Diseases of the Immune System PDF

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Diseases of the Immune System...

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Diseases of the Immune System 6 CHAPTER CONTENTS The Normal Immune Response 190 Mediators of Immediate Hypersensitivity 206 Sjögren Syndrome 229 Innate Immunity 190 Late-Phase Reaction 207 Systemic Sclerosis (Scleroderma) 231 Components of Innate Immunity 190 Development of Allergies 208 Inflammatory Myopathies 234 Cellular Receptors for Microbes, Products Systemic Anaphylaxis 208 Mixed Connective Tissue Disease 234 of Damaged Cells, and Foreign Local Immediate Hypersensitivity Polyarteritis Nodosa and Other Substances 191 Reactions 208 Vasculitides 234 Natural Killer Cells 192 Antibody-Mediated (Type II) IgG4-Related Disease 234 Reactions of Innate Immunity 192 Hypersensitivity 209 Rejection of Tissue Transplants 234 Adaptive Immunity 193 Opsonization and Phagocytosis 209 Mechanisms of Recognition and Rejection Cells of the Adaptive Immune System 193 Inflammation 210 of Allografts 234 Tissues of the Immune System 196 Cellular Dysfunction 210 Recognition of Graft Alloantigens by T and B Major Histocompatibility Complex Immune Complex–Mediated (Type III) Lymphocytes 234 Molecules: the Peptide Display System Hypersensitivity 210 Patterns and Mechanisms of Graft of Adaptive Immunity 198 Systemic Immune Complex Disease 211 Rejection 235 Cytokines: Messenger Molecules of the Local Immune Complex Disease 212 Methods of Increasing Graft Survival 237 Immune System 199 T Cell–Mediated (Type IV) Transplantation of Hematopoietic Stem Overview of Lymphocyte Activation and Hypersensitivity 212 Cells (HSCs) 238 Immune Responses 200 CD4+ T Cell–Mediated Inflammation 212 Immunodeficiency Diseases 240 Display and Recognition of Antigens 200 CD8+ T Cell–Mediated Cytotoxicity 214 Primary Immunodeficiencies 240 Cell-Mediated Immunity: Activation of T Autoimmune Diseases 215 Defects in Innate Immunity 241 Lymphocytes and Elimination of Intracellular Immunologic Tolerance 216 Defects in Adaptive Immunity 242 Microbes 200 Central Tolerance 216 Immunodeficiencies Associated With Systemic Humoral Immunity: Activation of B Lymphocytes Peripheral Tolerance 217 Diseases 245 and Elimination of Extracellular Mechanisms of Autoimmunity: General Secondary Immunodeficiencies 246 Microbes 201 Principles 218 Acquired Immunodeficiency Syndrome Decline of Immune Responses and Immunologic Role of Susceptibility Genes 218 (AIDS) 247 Memory 203 Role of Infections and Other Environmental Epidemiology 247 Hypersensitivity: Immunologically Factors 220 Etiology: the Properties of HIV 248 Mediated Tissue Injury 204 General Features of Autoimmune Diseases 221 Pathogenesis of HIV Infection and Classification of Hypersensitivity Systemic Lupus Erythematosus (SLE) 221 AIDS 248 Reactions 204 Spectrum of Autoantibodies in Systemic Lupus Natural History of HIV Infection 253 Immediate (Type I) Hypersensitivity 205 Erythematosus 221 Clinical Features of AIDS 255 Activation of Th2 Cells and Production of IgE Chronic Discoid Lupus Erythematosus 229 Amyloidosis 259 Antibody 205 Subacute Cutaneous Lupus Erythematosus 229 Properties of Amyloid Proteins 259 Sensitization and Activation of Mast Drug-Induced Lupus Erythematosus 229 Pathogenesis and Classification of Cells 206 Rheumatoid Arthritis 229 Amyloidosis 260 The immune system is vital for survival because it protects reactions to environmental substances that cause allergies us from infectious pathogens that abound in the environment and reactions against an individual’s own tissues and cells and from the development of cancer. Predictably, immune (autoimmunity). deficiencies render individuals easy prey to infections and This chapter is devoted to diseases caused by too little or increase the incidence of certain cancers. But the immune too much immunologic reactivity. We also consider amyloi- system is itself capable of causing tissue injury and disease. dosis, a disease in which an abnormal protein, derived in Examples of disorders caused by immune responses include many cases from immunoglobulins, is deposited in tissues. 189 190 CHAPTER 6 Diseases of the Immune System First, we review some of the important features of normal (mainly neutrophils and macrophages), dendritic cells, immune responses, to provide a foundation for under- natural killer cells and other innate lymphoid cells, and standing the abnormalities that give rise to immunologic several plasma proteins, including the proteins of the diseases. complement system. Epithelia of the skin and gastrointestinal and respiratory tracts act as mechanical barriers to the entry of microbes THE NORMAL IMMUNE RESPONSE from the external environment. Epithelial cells also produce antimicrobial molecules such as defensins, and The classic definition of immunity is protection from lymphocytes located in the epithelia combat microbes at infectious pathogens, and the normal immune response is these sites. If microbes breach epithelial boundaries, other best understood in this context. However, immunity in its defense mechanisms come into play. broader sense includes host reactions against cancers (tumor Monocytes and neutrophils are phagocytes in the blood that immunity), tissue transplants, and even self antigens (autoim- can be rapidly recruited to any site of infection; monocytes munity). The mechanisms of immunity fall into two broad that enter the tissues and mature are called macrophages. categories (Fig. 6.1). Innate immunity (also called natural, Some tissue-resident macrophages (Kupffer cells in the or native, immunity) refers to intrinsic mechanisms that liver, microglia in the brain, and alveolar macrophages are poised to react immediately, and thus constitute the in the lungs) develop from the yolk sac or fetal liver early first line of defense. It is mediated by cells and molecules in life and populate various tissues. Phagocytes sense the that recognize products of microbes and dead cells and presence of microbes and other offending agents, ingest induce rapid protective host reactions. Adaptive immunity (phagocytose) these invaders, and destroy them. Because (also called acquired, or specific, immunity) consists of macrophages are the dominant cells of chronic inflamma- mechanisms that are stimulated by (“adapt to”) exposure tion, we described them in more detail in Chapter 3 in to microbes and other foreign substances. It develops more the discussion of chronic inflammation. slowly than innate immunity, but is even more powerful Dendritic cells (DCs) are specialized cells present in epi- in combating infections. By convention, the term immune thelia, lymphoid organs, and most tissues. They capture response usually refers to adaptive immunity. protein antigens and display peptides for recognition by T lymphocytes. In addition to their antigen-presenting Innate Immunity function, DCs are endowed with a rich collection of receptors that sense microbes and cell damage and Innate immunity is always present, ready to provide stimulate the secretion of cytokines, mediators that play immediate defense against microbes and to eliminate critical roles in inflammation and antiviral defense. Thus, damaged cells. The receptors and components of innate DCs serve as sentinels that detect danger and initiate immunity have evolved to serve these purposes. innate immune responses, but, unlike macrophages, they are not key participants in the destruction of microbes Components of Innate Immunity and other offending agents. The major components of innate immunity are epithelial Innate lymphoid cells (ILCs) are tissue-resident lymphocytes barriers that block entry of microbes, phagocytic cells that lack T-cell antigen receptors and cannot respond to INNATE IMMUNITY ADAPTIVE IMMUNITY B lymphocytes Antibodies Epithelial barriers T lymphocytes Effector Phagocytes Dendritic cells T cells Complement NK cells Dendritic cell Hours Days 0 6 12 1 3 5 Time after infection Figure 6.1 The principal components of innate and adaptive immunity. NK, Natural killer.  The normal immune response 191 antigens, but instead are activated by cytokines and other EXTRACELLULAR mediators produced at sites of tissue damage. They are thought to be sources of inflammatory cytokines during Bacterial Microbial early phases of immune reactions. ILCs are classified products polysaccharide into groups based on the dominant cytokines they TLR produce: groups 1, 2, and 3 ILCs produce many of the Lectin same cytokines as Th1, Th2, and Th17 subsets of CD4+ T cells, described later. Natural killer (NK) cells are one type of ILC that provide early protection against many Plasma membrane viruses and intracellular bacteria; their properties and functions are described later. Other cell types. Several other cell types can sense and CYTOSOLIC ENDOSOMAL react to microbes. These include mast cells, which are capable of producing many mediators of inflammation NOD-like receptor (discussed later), and even epithelial and endothelial Nucleic acids cells. of ingested Plasma proteins. In addition to these cells, several soluble Bacterial microbes proteins play important roles in innate immunity. The peptidoglycan; complement system (described in Chapter 3) consists of products of TLR plasma proteins that are activated by microbes. Comple- damaged cells ment activation may occur through the alternative and Viral RNA lectin pathways as part of innate immune responses or RIG-like through the classical pathway, which involves antibody- receptor antigen complexes, as part of adaptive immune responses Endosomal membrane (Chapter 3). Other circulating proteins of innate immunity are mannose-binding lectin and C-reactive protein, both of which coat microbes and promote phagocytosis. Lung surfactant is also a component of innate immunity, provid- Figure 6.2 Cellular receptors for microbes and products of cell injury. ing protection against inhaled microbes. Phagocytes, dendritic cells, and many types of epithelial cells express different classes of receptors that sense the presence of microbes and Cellular Receptors for Microbes, Products of Damaged dead cells. Toll-like receptors (TLRs) located in different cellular compartments, as well as other cytoplasmic and plasma membrane Cells, and Foreign Substances receptors, recognize products of different classes of microbes. Major Cells that participate in innate immunity are capable of classes of innate immune receptors are TLRs, NOD-like receptors (NLRs) recognizing certain components that are shared among in the cytosol, C-type lectin receptors (CLRs), RIG-like receptors (RLRs) related microbes and that are often essential for infectivity for viral nucleic acids, and cytosolic receptors for DNA (not shown). RIG, (and thus cannot be mutated to allow the microbes to evade retinoic acid-inducible gene. the defense mechanisms). These microbial structures are called pathogen-associated molecular patterns. Leukocytes also recognize molecules released by injured and necrotic cells, which are called damage-associated molecular patterns. stimulate the production of the antiviral cytokines, type I Collectively, the cellular receptors that recognize these interferons. Inherited loss-of-function mutations affecting molecules are called pattern recognition receptors. TLRs and their signaling pathways are associated with rare Pattern recognition receptors are located in all cellular but serious immunodeficiency syndromes, described later compartments where microbes may be present: plasma in the chapter. membrane receptors detect extracellular microbes, endo- NOD-like receptors and the inflammasome. NOD-like receptors somal receptors detect ingested microbes, and cytosolic (NLRs) are cytosolic receptors named after the founding receptors detect microbes in the cytoplasm (Fig. 6.2). Several member NOD-2. They recognize a wide variety of substances, classes of these receptors have been identified. including products released from necrotic or damaged cells Toll-like receptors. The best known of the pattern recognition (e.g., uric acid and adenosine triphosphate [ATP]), loss of receptors are the Toll-like receptors (TLRs), whose founding intracellular K+ ions, and some microbial products. How this member, Toll, was discovered in Drosophila as a gene involved family of sensors is capable of detecting so many diverse in development of the fly. A family of related proteins was signs of danger or damage is not known. Several of the later shown to be essential for host defense against microbes. NLRs signal via a cytosolic multiprotein complex called Mammals have 10 TLRs, each recognizing a different set of the inflammasome, which activates an enzyme (caspase-1) microbial molecules. The TLRs are present in the plasma that cleaves a precursor form of the cytokine interleukin-1 membrane and endosomal vesicles (see Fig. 6.2). All TLRs (IL-1) to generate the biologically active form (Fig. 6.3). As signal by a common pathway that culminates in the activation discussed later, IL-1 is a mediator of inflammation that of two sets of transcription factors: (1) NF-κB, which recruits leukocytes and induces fever. Gain-of-function stimulates the synthesis and secretion of cytokines and the mutations in NLRs and related proteins, and loss-of- expression of adhesion molecules, both of which are critical function mutations in regulators of the inflammasome, for the recruitment and activation of leukocytes (Chapter result in periodic fever syndromes called autoinflammatory 3), and (2) interferon regulatory factors (IRFs), which syndromes (to be distinguished from autoimmune diseases, 192 CHAPTER 6 Diseases of the Immune System Pathogenic bacteria genes), which leads to the production of the antiviral cytokine Extracellular ATP interferon-α. Excessive activation of the STING pathway K+ Plasma causes systemic inflammatory disorders collectively called membrane interferonopathies. Plasma membrane G protein–coupled receptors on neutrophils, macrophages, and most other types of leukocytes recognize short bacterial peptides containing NLRP-3 K+ N-formylmethionyl residues. Because all bacterial proteins (sensor) and few mammalian proteins (only those synthesized within Bacterial products Crystals mitochondria) are initiated by N-formylmethionine, this Adapter K+ efflux receptor enables neutrophils to detect bacterial proteins and Caspase-1 Reactive oxygen species move toward their source (chemotaxis). Mannose receptors (inactive) recognize microbial sugars (which often contain terminal mannose residues, unlike mammalian glycoproteins) and induce phagocytosis of the microbes. Signals from NLRP-3 TLRs, other inflammasome receptors Natural Killer Cells The function of NK cells is to recognize and destroy severely stressed or abnormal cells, such as virus-infected Caspase-1 (active) cells and tumor cells. NK cells make up approximately 5% to 10% of peripheral blood lymphocytes. NK cells express Pro-IL1β gene CD16, a receptor for IgG Fc tails that confers on NK cells activation the ability to lyse IgG-coated target cells. This phenomenon IL-1β is known as antibody-dependent cellular cytotoxicity Pro-IL1β Nucleus (ADCC). Killing of target cells by NK cells is regulated by signals from activating and inhibitory receptors (Fig. 6.4). There are many types of activating receptors, which recognize Secreted IL-1β surface molecules that are induced by various kinds of stress, such as infection and DNA damage. Thus, these receptors Acute inflammation enable NK cells to recognize damaged or infected cells. NK cell inhibitory receptors recognize self class I MHC molecules, Figure 6.3 The inflammasome. The inflammasome is a protein complex which are expressed on all healthy cells. The inhibitory that recognizes products of dead cells and some microbes and induces the receptors prevent NK cells from killing normal cells. Virus secretion of biologically active interleukin 1. The inflammasome consists of infection or neoplastic transformation often enhances expres- a sensor protein (an example is the leucine-rich protein NLRP3), an adapter, and the enzyme caspase-1, which is converted from an inactive to sion of ligands for activating receptors and at the same time an active form. ATP, Adenosine triphosphate; IL, interleukin; TLR, Toll-like reduces the expression of class I MHC molecules. As a result, receptor. when NK cells engage these abnormal cells the balance is tilted toward activation, and the infected or tumor cell is killed. which result from T and B lymphocyte reactions against self NK cells also secrete cytokines such as interferon-γ (IFN-γ), antigens). The autoinflammatory syndromes respond very which activates macrophages to destroy ingested microbes, well to treatment with IL-1 antagonists. The inflammasome and thus NK cells provide an early defense against intracel- pathway may also play a role in many common disorders. lular microbial infections. The activity of NK cells is regulated For example, recognition of urate crystals by a class of NLRs by many cytokines, including the interleukins IL-2, IL-15, underlies the inflammation associated with gout. These and IL-12. IL-2 and IL-15 stimulate proliferation of NK cells, receptors are also capable of detecting lipids and cholesterol whereas IL-12 activates the killing of target cells and the crystals that are deposited in abnormally large amounts in secretion of IFN-γ. tissues, and the resulting inflammation appears to contribute to obesity-associated type 2 diabetes and atherosclerosis, Reactions of Innate Immunity respectively. The innate immune system provides host defense by two Other cellular receptors for microbial products. C-type lectin main reactions. receptors (CLRs) expressed on the plasma membrane of Inflammation. Cytokines and products of complement macrophages and DCs detect fungal glycans and elicit activation, as well as other mediators, are produced inflammatory reactions to fungi. RIG-like receptors during innate immune reactions and trigger the vascular (RLRs), named after the founding member RIG-I (retinoic and cellular components of inflammation. The recruited acid-inducible gene-I), are located in the cytosol of most leukocytes destroy microbes and ingest and eliminate cell types and detect nucleic acids of viruses that replicate damaged cells. The innate immune response also triggers in the cytoplasm of infected cells. These receptors stimulate the repair of damaged tissues. These processes are the production of antiviral cytokines. Cytosolic receptors described in Chapter 3. for microbial DNA, often derived from viruses in the cell, Antiviral defense. Type I interferons produced in response activate a pathway called STING (for stimulator of interferon to viruses act on infected and uninfected cells and activate  The normal immune response 193 There are two types of adaptive immunity: humoral A. Inhibitory receptor engaged immunity, which protects against extracellular microbes NK cell NK cell not and their toxins, and cell-mediated (or cellular) immunity, activated; which is responsible for defense against intracellular no cell killing microbes and against cancers. Humoral immunity is Activating Inhibitory mediated by B (bone marrow–derived) lymphocytes and receptor receptor their secreted products, antibodies (also called immunoglobulins, Self class I Ig), and cellular immunity is mediated by T (thymus-derived) MHC- Normal lymphocytes. Both classes of lymphocytes express highly peptide cell complex specific receptors for a wide variety of substances, which are called antigens. B. Inhibitory receptor not engaged, Cells of the Adaptive Immune System activating receptor engaged NK cell Although T and B lymphocytes and their subsets are NK cell activated; morphologically unimpressive and appear quite similar to killing of one another, they are actually remarkably heterogeneous infected cell and specialized in molecular properties and functions. Activating The major classes of lymphocytes and their functions in ligand for Virus inhibits class I adaptive immunity are illustrated in Fig. 6.5. Lympho- NK cell cytes and other cells involved in immune responses are MHC expression, increases expression not fixed in particular tissues (as are cells in most of the of activating ligands organs of the body) but constantly circulate among lym- for NK cells Virus-infected cell phoid and other tissues via the blood and the lymphatic (class I MHC negative) system. This feature promotes immune surveillance throughout the body and allows lymphocytes to home Figure 6.4 Activating and inhibitory receptors of natural killer (NK) cells. to any site of infection. In lymphoid organs, different (A) Healthy cells express self class I major histocompatibility complex classes of lymphocytes are anatomically segregated in (MHC) molecules, which are recognized by inhibitory receptors, thus such a way that they interact with one another only when ensuring that NK cells do not attack normal cells. Note that healthy cells stimulated to do so by encounters with antigens and other may express ligands for activating receptors (not shown) or may not stimuli. Mature lymphocytes that have not encountered express such ligands (as shown), but they do not activate NK cells because they engage the inhibitory receptors. (B) In infected and stressed cells, the antigen for which they are specific are said to be naïve class I MHC expression is reduced so that the inhibitory receptors are (immunologically inexperienced). After they are activated not engaged, and ligands for activating receptors are expressed. The result by recognition of antigens and other signals described is that NK cells are activated and the infected cells are killed. later, lymphocytes differentiate into effector cells, which perform the function of eliminating microbes, and memory cells, which live in a state of heightened awareness and are enzymes that degrade viral nucleic acids and inhibit viral able to react rapidly and strongly to combat the microbe replication, inducing what has been called an antiviral in case it returns. The process of lymphocyte differentia- state. NK cells recognize virus-infected cells, as described tion into effector and memory cells is summarized later. above. We start with a consideration of the diversity of T and B lymphocytes. In addition to these direct defense functions, innate immunity produces the danger signals that stimulate the Lymphocyte Diversity subsequent more powerful adaptive immune response. The Lymphocytes specific for a large number of antigens exist nature of some of these signals is described later. before exposure to antigen, and when an antigen appears Innate immunity, unlike adaptive immunity, does not it selectively activates the antigen-specific cells. This have memory or fine antigen specificity. It is estimated that fundamental concept is called clonal selection. Lymphocytes innate immunity uses about 100 different receptors to of the same specificity are said to constitute a clone; all recognize 1000 molecular patterns. In contrast, adaptive members of one clone express identical antigen receptors, immunity uses two types of receptors (antibodies and T-cell which are different from the receptors in all other clones. receptors [TCRs], described later), each with millions of There are about 1012 lymphocytes in a healthy adult, and it variations, to recognize millions of antigens. is estimated that there are 107 to 109 clones, each expressing receptors specific for a different antigen. It follows that the Adaptive Immunity number of cells specific for any one antigen is very small, probably fewer than 1 in 100,000 lymphocytes. It is remark- The adaptive immune system consists of lymphocytes and able that so few cells with a particular specificity can their products, including antibodies. The lymphocytes of accomplish the difficult task of combating various microbes; adaptive immunity use highly diverse receptors to recognize as discussed later, the immune system has developed many a vast array of foreign substances. In the remainder of this mechanisms for optimizing reactions to microbial antigens. introductory section, we focus on lymphocytes and the It is also remarkable that the system is capable of producing reactions of the adaptive immune system. so many receptors, far more than could be individually 194 CHAPTER 6 Diseases of the Immune System ANTIGEN RECOGNITION FUNCTION Antibody Neutralization of microbe, B lymphocyte B + phagocytosis, complement activation Microbe Activation of macrophages Helper Cytokines T + T Inflammation T lymphocyte Microbial antigen presented by antigen-presenting cells Activation (proliferation B T and differentiation) of B T T and B lymphocytes Cytotoxic T lymphocyte T + T Killing of infected cell (CTL) Infected cell presenting microbial antigen T Regulatory Suppression of T lymphocyte T immune response T T Figure 6.5 The principal classes of lymphocytes and their functions. B and T lymphocytes are the cells of adaptive immunity. Several other classes of lymphocytes have been identified, including NK-T cells and so-called innate lymphoid cells (ILCs); the functions of these cells are not as well established as those of B and T lymphocytes. NK cells are discussed earlier. encoded in the genome. The mechanisms by which this germline antigen receptor genes are present in all cells in happens are now well understood and have many interesting the body, but only T and B cells contain recombined (also clinical implications. called rearranged) antigen receptor genes (the TCR in T Antigen receptor diversity is generated by somatic cells and Ig in B cells). Hence, the presence of recombined recombination of the genes that encode antigen receptors. TCR or Ig genes, which can be demonstrated by molecular All cells of the body, including lymphocyte progenitors, analysis, is a marker of T- or B-lineage cells. Furthermore, contain antigen receptor genes in the germline (inherited) because each T or B cell and its clonal progeny have a unique configuration, in which the genes encoding these receptors DNA rearrangement (and hence a unique antigen receptor), consist of spatially separated segments that cannot be it is possible to distinguish polyclonal (nonneoplastic) expressed as mRNAs. During lymphocyte maturation (in lymphocyte proliferations from monoclonal (neoplastic) the thymus for T cells and the bone marrow for B cells), lymphoid tumors by assessing the diversity of antigen these gene segments are assembled by recombination, and receptor rearrangements within a population of lymphocytes. DNA sequence variation is introduced at the sites where Thus, assays that assess the clonality of antigen receptor the gene segments are joined. This creates many different gene rearrangements are useful in diagnosing lymphoid genes that can be transcribed and translated into antigen neoplasms (Chapter 13). receptors with diverse amino acid sequences, particularly in the regions of the receptors that recognize and bind T Lymphocytes antigen. The enzyme in developing lymphocytes that medi- There are three major populations of T cells, which serve ates recombination of these gene segments is the product distinct functions. Helper T lymphocytes stimulate B of RAG-1 and RAG-2 (recombination-activating genes); lymphocytes to make antibodies and activate other inherited defects in RAG proteins result in a failure to leukocytes (e.g., phagocytes) to destroy microbes; cytotoxic generate mature lymphocytes. It is important to note that (killer) T lymphocytes (CTLs) kill infected cells; and  The normal immune response 195 regulatory T lymphocytes limit immune responses and A small population of mature T cells expresses another prevent reactions against self antigens. type of TCR composed of γ and δ polypeptide chains. The T lymphocytes develop in the thymus from precursors γδ TCR recognizes peptides, lipids, and small molecules, that arise from hematopoietic stem cells (HSCs). Mature T without a requirement for display by MHC proteins. γδ T cells are found in the blood, where they constitute 60% to cells tend to aggregate at epithelial surfaces, such as the 70% of lymphocytes, and in T-cell zones of secondary skin and mucosa of the gastrointestinal and urogenital lymphoid organs (described later). Each T cell recognizes tracts, suggesting that these cells are sentinels that protect a specific cell-bound antigen by means of an antigen-specific against microbes that try to enter through epithelia. TCR. In approximately 95% of T cells, the TCR consists of However, the functions of γδ T cells are not established. a disulfide-linked heterodimer made up of an α and a β Another small subset of T cells expresses markers that are polypeptide chain (Fig. 6.6), each having a variable (antigen- also found on NK cells; these cells are called NK-T cells. binding) region and a constant region. The αβ TCR recog- NK-T cells express a very limited diversity of TCRs, and they nizes peptide antigens that are bound to and presented recognize glycolipids that are displayed by the MHC-like by major histocompatibility complex (MHC) molecules molecule CD1. The functions of NK-T cells are also not on the surfaces of antigen-presenting cells (APCs). By well defined. limiting the specificity of T cells for peptides displayed by In addition to CD3 and ζ proteins, T cells express several cell surface MHC molecules, called MHC restriction, the other proteins that assist the TCR complex in functional immune system ensures that T cells see only cell-associated responses. These include CD4, CD8, CD28, and integrins. antigens (e.g., those derived from microbes in cells or from CD4 and CD8 are expressed on two mutually exclusive proteins ingested by cells). subsets of αβ T cells. Normally, approximately 60% of mature Each TCR is noncovalently linked to six polypeptide T cells are CD4+, and about 30% are CD8+. Most CD4+ T chains, which form the CD3 complex and the ζ chain dimer cells function as cytokine-secreting helper cells that assist (see Fig. 6.6). The CD3 and ζ proteins are invariant (i.e., macrophages and B lymphocytes to combat infections. Most identical) in all T cells. They are involved in the transduction CD8+ cells function as CTLs that destroy host cells harboring of signals into the T cell that are triggered by binding of microbes. CD4 and CD8 serve as coreceptors in T-cell activa- antigen to the TCR. Together with the TCR, these proteins tion. During antigen recognition, CD4 molecules bind to form the TCR complex. class II MHC molecules that are displaying antigen (see Fig. 6.6); CD8 molecules bind to class I MHC molecules; and the CD4 or CD8 coreceptor initiates signals that are necessary for activation of the T cells. Because of this require- ANTIGEN-PRESENTING CELL ment for coreceptors, CD4+ helper T cells can recognize and respond to antigen displayed only by class II MHC Class II MHC molecule molecules, whereas CD8+ cytotoxic T cells recognize cell- α chain β chain bound antigens only in association with class I MHC molecules; this segregation is described later. Integrins are adhesion molecules that promote the attachment of T-cells to APCs. CD80 To respond, T cells have to not only recognize antigen- or CD86 MHC complexes, but also have to receive additional signals CD4 CD28 provided by antigen-presenting cells. This process, in which Peptide CD28 plays an important role, is described later, when the antigen steps in cell-mediated immune responses are summarized. α β B Lymphocytes S S B lymphocytes are the only cells in the body capable of ε γ ξ ξ δ ε producing antibodies, the mediators of humoral immunity. B lymphocytes develop from precursors in the bone marrow. Mature B cells constitute 10% to 20% of lymphocytes in the blood and are also present in peripheral lymphoid tissues such as lymph nodes, spleen, and mucosa-associated CD3 ζ TCR CD3 lymphoid tissues. B cells recognize antigen via the B-cell proteins chains heterodimer proteins antigen receptor complex. Membrane-bound antibodies of the IgM and IgD isotypes, present on the surface of all CD4+ T CELL Signal 1 Signal 2 mature, naïve B cells, are the antigen-binding component of the B-cell receptor (BCR) complex (Fig. 6.7). After stimula- Figure 6.6 The T-cell receptor (TCR) complex and other molecules tion by antigen and other signals (described later), B cells involved in T-cell activation. The TCR heterodimer, consisting of an α and a develop into plasma cells, veritable protein factories for β chain, recognizes antigen (in the form of peptide-MHC complexes producing antibodies, as well as long-lived memory cells. expressed on antigen-presenting cells, or APCs), and the linked CD3 complex and ζ chains initiate activating signals. CD4 and CD28 are also It is estimated that a single plasma cell can secrete hundreds involved in T-cell activation. (Note that some T cells express CD8 and not to thousands of antibody molecules per second, a remarkable CD4; these molecules serve analogous roles.) The sizes of the molecules measure of the power of the immune response for combating are not drawn to scale. MHC, Major histocompatibility complex. pathogens. 196 CHAPTER 6 Diseases of the Immune System foreign antigens, and in the interstitia of all tissues, where Antigen antigens may be produced. Immature DCs within the IgM IgM Complement epidermis are called Langerhans cells. Second, DCs express protein many receptors for capturing and responding to microbes CD21 (and other antigens), including TLRs and lectins. Third, in response to microbes, DCs are recruited to the T-cell zones of lymphoid organs, where they are ideally located to present antigens to naïve T cells. Fourth, DCs express high levels of MHC and other molecules needed for antigen presentation and T-cell activation. A second type of cell with dendritic morphology is present Igβ Igα Igβ Igα in the germinal centers of lymphoid follicles in the spleen and lymph nodes and is called the follicular dendritic cell A Signal 1 Signal 2 (FDC). These cells bear Fc receptors for IgG and receptors for C3b and can trap antigen bound to antibodies or comple- ment proteins. They play a role in humoral immune responses VL by presenting antigens to B cells in the germinal center, part of a process through which only B cells that express CL antibodies with high affinity for antigen survive and go on to mature into plasma cells or memory cells. Macrophages VH Macrophages are a part of the mononuclear phagocyte CH1 system; their origin, differentiation, and role in inflammation are discussed in Chapter 3. Here, their important functions in the induction and effector phases of adaptive immune CH2 responses are discussed. Macrophages that have phagocytosed microbes and protein antigens process the antigens and present peptide fragments to B CH3 T cells. Thus, macrophages function as antigen-presenting cells in T-cell activation. Figure 6.7 Structure of antibodies and the B-cell antigen receptor. Macrophages are key effector cells in certain forms of cell- (A) The B-cell antigen receptor complex is composed of membrane mediated immunity, the reaction that serves to eliminate immunoglobulin M (IgM; or IgD, not shown), which recognizes antigens, and intracellular microbes. In this type of response, T cells the associated signaling proteins Igα and Igβ. CD21 is a receptor for a activate macrophages and enhance their ability to kill complement component that also promotes B-cell activation. (B) Crystal ingested microbes (discussed later). structure of a secreted IgG molecule, showing the arrangement of the variable (V) and constant (C) regions of the heavy (H) and light (L) chains. Macrophages also participate in the effector phase of humoral (Courtesy Dr. Alex McPherson, University of California, Irvine, Calif.) immunity. Macrophages efficiently phagocytose and destroy microbes that are opsonized (coated) by IgG or C3b. In addition to membrane Ig, the B-cell antigen receptor complex contains a heterodimer of two invariant proteins Tissues of the Immune System called Igα and Igβ. Similar to the CD3 and ζ proteins of the The tissues of the immune system consist of the primary TCR complex, Igα (CD79a) and Igβ (CD79b) are essential (also called generative, or central) lymphoid organs, in which for signal transduction in response to antigen recognition. T and B lymphocytes mature and become competent to B cells also express several other molecules that are essential respond to antigens, and the secondary (or peripheral) lym- for their responses. These include the type 2 complement phoid organs, in which adaptive immune responses to receptor (CR2, or CD21), which recognizes complement microbes are initiated. products generated during innate immune responses to microbes, and CD40, which receives signals from helper T Primary Lymphoid Organs. The principal primary lym- cells. CR2 is also used by Epstein-Barr virus (EBV) as a phoid organs are the thymus, where T cells develop, and receptor to enter and infect B cells. the bone marrow, the site of production of all other blood cells, including naïve B cells. These organs are described Dendritic Cells (DCs) in Chapter 13. DCs (sometimes called interdigitating DCs) are the most important antigen-presenting cells for initiating T-cell Secondary Lymphoid Organs. The secondary lymphoid responses against protein antigens. These cells have organs—lymph nodes, spleen, and the mucosal and cutane- numerous fine cytoplasmic processes that resemble dendrites, ous lymphoid tissues—are the tissues where adaptive from which they derive their name. Several features of DCs immune responses occur. Several features of these organs account for their key role in antigen presentation. First, promote the generation of adaptive immunity—antigens these cells are located at the right place to capture antigens— are concentrated in these organs, naïve lymphocytes circulate under epithelia, the common site of entry of microbes and through them searching for the antigens, and different  The normal immune response 197 lymphocyte populations (such as T and B cells) are brought Follicles together when they need to interact. Lymph nodes are nodular aggregates of lymphoid tissues located along lymphatic channels throughout the body (Fig. 6.8). As lymph slowly suffuses through lymph nodes, antigen-presenting cells are positioned to recognize anti- gens (e.g., derived from microbes that may enter through epithelia into tissues and are carried in the lymph). In addition, DCs pick up and transport antigens of microbes from epithelia and tissues via lymphatic vessels to the lymph nodes. Thus, the antigens of microbes that enter through epithelia or colonize tissues become concentrated in draining lymph nodes. Because most foreign antigens enter through epithelia or are produced in tissues, lymph A Cortex nodes are the site of generation of the majority of adaptive Medulla immune responses. The spleen is an abdominal organ that serves the same role in immune responses to blood-borne antigens as the Afferent lymph nodes do in responses to lymph-borne antigens. Dendritic lymphatic Naïve Blood entering the spleen flows through a network of cell vessel B cell sinusoids lined by macrophages and DCs. Blood-borne Naïve antigens are trapped in the spleen by these cells, which T cell can then initiate adaptive immune responses to these antigens. The cutaneous and mucosal lymphoid systems are located under the epithelia of the skin and the gastrointestinal T-cell zone and respiratory tracts, respectively. They respond to B-cell zone antigens that enter through breaches in the epithelium. Pharyngeal tonsils and Peyer patches of the intestine are two anatomically defined mucosal lymphoid tissues. At any time, a large fraction of the body’s lymphocytes are in the mucosal tissues (reflecting the large size of these Artery tissues), and many of these are memory cells. B Within the secondary lymphoid organs, naïve T and B T cell B cell lymphocytes are segregated into different regions (see Fig. 6.8). In lymph nodes, the B cells are concentrated in discrete structures, called follicles, located around the periphery, or cortex, of each node. If the B cells in a follicle have recently responded to an antigen, this follicle may contain a central region called a germinal center. The T lymphocytes are concentrated in the paracortex, adjacent to the follicles. The follicles contain the FDCs that are involved in the activation of B cells, and the paracortex contains the DCs that present antigens to T lymphocytes. In the spleen, T lymphocytes are concentrated in periarteriolar lymphoid sheaths sur- rounding small arterioles, and B cells reside in follicles akin to those found in lymph nodes (the so-called splenic white pulp). Lymphocyte Recirculation Lymphocytes constantly recirculate between tissues and C B cells T cells home to particular sites; naïve lymphocytes traverse the secondary lymphoid organs where immune responses are Figure 6.8 Morphology of a lymph node. (A) The histology of a lymph node, with an outer cortex containing follicles and an inner medulla. (B) initiated, and effector lymphocytes migrate to sites of infec- The segregation of B cells and T cells in different regions of the lymph tion and inflammation. This process of lymphocyte recircula- node, illustrated schematically. (C) The location of B cells (stained green, tion is most important for T cells, because naïve T cells have using the immunofluorescence technique) and T cells (stained red) in a to circulate through the secondary lymphoid organs where lymph node. (Courtesy Drs. Kathryn Pape and Jennifer Walter, University antigens are concentrated and effector T cells have to migrate of Minnesota School of Medicine, Minneapolis, Minn.) to sites of infection to eliminate microbes. In contrast, plasma cells remain in lymphoid organs and the bone marrow and do not need to traffic to sites of infection because they secrete 198 CHAPTER 6 Diseases of the Immune System antibodies that are carried through the blood to distant On the basis of their structure, cellular distribution, and tissues. function, MHC gene products are divided into two major classes. Major Histocompatibility Complex Molecules: the Class I MHC molecules are expressed on all nucleated cells Peptide Display System of Adaptive Immunity and platelets. They are heterodimers consisting of a polymorphic α, or heavy, chain (44-kD) linked The function of MHC molecules is to display peptide noncovalently to a smaller (12-kD) nonpolymorphic fragments of protein antigens for recognition by antigen- protein called β2-microglobulin. The α chains are encoded specific T cells. Because MHC molecules are fundamental by three genes, designated HLA-A, HLA-B, and HLA-C, to antigen recognition by T cells and are linked to many that lie close to one another in the MHC locus (see Fig. autoimmune diseases, it is important to briefly review their 6.9). The extracellular region of the α chain is divided structure and function. MHC molecules were discovered into three domains: α1, α2, and α3. The α1 and α2 domains as products of genes that evoke rejection of transplanted form a cleft, or groove, where peptides bind. The poly- organs, and their name derives from their role in determining morphic amino acid residues line the sides and the base tissue compatibility between individuals. In humans, the of the peptide-binding groove, explaining why different MHC molecules are called human leukocyte antigens (HLA) class I alleles bind different peptides. because they were initially detected on leukocytes. The genes Class I MHC molecules display peptides that are encoding HLA molecules are clustered on a small segment derived from cytoplasmic proteins, including normal of chromosome 6 (Fig. 6.9). The HLA system is highly proteins and virus- and tumor-specific antigens, which polymorphic; there are thousands of distinct MHC gene are all recognized bound to class I MHC molecules by alleles in humans, and as a result each individual’s HLA CD8+ T cells. Cytoplasmic proteins are degraded in alleles differ from those inherited by most other individuals proteasomes, and peptides are transported into the in the population. This, as we see subsequently, constitutes endoplasmic reticulum (ER), where they bind to newly a formidable barrier in organ transplantation. synthesized class I molecules. Peptide-loaded MHC A. Complement proteins, DP DQ DR others TNF LT B C A β α β α β α β β β α Class II MHC “Class III” molecules Cytokines Class I MHC molecules molecules Peptide-binding cleft Peptide-binding cleft Peptide Peptide α2 B. β1 Peptide α1 Peptide α1 α1 α2 S domain domain S NH2 H2N NH2 S S NH2 α2 β2 α3 S S β2m S S S S α3 α chain S S β chain domain β2 microglobulin α chain HOOC HOOC COOH COOH Figure 6.9 The human leukocyte antigen (HLA) complex and the structure of HLA molecules. (A) The location of genes in the HLA complex. The relative locations, sizes, and distances between genes are not to scale. Genes that encode several proteins involved in antigen processing (the TAP transporter, components of the proteasome, and HLA-DM) are located in the class II region (not shown). (B) Schematic diagrams and crystal structures of class I and class II HLA molecules. (Crystal structures are courtesy Dr. P. Bjorkman, California Institute of Technology, Pasadena, Calif.)  The normal immune response 199 molecules then associate with β2-microglobulin to form grafts exchanged between these individuals are recognized a stable complex, which is transported to the cell surface. as foreign and attacked by the immune system. Because The nonpolymorphic α3 domain of class I MHC molecules each haplotype is inherited as a block, and there are two has a binding site for CD8, and therefore the peptide-class sets of genes from each parent, the chance that siblings will I complexes are recognized by CD8+ T cells, which func- have the same MHC is 1 in 4. This is why siblings are tion as CTLs. In this interaction, the TCR recognizes the screened first as potential donors for patients in need of a MHC-peptide complex, and the CD8 molecule, acting kidney or hematopoietic stem cell transplant. as a coreceptor, binds to the class I heavy chain. Since MHC molecules play several key roles in regulating T CD8+ T cells recognize peptides only if presented as a cell–mediated immune responses. First, because different complex with class I MHC molecules, CD8+ T cells are antigenic peptides bind to different MHC molecules, it said to be class I MHC-restricted. Because important follows that an individual mounts an immune response functions of CD8+ CTLs include the elimination of viruses, against a protein antigen only if he or she inherits an MHC which may infect any nucleated cell, and killing of tumor variant that can bind peptides derived from the antigen cells, which may arise from any nucleated cell, it makes and present it to T cells. The consequences of inheriting a good sense that all nucleated cells express class I MHC given MHC (e.g., class II) variant depend on the nature of molecules and can be surveyed by CD8+ T cells. the antigen bound by the class II molecule. For example, if Class II MHC molecules are encoded in a region called the antigen is a peptide from ragweed pollen, the individual HLA-D, which has three subregions: HLA-DP, HLA-DQ, who expresses class II molecules capable of binding the and HLA-DR. Each class II molecule is a heterodimer antigen would be genetically prone to allergic reactions consisting of a noncovalently associated α chain and β against ragweed. In contrast, an inherited capacity to bind chain, both of which are polymorphic. The extracellular a bacterial peptide may provide resistance to the infection by portions of the α and β chains both have two domains evoking a protective antibody response. Second, by segregat- designated α1 and α2, and β1 and β2. The crystal structure ing cytoplasmic and internalized antigens, MHC molecules of class II molecules has revealed that, similar to class I ensure that the correct immune response is mounted against molecules, they have peptide-binding clefts facing different microbes—CTL-mediated killing of cells harboring outward (see Fig. 6.9). This cleft is formed by an interac- cytoplasmic microbes and tumor antigens, and helper T tion of the α1 and β1 domains, and it is in this portion cell–mediated antibody production and macrophage activa- that most class II alleles differ. Thus, as with class I tion to combat extracellular and phagocytosed microbes. molecules, polymorphism of class II molecules is associ- Interest in HLA molecules was spurred by the realization, ated with differential binding of antigenic peptides. in the 1960s and 1970s, that a number of autoimmune and Class II MHC molecules present antigens derived other diseases are associated with the inheritance of particular from extracellular microbes and proteins following their HLA alleles. These associations are discussed when the internalization into endosomes or lysosomes. Here, the pathogenesis of autoimmune diseases is considered later internalized proteins are proteolytically digested, produc- in the chapter. ing peptides that then associate with class II heterodimers in the vesicles, from which they are transported to the Cytokines: Messenger Molecules of cell surface as stable peptide-MHC complexes. The class the Immune System II β2 domain has a binding site for CD4, and therefore, the class II-peptide complex is recognized by CD4+ T The induction and regulation of immune responses involve cells, which function as helper cells. Because CD4+ T multiple interactions among lymphocytes, DCs, macrophages, cells can recognize antigens only in the context of self other inflammatory cells (e.g., neutrophils), and endothelial class II molecules, they are referred to as class II MHC- cells. Some of these interactions depend on cell-to-cell contact; restricted. In contrast to class I molecules, class II molecules however, many functions of leukocytes are stimulated and are mainly expressed on cells that present ingested regulated by secreted proteins called cytokines. Molecularly antigens and respond to T-cell help (macrophages, B defined cytokines are called interleukins because they mediate lymphocytes, and DCs). communications between leukocytes (although many also act on cells other than leukocytes). Most cytokines have a The combination of HLA alleles in each individual is wide spectrum of effects, and some are produced by several called the HLA haplotype. Any given individual inherits different cell types. The majority of these cytokines act on the one set of HLA genes from each parent and (assuming the cells that produce them (autocrine actions) or on neighboring parents are unrelated) typically expresses two different cells (paracrine) and rarely at a distance (endocrine). molecules for every locus. Because of the polymorphism of Cytokines contribute to different types of immune the HLA genes, virtually innumerable combinations of responses. molecules exist in the population, and each individual In innate immune responses, cytokines are produced expresses an MHC profile on his or her cell surface that is rapidly after encounter with microbes and other stimuli, different from the haplotypes of most other individuals. It and they function to induce inflammation and inhibit is believed that this degree of polymorphism evolved to virus replication. These cytokines include TNF, IL-1, IL-12, ensure that at least some individuals in a species would be type I IFNs, IFN-γ, and chemokines (Chapter 3). Their able to display any microbial peptide and thus provide major sources are macrophages, DCs, ILCs, and NK cells, protection against any infection. This polymorphism also but endothelial and epithelial cells can also produce them. means that no two individuals (other than identical twins) In adaptive immune responses, cytokines are produced are likely to express the same MHC molecules, and therefore principally by CD4+ T lymphocytes activated by antigen 200 CHAPTER 6 Diseases of the Immune System and other signals, and they function to promote lymphocyte different chemical types, including proteins, polysaccharides, proliferation and differentiation and to activate effector and lipids. cells. The main ones in this group are IL-2, IL-4, IL-5, IL-17, Even before the antigens of a microbe are recognized by and IFN-γ; their roles in immune responses are described T and B lymphocytes, the microbe elicits an immune response later. Some cytokines serve mainly to limit and terminate through pattern recognition receptors expressed on innate immune responses; these include TGF-β and IL-10. immune cells; this is the first line of defense that also serves Some cytokines stimulate hematopoiesis and are called to activate adaptive immunity. In the case of immunization colony-stimulating factors (CSFs) because they are with a protein antigen, microbial mimics, called adjuvants, assayed by their ability to stimulate formation of blood are given with the antigen, and these stimulate innate cell colonies from bone marrow progenitors (Chapter 13). immune responses. During the innate response, the microbe Their functions are to increase leukocyte production during or adjuvant activates antigen-presenting cells to express immune and inflammatory responses, both to increase their molecules called costimulators and to secrete cytokines that numbers and to replace leukocytes that die during such stimulate the proliferation and differentiation of T lympho- responses. They are produced by marrow stromal cells, cytes. The principal costimulators for T cells are the B7 T lymphocytes, macrophages, and other cells. Examples proteins (CD80 and CD86) that are expressed on antigen- include GM-CSF and other CSFs, and IL-3. presenting cells and are recognized by the CD28 receptor on naïve T cells. Thus, antigen (“signal 1”) and costimulatory The knowledge gained about cytokines has numerous molecules produced during innate immune responses to practical therapeutic applications. Inhibiting cytokine produc- microbes (“signal 2”) function cooperatively to activate tion or actions is an approach for controlling the harmful antigen-specific lymphocytes (see Fig. 6.6). The requirement effects of inflammation and tissue-damaging immune for microbe-triggered signal 2 ensures that the adaptive reactions. Patients with rheumatoid arthritis often show immune response is induced by microbes and not by harm- dramatic responses to TNF antagonists, an elegant example less substances. In immune responses to tumors and of rationally designed and molecularly targeted therapy. transplants, “signal 2” may be provided by substances Many other cytokine antagonists are now approved for the released from necrotic cells (the “damage-associated molecu- treatment of various inflammatory disorders. Conversely, lar patterns” mentioned earlier). administration of cytokines is used to boost reactions that are The reactions and functions of T and B lymphocytes differ normally dependent on these proteins, such as hematopoiesis in important ways and are best considered separately even and defense against some viruses. An important therapeutic though both may be activated concurrently in an immune application of cytokines is to mobilize hematopoietic stem response. cells from bone marrow to peripheral blood, from which they can be collected for stem cell transplantation. Cell-Mediated Immunity: Activation of T Lymphocytes and Elimination of Intracellular Microbes Overview of Lymphocyte Activation Naïve T lymphocytes are activated by antigen and costimu- and Immune Responses lators in peripheral lymphoid organs, and proliferate and differentiate into effector cells that migrate to any site where All adaptive immune responses develop in steps, consisting microbial antigens are present (see Fig. 6.10). One of the earliest of: antigen recognition; activation of specific lymphocytes responses of CD4+ helper T cells is secretion of the cytokine to proliferate and differentiate into effector and memory IL-2 and expression of high-affinity receptors for IL-2. This cells; elimination of the antigen; and decline of the response, creates an autocrine loop wherein IL-2 acts as a growth factor with memory cells being the long-lived survivors. The major that stimulates T-cell proliferation, leading to an increase in events in each step are summarized next; these general the number of antigen-specific lymphocytes. The functions principles apply to protective responses against microbes of helper T cells are mediated by the combined actions of as well as pathologic responses that injure the host. CD40-ligand (CD40L) and cytokines. When CD4+ helper T cells recognize antigens being displayed by macrophages or Display and Recognition of Antigens B lymphocytes, the T cells express CD40L, which engages Microbes and other foreign antigens can enter the body CD40 on the macrophages or B cells and activates these cells. anywhere. It is obviously impossible for lymphocytes to Some of the activated CD4+ T cells differentiate into effectively patrol every possible portal of antigen entry, effector cells that secrete distinct sets of cytokines and because there are not enough antigen-specific lymphocytes perform different functions (Fig. 6.11). Cells of the Th1 to constantly cover all of this “terrain.” To overcome this subset secrete the cytokine IFN-γ, which is a potent problem, antigens are captured and concentrated in second- macrophage activator. The combination of CD40- and IFN- ary lymphoid organs through which naïve lymphocytes γ-mediated activation results in “classical” macrophage circulate, thus increasing the likelihood of a lymphocyte activation (Chapter 3), leading to the production of micro- finding antigens it can recognize. Microbes and their protein bicidal substances in macrophages and the destruction of antigens are captured by DCs that are resident in epithelia ingested microbes. Th2 cells produce IL-4, which stimulates and tissues. These cells carry their antigenic cargo to draining B cells to differentiate into IgE-secreting plasma cells, and lymph nodes (Fig. 6.10). Here the antigens are processed IL-5, which stimulates the production of eosinophils in the and displayed complexed with MHC molecules on the cell marrow and activates eosinophils at sites of immune surface, where the antigens are recognized by T cells. responses. Eosinophils and mast cells bind to IgE-coated B lymphocytes use their antigen receptors (membrane- microbes such as helminthic parasites, and function to bound antibody molecules) to recognize antigens of many eliminate helminths. Th2 cells also induce the “alternative”  The normal immune response 201 Dendritic cell with antigen Antigen recognition in lymphoid organs T cell proliferation and differentiation CD4+ CD8+ T cells T cells Naïve IL-2R T cell IL-2 CD4+ CD8+ APC Effector Memory effector T cells T cell T cell T cells (CTLs) Migration of effector T cells to site of antigen Differentiated effector and memory T cells enter circulation Infected cell with microbes Phagocytes in cytoplasm with ingested microbes CD4+ effector T cells CD8+ T cells (CTLs) Cytokine secretion INFLAMMATION MACROPHAGE ACTIVATION, KILLING OF KILLING OF INGESTED MICROBES INFECTED CELLS Figure 6.10 Cell-mediated immunity. Dendritic cells capture microbial antigens from epithelia and tissues and transport the antigens to lymph nodes. During this process, the dendritic cells mature, and express high levels of MHC molecules and costimulators. Naïve T cells recognize MHC-associated peptide antigens displayed on dendritic cells. The T cells are activated to proliferate and to differentiate into effector and memory cells, which migrate to sites of infection and serve various functions in cell-mediated immunity. CD4+ effector T cells of the Th1 subset recognize the antigens of microbes ingested by phagocytes and activate the phagocytes to kill the microbes; other subsets of effector cells enhance leukocyte recruitment and stimulate different types of immune responses. CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells harboring microbes in the cytoplasm. Some activated T cells remain in the lymphoid organs and help B cells to produce antibodies, and some T cells differentiate into long-lived memory cells (not shown). APC, Antigen-presenting cell. pathway of macrophage activation, which is associated with tissue repair and fibrosis (Chapter 3). Th17 cells, so called Humoral Immunity: Activation of B Lymphocytes and because the signature cytokine of these cells is IL-17, recruit Elimination of Extracellular Microbes neutrophils and monocytes, which destroy extracellular Upon activation, B lymphocytes proliferate and then dif- bacteria and fungi and are involved in some inflammatory ferentiate into plasma cells that secrete different classes diseases. of antibodies with distinct functions (Fig. 6.12). Antibody Activated CD8+ T lymphocytes differentiate into CTLs responses to most protein antigens require T cell help and are that kill cells harboring microbes in the cytoplasm. By said to be T-dependent. In these responses, B cells that recog- destroying the infected cells, CTLs eliminate the reservoirs nize protein antigens by their Ig receptors endocytose these of infection. CTLs also kill tumor cells by recognizing tumor- antigens into vesicles, degrade them, and display peptides specific antigens derived from mutated or abnormal cyto- bound to class II MHC molecules for recognition by helper plasmic proteins. T cells. The helper T cells are activated and express CD40L 202 CHAPTER 6 Diseases of the Immune System APC Naïve CD4+ T cell Cytokines Th1 Th2 Th17 Cytokines produced IFN-γ IL-4, IL-5, IL-13 IL-17, IL-22 Cytokines that induce this subset IFN-γ, IL-12 IL-4 TGF-β, IL-6, IL-1, IL-23 Immunological Stimulation of IgE Macrophage Recruitment of reactions triggered production, activation of activation neutrophils, monocytes mast cells and eosinophils Host defense against Intracellular microbes Helminthic parasites Extracellular bacteria, fungi Immune-mediated chronic Immune-mediated chronic Role in disease inflammatory diseases Allergies inflammatory diseases (often autoimmune) (often autoimmune) Figure 6.11 Subsets of helper T (Th) cells. In response to stimuli (mainly cytokines) present at the time of antigen recognition, naïve CD4+ T cells may differentiate into populations of effector cells that produce distinct sets of cytokines and perform different functions. The dominant immune reactions elicited by each subset, and its role in host defense and immunologic diseases, are summarized. These populations may be capable of converting from one to another. Some activated T cells produce multiple cytokines and do not fall into a distinct subset. Functions of antibodies Neutralization secretion Antibody of microbe and toxins IgM Proliferation Antibody-secreting Phagocyte plasma cells Opsonization Naïve IgM+, IgD+ B cell and phago- Differentiation IgG cytosis switching Class Fc receptor