effector cells of the humoral immune response, going through various stages starting with maturing in the bone marrow, circulating in the blood and lymphatics, and, following antigen encounter, maturing into plasma cells (that secrete antibodies) and memory cells. Surface expression of CD22 increases during B-cell activation, then decreases on the surface of the plasma cell during antibody production. Thymus-independent (TI) antigens stimulate antibody production in the absence of major histocompatibility complex (MHC) class II-restricted T-cell help since they cannot be processed into peptides that can be bound to MHC molecules. One of the main regulatory mechanisms for isotype switching and induction of antibody production is the secretion of cytokines by the T lymphocytes. After antigen stimulation, B-cell activation and proliferation occur followed by the production of antibody of isotypes other than IgM. This mechanism of isotype switching enables antibodies of a given antigenic specificity to change their biologic effector function by switching H chains encoded by constant region genes. B-cell apoptosis can be initiated when the MHC class II of an already activated B cell is cross-linked. The function of the regulatory mechanism may be to dampen B-cell-mediated T-cell activation once the immune response is activated.

The major histocompatibility complex (MHC) proteins display peptides on the surface of an antigen-presenting cell (APC). Since T lymphocytes recognize antigen only when the antigen is bound to MHC proteins, the latter play a central role in the acquired immune response. The MHC genes are categorized into three classes on the basis of the structure and function of the proteins they encode. Genes encoding the MHC class I products are located at both ends of the MHC, whereas the genes encoding the MHC class II and class III proteins are located between the two class I regions. In one recent study, this experimental system allowed a tumor-specific human cytotoxic T-lymphocyte clone to be studied in a tumor-bearing mouse that possessed a human MHC transgene. In this study, the antigenic peptide bound to the human MHC proteins and the T-cell antigen receptor (TCR) that recognized the antigen were similar to the peptides and TCR that might work during actual tumor rejection in a human patient. The different types were designated by the particular human leukocyte antigen (HLA) class I protein followed by a number, given out in nonsequential order. Thus, serologically distinct HLA-A alleles could be classified as HLAA1, -A2, -A3, -A9, etc. However, as more antibody reagents were developed, it became clear that some of the HLA specificities could be further subdivided into a related set.

This chapter covers antigen-processing cells, processing and presentation of: proteins produced within a host cell, proteins brought into a host cell via endocytosis, and nonprotein antigens, and bacterial and viral strategies to evade the antigen-processing pathways. A variety of antigen-presenting cells (APCs) have been identified in which dendritic cells, macrophages, and B cells are the major ones. Each of these differs in important ways and in their properties, and one of the most important is the endogenous and inducible level of costimulatory signals that affect the relative potency of the different types of APCs. The basic division of pathways holds up in a number of instances and can be experimentally demonstrated by use of selective variants of a given antigen. One of the major functions of CD8+ T cells responding to antigenic peptides presented by major histocompatibility complex (MHC) class I molecules is to kill via a cytotoxic activity the cell that is presenting the antigen. The role of the immunoproteasome in antigen processing, presentation, and T-cell development has been demonstrated by the use of biochemical inhibitors of proteasome catalytic function and in transgenic knockout mice. The MHC class II antigen-processing pathway, unlike that of MHC class I, is generally intended to present antigens obtained by endocytosis from the extracellular milieu, although some cytosolic proteins are shunted into this processing pathway.

On B cells, specificity is mediated by surface immunoglobulin. On T cells, specificity is mediated by the T-cell receptor (TCR) for antigen. The first indications that T cells recognized antigen through a TCR were derived from functional assays using specific target-cell interactions. The initial identification and isolation of the TCR awaited the development of a panel of monoclonal antibodies (MAbs) that could be used to bind specifically to the TCR. Southern blots were used to find those cDNA molecules that hybridized to a different pattern of restriction-digested DNA when comparing germ line DNA with DNA in the T-cell clones. A transmembrane region, which is characterized by a high level of positively charged amino acids, allows the TCR to be inserted and maintained in the T-cell membrane. Both T cells and B cells express the recombination-activating genes known as Rag-1 and Rag-2 that are responsible for rearrangement of these genes. For the TCR to produce a functional receptor, it must be assembled into the plasma membrane such that it can recognize an appropriate antigen-major histocompatibility complex (MHC) complex displayed to the T cell and must also be able to signal this event to the T cell. Overall, the TCR plays a central role in antigen recognition, and the structural diversity in this molecule represents another example of the use of multiple gene segments to produce a functional molecule with the capacity for recognizing an enormous number of MHC-peptide complexes.

The structure of the thymus provides an environment where immature thymocytes can interact with a variety of cells, including thymic epithelial cells and dendritic cells, to acquire their final functional properties—expression of a major histocompatibility complex (MHC)-restricted T-cell receptor (TCR), presence of either CD4 or CD8 in the plasma membrane, and ability to interact with antigen-presenting cells (APCs) or nucleated target cells to respond to foreign antigens. Negative selection that occurs in the thymus forms the basis for central tolerance or the process whereby the large pool of emerging mature lymphocytes is screened for self-reactivity and eliminated if improperly reactive. As with positive selection, controversy particularly exists over which cells in the thymus mediate negative selection and whether it takes place in the cortex or the medulla of the thymus. Peripheral tolerance refers to all of the tolerogenic mechanisms acting on mature lymphocytes that have already proceeded through all of the B- and T-cell maturation stages, have left the primary lymphoid organs, and have entered the periphery. The major transcription factor is NF-κB, generated from a cytoplasmic precursor held in check by binding to its inhibitor, IκB. While obviously not physiologically relevant to T-cell activation, laboratory methods represent important tools for studying the complexity of T-cell responses.

Cellular growth and differentiation ensue, leading to a specific immunologic response. The basic components of the immune system that interact, and therefore must communicate with each other, include antigen-presenting cells (APCs), T cells, and B cells. B cells also function as APCs for certain types of T cells. In addition, the activity of other participatory cells, principally leukocytes, including monocytes/macrophages and the granulocytes, is also influenced by cellular communication. Almost every aspect of cellular communication and interaction in the immune system is modulated in some way by these molecules. Chemokines are a large family of structurally related chemoattractant proteins 8 to 10 kDa in size. They serve as soluble mediators of inflammation and cellular communication and are derived from a variety of cells, with platelets, lymphocytes, activated monocytes/macrophages, and granulocytes being among the prime producers of chemokines. The major function of interleukin (IL)-8 is neutrophil activation and recruitment. IL-8 also augments production of lysosomal enzymes by neutrophils and increases a variety of cell-adhesion molecules. Recent evidence suggests that IL-8 is a dimeric molecule bearing considerable homology to the human major histocompatibility complex (MHC) class I molecule. Cell-adhesion molecules, such as lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1), as well as very late activation 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1), found on lymphocytes and leukocytes, have been found to participate in antigen-dependent and antigen-independent T-cell responses.

Cell-mediated immunity (CMI), also known as cellular immunity, is a historical definition that now serves to distinguish immune responses that are mediated by cells at the effector phase from those mediated by antibodies in the humoral arm of the immune response. Regulation of immunity also uses a number of common mechanistic approaches involving molecular and cellular players that can function in both the humoral and cell-mediated immune systems. The classic TH1 cytokines--IFN-γ, IL-2, and TNF-β or lymphotoxin (LT)--favor CMI, including inflammation and delayed-type hypersensitivity (DTH) reactions. DTH reactions contrast with immediate hypersensitivity reactions, such as those mediating allergies, and manifest themselves within minutes of contact with antigen. Granulomas are organized inflammatory tissues characteristic of ongoing DTH reactions that are made in response to chronic infectious or other antigenic stimuli. T-cell-mediated cytolysis of target cells, particularly that by MHC class I-restricted CD8+ cytotoxic T lymphocytes (CTLs), constitutes one of the earliest described and perhaps best mechanistically characterized systems of cytotoxic effector cells. Eosinophil antibody-dependent cell-mediated cytotoxicity (ADCC) of helminthic parasites appears to occur primarily via secretion of the toxic basic granule-derived protein, probably supplemented by production of reactive oxygen and nitrogen intermediates, proteolytic enzymes, and other toxic substances possessed in common with PMNs and monocytes/macrophages. Overall, CMI is a potent and necessary component of immune resistance to a variety of pathogenic microbes, and the loss of CMI function in diseases such as acquired immunodeficiency syndrome (AIDS) leads to very high susceptibility to opportunistic infections and their consequences.

The mucosal immune system consists of an integrated network of anatomic sites, immune effector cells, and tissues, commonly called mucosa-associated lymphoid tissue (MALT). The functions of MALT can be subdivided into three main categories: (i) primary lymphoid development, (ii) induction and amplification of local mucosal immune responses, and (iii) production of the effector mechanisms of local mucosal immunity. Gut-associated lymphoid tissue (GALT), the best characterized component of MALT, consists of both highly organized local sites, where lymphocytes collect and are responsible for the inductive phase of the mucosal immune response, and vast diffuse effector sites, where activated cells reside. MALTs have evolved an elaborate set of protective mechanisms to prevent infection or colonization. These defenses can be categorized as specific and innate. Specific mucosal defense mechanisms consist of both the humoral and cellular immune systems. Pathogens, particulate antigens, or macromolecules are taken up only via a type of highly restricted active vesicular transport across epithelial cells at a site termed the follicle-associated epithelium (FAE). Oral tolerance is not mediated by a single immunologic mechanism; the primary mechanisms are active suppression, clonal anergy, and clonal deletion. The protective mechanisms that defend mucosal sites from colonization or invasion by microorganisms are essential for health and survival since this is the route of entry of inhaled, ingested, or sexually encountered pathogens.

The molecular biology revolution of the last half of the 20th century led to major advances in the understanding of the molecular and cellular bases for the ways in which bacteria cause diseases, and this century similarly saw the development of numerous important vaccines to prevent serious bacterial infections. Virulence factors can disrupt host cellular function due to secreted toxins or toxic bacterial metabolites. Studies of the effect of antibody and complement in the serum talk about the protective immunity against extracellular bacterial pathogens. Convincing data demonstrating that immunoglobulin A (IgA) has a major role in resistance to infection in vivo are limited. However, it is obvious that preventing bacterial entry and attachment would be the most effective mechanism of immunity, attacking the infectious inocula early on and limiting the development of disease. Bacterial pathogens usually enter our bodies through the mucosal and skin surfaces, including the respiratory, ocular, gastrointestinal, and genitourinary tracts. Skin can be an important site of bacterial colonization, particularly for staphylococci, and direct inoculation of pathogens into the host via or through the skin is always a risk factor for subsequent disease. The most effective antigens for obtaining protective immunity due to antibody and complement activation are bacterial surface structures. The anthrax outbreak that occurred in the United States in the fall of 2001 generated a strong interest in further understanding how the bacterial agents of bioterrorism cause disease and how the public can be protected.

Although biologically and genetically simple by comparison to other organisms, viruses nonetheless have potent means to evade the immune response, indicating that their genetic constitution is sufficient for them to be adept at confounding and frustrating both innate and acquired immunity. The antiviral antibodies directed to antigens on the viral surface, referred to as envelope or capsid antigens, are the most effective in controlling and clearing viral infections, although antibodies to other viral components, such as enzymes involved in replication or proteins found in the core of the virus particle, also are present in the host and may be beneficial. With enveloped viruses, the membrane of the virus fuses with the host-cell membrane and the viral capsid enters the cell, where it is degraded by intracellular proteolytic enzymes, releasing the viral genome into the host-cell cytoplasm. Disruption of the mitotic spindle apparatus in cells infected with some types of viruses produces crescent-shaped bodies in their cytoplasm. Many viruses have developed mechanisms to modulate the host’s defense system. Poxviruses also encode soluble receptors for interferon (IFN)- γ, tumor necrosis factor (TNF)- α and -β, and interleukin-10 (IL-10), enabling them to prevent these cytokines from binding to their receptors on natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) involved in controlling the virus. Although viruses are generally cytopathic, some viral infections lead to chronic production of virus, dormancy, or in some cases, oncogenesis.

Infections with protozoa and helminths are typically chronic (often lasting for the remainder of the lifetime of the host), with the onset of disease symptoms in many instances developing years after the initial infection. Cutaneous leishmaniasis (also called Oriental sore) is probably the only major human parasitic infection for which there appears to be immunity to reinfection. As with many other intracellular infections, cell-mediated immunity seems to be the most important mechanism of resolving the infection, with little if any role for antibodies. T cells are critical in the control of all parasitic infections. Despite an apparent absence of protective immunity that protects against reinfection, the cell-mediated arm of the immune system is required to control parasitic infections. The most serious fungal infections are the systemic mycoses, including histoplasmosis, cryptococcosis, and coccidioidomycosis, which usually begin as lung infections and are acquired by inhaling the spores of free-living fungi. If macrophages are not activated, they are less potent at killing fungi than are neutrophils. Thus, the role of macrophages in resistance to fungal infection is more important in acquired immunity, where they become an effective tool of the specific immune response following activation by TH1-cell-derived cytokines.

The impending elimination of paralytic polio emphasizes how effective vaccines can be in preventing infectious diseases. Live, attenuated viral vaccines offer potent immunity, but the fact that these are live pathogens means that some individuals, usually those with underlying immunocompromise, become ill in response to the vaccine strain of the virus. Provoking both cell-mediated and humoral immunity is another advantage of DNA vaccines. Salmonellae are normally enteric pathogens, initiating infection by invading the epithelial layer of the small intestine. Due to this route of infection, salmonellae are natural candidates for the development of vaccines intended to generate mucosal immunity. A factor that inhibits the effectiveness of antibacterial vaccines is the ability of many bacterial species to vary the antigens they express. It has been proposed that cytotoxic T lymphocytes (CTLs) may be needed for resolution of a primary infection while antiantibody is important for preventing the initiation of a subsequent infection. As many of the currently licensed or available vaccines for viral infections use live, attenuated virus particles, safety is of paramount importance in the development of viral vaccines. The development of vaccines has been, and continues to be, one of the greatest accomplishments in modern medicine. Passive therapy also has shown efficacy in prevention and even treatment of some infectious diseases, and newer technologies involved in production of human monoclonal antibodies likely will increase the range of diseases that are amenable to therapy by passive reagents.

This chapter discusses 1) the basics of acquired immunodeficiency syndrome (AIDS), 2) the structure, function, and biology of human immunodeficiency virus (HIV), 3) genetic and molecular characterization of the HIV genome, 4) pathogenesis of HIV infection and development of AIDS, 5) compromise to the immune system by HIV infection, 6) immune responses to HIV, 7) HIV evasion of immune responses, 8) drugs that are used to treat HIV infection, and 9) vaccines to prevent HIV infection and AIDS. HIV-1 contains the three major genes for structural proteins typical of retroviruses: gag, polymerase (pol), and envelope (env). In general, these genes are translated into precursor proteins that then undergo cleavage and processing to form the mature subunit proteins used for virus assembly. Functionally, almost all aspects of immunity are affected as the disease progresses. There is a conspicuous loss of cellular immunity and an increased susceptibility to intracellular pathogens such as mycobacteria and viruses. In time, drugs that targeted HIV-1 itself were developed, the first being zidovudine (ZDV [AZT]). All the early agents were nucleoside analog inhibitors of viral reverse transcriptase. Most of the attempts at human HIV vaccines have been based on empirical approaches without the intent of generating a specific type of immune effector. Combination multidrug therapy has temporarily provided a solution to this problem, since the application of several antiviral drugs requires that a viral variant become simultaneously resistant to all of the component drugs.

This chapter talks about molecular basis of congenital immunodeficiencies; immune consequences of defects in hematopoiesis and clinical features of various immunodeficient states. During the past two decades, the identification and detailed investigation of the acquired immunodeficiency syndrome (AIDS) have not only heightened one's awareness of immunodeficiency, but have expanded the understanding of the relationship between specific immune defects, opportunistic pathogens, and clinical syndromes. For many years the discussion of immunodeficiency diseases was primarily limited to clinical descriptions of disease courses. Immunodeficiency disorders may manifest solely as recurrent infection of a given tissue or anatomic site or may be encountered as part of a syndrome with many other features. Manifestations of immune dysfunction frequently target the respiratory tract, skin, and gastrointestinal tract or are associated with invasive (systemic) infectious disease. Invasive bacterial disease is common among children because of their frequent environmental exposure to respiratory pathogens, as in day care facilities; their naive immune systems, which lack immunologic memory; and the diminished barrier protection afforded by their skin (especially in premature infants). Periodontitis and gingivitis are common in individuals with genetic, developmental, or acquired disorders involving either phagocyte deficiencies or functional abnormalities of neutrophils. Severe gingivitis also is seen in patients infected with HIV and patients with severe malnutrition, viral illnesses, or unusually severe complications of vaccination with live virus vaccines.

Immunological control of cancers could conceivably play a role in the eradication of primary tumors and disseminated metastases as well as the residual cancer cells that remain after conventional treatment regimens. The ideal result of immunotherapy would be the specific eradication of cancer cells with minimal damage to normal host cells. Attainment of the goal of effective immunotherapy for tumors requires an understanding of how the immune system both fails to respond to cancer cells and has the potential to respond and the ways in which this response can be strategically manipulated. Early experimental studies of the immune response to tumors focused on the outgrowth versus rejection of tumor fragments transplanted between outbred mice. Tumor rejection in these cases was thought to reveal the existence of tumor-specific antigens and suggested that the immune system could be used to control cancer. The tumor surveillance theory states that mammalian cells undergo transformation to cancerous or precancerous states very frequently, but that the immune system successfully recognizes and destroys these transformed cells in most cases. Individuals with Chediak-Higashi syndrome (CHS) are at an increased risk for some types of cancer, as predicted by the tumor surveillance theory. The first generation of tumor-specific vaccines was relatively crude and consisted of whole cancer cells that were either irradiated or lysed.

This chapter deals with the types of hypersensitive reactions; immunological mechanisms of hypersensitivity; factors that predispose to hypersensitivity and clinical manifestations of hypersensitivity. The allergic diseases have been known since antiquity, but there was little insight into their causes until the late 19th century, when advances in histology led to the early delineation of the hematopoietic and mesenchymal cell lineages at the heart of all allergic reactions. At that time, three broad classes of cells were identified-mast cells, granulocytes, and mononuclear cells-that play different roles in hypersensitivity diseases. Allergy encompasses two different kinds of responses: immunity and hypersensitivity. Pathologic examination of the airways from patients with advanced asthma demonstrates infiltration by eosinophils and monocytes, increased size and number of the mucus-producing goblet cells, and damage to the protective epithelial lining of the airway. Food allergies can be the result of sensitization of the immune system through any of the four Gell and Coombs types of hypersensitivity, but IgE-mediated immediate hypersensitivity is probably involved in most cases.

Normally, the presence of self-reactive (autoimmune) cells does not always lead to autoimmune diseases because their numbers are small and are kept in check by peripheral tolerance mechanisms. In this sense, autoimmunity should be distinguished from autoimmune diseases. The biologic effectors that amplify many immunologic reactions that lead to important biologic outcomes of immune recognition, including complement, activated phagocytes, chemokine and cytokine production, and cellular cytotoxicity, are essential components of the pathology of autoimmunity. Systemic lupus erythematosus (SLE) is a complex connective tissue disease with autoimmune characteristics affecting multiple organ systems. Clinical symptoms of SLE are highly variable among patients, ranging from mild skin lesions and arthritis to severe renal dysfunction, cardiomyopathy, and neuropsychiatric manifestations. T cells are thought to play a central role in the initiation and perpetuation of rheumatoid arthritis (RA). Susceptibility to RA is strongly influenced by genetic predisposition. Disease concordance between monozygotic twins is approximately 20% versus 5% in dizygotic twins. Self-reactive lymphocytes are common in normal individuals, and their inappropriate activation and expansion may be responsible for initiating autoimmunity. An ideal therapy for autoimmune diseases would selectively block the lymphocytes that cause autoimmunity without affecting the remainder of the immune system. The newest forms of therapy for autoimmunity are directed at the specific cells or cytokines that contribute to or regulate the aberrant immune response.

This chapter provides definitions and key concepts of different types of transplantation. It discusses the roles of major histocompatibility complex and minor histocompatibility loci in graft acceptance and rejection. It talks about mechanisms of antigen recognition during graft rejection, immune effector mechanisms mediating rejection, immunological tolerance in graft acceptance and immune suppression for the prevention of rejection. Early experiments in transplantation were the experimental basis for identifying the MHC antigens. The key conclusions were based on the observations that it was possible to transplant tissues from one site to another on the same individual (autograft) whereas tissue transplanted from one individual to another (allograft) was inevitably destroyed or rejected by the recipient. The first major tissue typing system was the definition of the ABO blood group antigens by Karl Landsteiner in 1930. Mycophenolate mofetil is one of the new generation of synthetic drugs designed especially for use in transplantation. The major side effects of mycophenolate mofetil are gastrointestinal toxicity, especially dose-dependent diarrhea, esophagitis, and gastritis. Sirolimus interferes with late T-cell function and is classified as a target of rapamycin inhibitor. With greater understanding of the immune mechanisms that effect transplant rejection, better modalities of treatment can be developed with fewer side effects.