Hypersen - KUBY PDF

Allergy, Hypersensitivities, 15 and Chronic Inflammation T he same immune reactions that protect us from infection can also inflict a great deal of damage, not simply...

Allergy, Hypersensitivities, 15 and Chronic Inflammation T he same immune reactions that protect us from infection can also inflict a great deal of damage, not simply on a pathogen, but on our own cells and tissues. As you have learned, the immune response uses multiple strategies to reduce damage to self by turning off responses when pathogen is cleared and avoiding reactions to self antigens. However, these checks and balances can break down, leading to immune-mediated reactions that are more detrimental Young girl sneezing in response to flowers. than protective. Some immune-mediated disorders are [Brand New Images/Getty Images] caused by a failure of immune tolerance. These autoimmune disorders will be discussed in Chapter 16. Allergy: A Type I Hypersensitivity Reaction Others are caused by an inappropriately vigorous innate and/or adaptive response to antigens that pose little or Antibody-Mediated (Type II) Hypersensitivity no threat. These disorders, called hypersensitivities, will Reactions be the main focus of this chapter. Finally, some disorders are caused by a failure to turn off innate or adaptive Immune Complex-Mediated (Type III) responses, resulting in a chronic inflammatory state. We Hypersensitivity will close this chapter with a discussion of the causes Delayed-Type (Type IV) Hypersensitivity (DTH) and consequences of chronic inflammation, a condition that is of interest to many because of its intriguing Chronic Inflammation association with the current obesity epidemic. Two French scientists, Paul Portier and Charles Richet, were the first to recognize and describe subsequently awarded the Nobel Prize in Physiology or hypersensitivities. In the early twentieth century, as part Medicine in 1913. of their studies of the responses of bathers in the Since that time, immunologists have learned that there Mediterranean to the stings of Portuguese man-o’-war are multiple types of hypersensitivity reactions. Immediate jellyfish (Physalia physalis), they demonstrated that the hypersensitivity reactions result in symptoms that toxic agent in the sting was a small protein. They manifest themselves within very short time periods after reasoned that eliciting an antibody response that could the immune stimulus, like those described above. Other neutralize the toxin may serve to protect the host. types of hypersensitivity reactions take hours or days to Therefore, they injected low doses of the toxin into dogs manifest themselves, and are referred to as delayed-type to elicit an immune response, and followed with a hypersensitivity (DTH) reactions. In general, immediate booster injection a few weeks later. However, instead of hypersensitivity reactions result from antibody-antigen generating a protective antibody response, the reactions, whereas DTH is caused by T-cell reactions. unfortunate dogs responded immediately to the second As it became clear that different immune mechanisms injection with vomiting, diarrhea, asphyxia, and death. give rise to distinct hypersensitivity reactions, two Richet coined the term “anaphylaxis,” derived from the immunologists, P. G. H. Gell and R. R. A. Coombs, Greek and translated loosely as “against protection” to proposed a classification scheme to discriminate among the describe this overreaction of the immune system, the first various types of hypersensitivity (see Figure 15-1). Type I description of a hypersensitivity reaction. Richet was hypersensitivity reactions are mediated by IgE antibodies, 485 486 PA R T V I | The Immune System in Health and Disease ADCC Immune complex C3b Allergen FcεR C3b Sensitized T cell for IgE FcεR C3b Allergen- Complement Cytotoxic specific activation Surface cell Cytokines IgE Target antigen cell Complement C3b activation Neutrophil Immune Tissue Degranulation (Allergy) complex damage Activated macrophage Type I C3b Type II Type III Type IV Allergy and Atopy Antibody-mediated Immune complex-mediated Delayed type hypersensitivity (DTH) hypersensitivity hypersensitivity Immune IgE IgG or IgM Immune complexes T cells mediator Mechanism Ag induces cross- Ab directed against cell surface Ag-Ab complexes deposited Sensitized T cells (TH1, TH2 and linking of IgE bound antigens mediates cell in various tissues induce others) release cytokines that to mast cells and destruction via complement complement activation and activate macrophages or TC cells basophils with activation or ADCC. an ensuing inflammatory which mediate direct cellular release of vasoactive response mediated by damage. mediators. massive infiltration of neutrophils. Typical Includes systemic Includes blood transfusion Includes localized Arthus Includes contact dermatitis, manifestat- anaphylaxis and reactions, erythroblastosis reaction and generalized tubercular lesions, and graft ions localized anaphylaxis fetalis, and autoimmune reactions such as serum rejection. such as hay fever, hemolytic anemia. sickness, necrotizing asthma, hives, food vasculitis, allergies, and eczema. glomerulonephritis, rheumatoid arthritis, and systemic lupus erythematosus. FIGURE 15-1 The four types of hypersensitivity reactions. and include many of the most common allergies to Pirquet noted that the response to some antigens resulted respiratory allergens, such as pollen and dust mites. Type II in damage to the host, rather than in a protective hypersensitivity reactions result from the binding of IgG response. Although most familiar respiratory allergies or IgM to the surface of host cells, which are then destroyed result from the generation of IgE antibodies toward the by complement- or cell-mediated mechanisms. In type III eliciting agent, and therefore are type I hypersensitivity hypersensitivity reactions, antigen-antibody complexes reactions, other common reactions that are associated deposited on host cells induce complement fixation and an with allergy, such as the response to poison ivy, result ensuing inflammatory response. Type lV hypersensitivity from T-cell-mediated, type IV responses. reactions result from inappropriate T-cell activation. It should be noted that, although this classification method has proven to be a useful analytical and descriptive tool, Allergy: A Type I Hypersensitivity many clinical hypersensitivity disorders include molecular Reaction and cellular contributions from components belonging to more than one of these categories. The subdivisions are not More than half of the U.S. population (54.3%) suffers from as frequently evoked in real-world clinical settings as they type I hypersensitivity reactions, which encompass the most once were. common allergic reactions, including hay fever, asthma, The term allergy first appeared in the medical atopic dermatitis, and food allergies. The incidence of allergy literature in 1906, when the pediatrician Clemens von continues to rise in the human population, and understanding  Allergy, Hypersensitivities, and Chronic Inflammation | CHAPTER 15 487 immune mechanisms behind the response has already led to susceptible individuals, but recently several features shared new therapies. Below we describe the molecular and cellular by many allergens have begun to provide clues to the bio- participants in the various type I hypersensitivities, as well as logical basis of their activity. the rationale behind current treatments. First, many allergens have intrinsic enzymatic activity that affects the immune response. For example, allergen extracts from dust mites and cockroaches as well as from fungi and IgE Antibodies Are Responsible bacteria are relatively high in protease activity. Some of these for Type I Hypersensitivity proteases have been shown to be capable of disrupting the Type I hypersensitivity reactions (allergies) are initiated by the integrity of epithelial cell junctions, and allowing allergens to interaction between an IgE antibody and a multivalent anti- access the underlying cells and molecules of the innate and gen. Classic Experiment Box 15-1 describes the brilliant series adaptive immune systems. Others, including a protease (Der of experiments by K. Ishizaka and T. Ishizaka in the 1960s and p 1) produced by the dust mite, cleave and activate comple- 1970s that led to the identification of IgE as the class of anti- ment components at the mucosal surface. Still others cleave body responsible for allergies. In normal individuals, the level and stimulate protease-activated receptors on the surfaces of of IgE in serum is the lowest of any of the immunoglobulin immune cells, enhancing inflammation. Thus, one factor that classes, making further physiochemical studies of this mole- distinguishes allergenic from nonallergenic molecules may cule particularly difficult. It was not until the discovery of an be the presence of enzymatic activity that affects the cells and IgE-producing myeloma by Johansson and Bennich in 1967 molecules of the immune system. that extensive analyses of IgE could be undertaken. Second, many allergens contain potential pathogen- associated molecular patterns, or PAMPS (see Chapter 5), capable of interacting with receptors of the innate immune Many Allergens Can Elicit a Type I Response system, and initiating a cascade of responses leading to an Healthy individuals generate IgE antibodies only in response allergic response. However, it is unclear why this cascade is to parasitic infections. However, some people, referred to as stimulated in only a subset of individuals. atopic, are predisposed to generate IgE antibodies against Third, many allergens enter the host via mucosal tissues at common environmental antigens, such as those listed in very low concentrations, which tend to predispose the individ- Table 15-1. Chemical analysis revealed that most, if not all, ual to generate TH2 responses, leading to B-cell secretion of IgE. allergens are either protein or glycoprotein in nature, with multiple antigenic sites, or epitopes, per molecule. For many IgE Antibodies Act by Cross-Linking Fc␧ years, scientists tried unsuccessfully to find any structural Receptors on the Surfaces of Innate commonalities among molecules that induced distress in Immune Cells IgE antibodies alone are not destructive. Instead, they cause Common allergens associated hypersensitivity by binding to Fc receptors specific for their TABLE 15-1 with type I hypersensitivity constant regions (Fc␧Rs). These are expressed by a variety of Plant pollens Foods innate immune cells, including mast cells, basophils, and eosinophils (Chapter 2). The binding of IgE antibodies to Rye grass Nuts Fc␧Rs activates these granulocytes, inducing a signaling cas- cade that causes cells to release the contents of intracellular Ragweed Seafood granules into the blood, a process called degranulation (see Timothy grass Eggs Figure 15-2). The contents of granules vary from cell to cell, Birch trees Peas, Beans but typically include histamine, heparin, and proteases. Drugs Milk Together with other mediators that are synthesized by acti- vated granulocytes (leukotrienes, prostaglandins, chemo- Penicillin kines, and cytokines), these mediators act on surrounding Sulfonamides Insect products tissues and other immune cells, causing allergy symptoms. Local anesthetics Bee venom Interestingly, the serum half-life of IgE is quite short (only Salicylates Wasp venom 2 to 3 days). However, when bound to its receptor on an innate immune cell, IgE is stable for weeks. IgE actually binds two Ant venom different receptors, the high-affinity Fc␧RI, which is respon- Mold spores Cockroach calyx sible for most of the symptoms we associate with allergy, and Animal hair and dander Dust mites the lower-affinity Fc␧RII, which regulates the production of Latex IgE by B cells, as well as its transport across cells (Chapter 13). The role of Fc␧RI in type I hypersensitivities is confirmed by Foreign serum experiments conducted in mice that lack an Fc␧RI ␣ chain; Vaccines they are resistant to localized and systemic allergic responses, despite having normal numbers of mast cells. c15Allergy,Hypersensitivities,andChronicInflammation.indd Page 488 12/20/12 5:39 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 488 PA R T V I | The Immune System in Health and Disease CLASSIC EXPERIMENT The Discovery and Identification of IgE as the Carrier of Allergic Hypersensitivity In a stunning series of papers pub- responsible for the P-K reaction would be with radioactive antigen E. Perhaps lished between 1966 and the mid-1970s, the serum of an allergic individual who another antibody class was responsible Kimishige Ishizaka and Teruko Ishizaka, displayed hypersensitivity to ragweed pol- for the line of immunoprecipitation on working with a number of collaborators, len E. (Serum is that component of the the immunodiffusion gel? identified a new class of immunoglobulins, blood remaining after the cells and clotting The fractions containing the highest which they called IgE antibodies, as being components have been removed.) To concentration of protein able to bind to the major effector molecules in type 1 purify the serum protein responsible for allergen E were further purified using gel antibody-mediated hypersensitivity the allergic reaction, they took whole chromatography, which separates proteins reactions. human serum and subjected it to ammo- on the basis of size and molecular shape. The Ishizakas built on work performed nium sulfate precipitation (different proteins Again, the presence of the protein was in 1921 by K. Prausnitz and H. Kustner, who precipitate out at varying concentrations detected on the basis of its ability to bind injected serum from an allergic person of ammonium sulfate), and ion exchange to radioactive antigen E and to induce a into the skin of a nonallergic individual. chromatography, which separates proteins P-K reaction in the skin of a test subject When the appropriate antigen was later on the basis of their intrinsic charge. who had been injected with antigen E. injected into the same site, a wheal and Different fractions from the chroma- The resulting protein still contained flare reaction (swelling and reddening) tography column were tested by radio- small amounts of IgG and IgA antibodies, was detected. This reaction, called the P-K immunodiffusion for their ability to bind which were eliminated by mixing the frac- reaction after its originators, was the basis to radioactive antigen E from ragweed tions with antibodies directed toward for the first biological assay for IgE activity. pollen. Portions of the different fractions those human antibody subclasses, and In their now classic experiments, the were also injected at varying dilutions into then removing the resultant immunopre- Ishizakas assayed for the presence of aller- volunteers, along with antigen, to test for cipitate. The Ishizakas’ final protein product gen-specific antibody using the wheal and a P-K reaction. Finally, each fraction was was 500 to 1000 times more potent than flare reaction. They also employed radio- also tested semiquantitatively for the the original serum in its ability to generate immunodiffusion, using the ability of presence of IgG and IgA antibodies. The a P-K reaction, and the most active prepa- radioactive allergen E derived from rag- results of these experiments are shown for ration generated a positive skin reaction at weed pollen to bind to and precipitate the serum from one of the three individu- a dilution of 1:8000. None of its reactivities pollen-specific antibodies as an additional als they tested (see Table 1 below). correlated with the presence of any of the assay; the antibodies formed a radioactive From the results in this table, it is clear other known classes of antibody, and so a precipitate on binding to the ragweed that the ability of proteins in the various new class of antibody was named, IgE, allergen. (Note that both the antigen and fractions to induce a P-K reaction did not based on its ability to bind to allergens and the immunoglobulin class are designated correlate with the amounts of either IgG bring about a P-K reaction. “E” in this series of experiments.) or IgA antibodies, but it did correlate with As described in Chapter 3, the level of The Ishizakas reasoned that the best the amounts of antibodies that could be IgE in the serum is the lowest of all the starting material for purifying the protein detected in an immunodiffusion reaction antibody classes, falling within the range The High-Affinity IgE Receptor, Fc␧RI bind the IgE heavy chains, whereas the ␤ and ␥ chains are Mast cells and basophils constitutively express high levels of responsible for signal transduction. They contain immunore- the high-affinity IgE receptor, Fc␧RI, which binds IgE with an ceptor tyrosine-based activation motifs (ITAMs) (see Chap- exceptionally high-affinity constant of 1010M⫺1. This affinity ter 3) that are phosphorylated in response to IgE cross-linking. helps overcome the difficulties associated with responding to IgE-mediated signaling begins when an allergen cross- an exceptionally low concentration of IgE in the serum links IgE that is bound to the surface Fc␧RI receptor (Figure (1.3 ⫻ 10⫺7 M). Eosinophils, Langerhans cells, monocytes, 15-2). Although the specific biochemical events that follow and platelets also express Fc␧RI, although at lower levels. cross-linking of the Fc␧RI receptor vary among cells and Most cells express a tetrameric form of Fc␧RI, which modes of stimulation, the Fc␧RI signaling cascade generally includes an ␣ and ␤ chain and two identical disulfide-linked resembles that initiated by antigen receptors and growth fac- ␥ chains (Figure 15-3a). Monocytes and platelets express an tor receptors (Chapter 3). Briefly, IgE cross-linking induces alternative form lacking the ␤ chain. The ␣ chains of the the aggregation and migration of receptors into membrane Fc␧RI, members of the immunoglobulin superfamily, directly lipid rafts, followed by phosphorylation of ITAM motifs by c15Allergy,Hypersensitivities,andChronicInflammation.indd Page 489 12/20/12 5:39 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Allergy, Hypersensitivities, and Chronic Inflammation | CHAPTER 15 489 BOX 15-1 Data from original paper identifying the immunoglobulins responsible for TABLE 1 skin sensitization Serum Minimum dose Relative Relative Relative donor Fraction for P-K reaction amount IgE amount IgG amount IgA U A 0.04 ⫹ ⫹ ⫺ n B 0.008 ⫹⫹ ⫹ ⫺ C 0.26 ⫹ ⫺ ⫹/⫺ D ⬎ 0.9 ⫺ ⫺ ⫺ A A 0.002 ⫹⫹ ⫹⫹ ⫺ n B 0.0006 ⫹⫹⫹ ⫹ ⫹/⫺ C 0.0014 ⫹⫹ ⫹ ⫹/⫺ D 0.005 ⫹⫹ ⫹ ⫹ E 0.017 ⫹⫹ ⫺ ⫹ F 0.13 ⫹ ⫺ ⫹ Modified from original table entitled “Distribution of skin-sensitizing activity and of ␥G (IgG) and ␥A (IgA) globulin following diethylaminoethyl (DEAE) Sephadex column fractionation,” in Ishizaka, K., and T. Ishizaka, (1967), Identification of ␥E-antibodies as a carrier of reaginic activity. Journal of Immunology 99(6):1187–1198. of 0.1 to 0.4 ␮g/ml, although atopic indi- using rabbit antisera against the two amount of P-K responsive antibody in the viduals can have as much as 10 times this immunoglobulin subclasses, and for the fraction (i.e., fraction B had the highest concentration of IgE in their circulation. presence of the putative “IgE” using radio- amount of the allergenic antibody). However, in 1967, Johansson and Bennich immunodiffusion (as described in this It can readily be seen that the fractions discovered an IgE-producing myeloma, chapter’s text). IgG is the most common showing the strongest P-K responses (high- which enabled a full biochemical analysis class of immunoglobulin in serum, and lighted arrows: n) are also those in which of the molecule. The structure of IgE is IgA was included because early experi- the highest amounts of the so-called ␥E described in Chapter 3. ments had suggested that IgA may be the were measured by radio-immunodiffusion. In Table 1, which is modified from the antibody responsible for the wheal and P-K reactions did not correlate with either original data in this classic 1967 paper, flare reaction. The “Minimum dose for P-K” IgG or with IgA levels in the serum from serum protein fractions from two separate column refers to the quantity of the frac- this, or from two other donors. donors were evaluated for the relative tion required to yield a measureable Ishizaka, K., and T. Ishizaka. (1967). Identification amounts of IgA or IgG (referred to as ␥A wheal and flare response. In this column, of ␥E-antibodies as a carrier of reaginic activ- and ␥G, respectively, in this publication), the lower the number, the higher the ity. Journal of Immunology 99(6):1187–1198. associated tyrosine kinases. Adapter molecules then latch The Low-Affinity IgE Receptor, Fc␧RII onto the phosphorylated tyrosine residues and initiate signal- The other IgE receptor, designated Fc␧RII, or CD23, has a much ing cascades culminating in enzyme and/or transcription lower affinity for IgE (Kd of 1 ⫻ 106 M⫺1) (Figure 15-3b). CD23 factor activation. Figure 15-4 identifies just a few of the sig- is structurally distinct from Fc␧RI (it is a lectin and a type II naling events specifically associated with mast cell activation. membrane protein) and exists in two isoforms that differ only Fc␧RI signaling leads to mast cell and basophil (1) slightly in the N-terminal cytoplasmic domain. CD23a is found degranulation of vesicles containing multiple inflammatory on activated B cells, whereas CD23b is induced on various cell mediators (Figure 15-5a), (2) expression of inflammatory types by the cytokine IL-4. Both isoforms also exist as mem- cytokines and (3) conversion of arachidonic acid into leu- brane-bound and soluble forms, the latter being generated by kotrienes and prostaglandins, two important lipid mediators proteolysis of the surface molecule. Interestingly, CD23 binds of inflammation. These mediators have multiple short-term not only to IgE, but also to the complement receptor CD21. and long-term effects on tissues that will be described in The outcome of CD23 ligation depends on which ligands more detail below (Figure 15-5b). it binds to (IgE or CD21) and whether it does so as a soluble c15Allergy,Hypersensitivities,andChronicInflammation.indd Page 490 12/20/12 5:39 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Allergen CD4 Histamine, heparin, proteases IL-4 B cell TH2 cell Smooth muscle cell Allergen Small blood vessel Vasoactive Fc receptor amines for IgE Mucous gland Blood platelets + Allergen Memory cell Plasma cell Sensitized mast cell Degranulation Sensory nerve endings Allergen- specific IgE Eosinophil FIGURE 15-2 General mechanism underlying an immediate type I hypersensitivity reaction. Exposure to an allergen activates TH2 cells that stimulate B cells to form IgE-secreting plasma cells. The secreted IgE molecules bind to IgE-specific Fc receptors (Fc␧RI) on mast cells and blood basophils. (Many molecules of IgE with various specificities can bind to the Fc␧RI.) Second exposure to the allergen leads to cross-linking of the bound IgE, triggering the release of pharmacologically active mediators (vasoactive amines) from mast cells and basophils. The mediators cause smooth muscle contraction, increased vascular permeability, and vasodilation. (a) FcεRI: (b) FcεRII (CD23): High-affinity IgE receptor Low-affinity IgE receptor S NH2 Soluble S CD23 S S S S S α Ig-like COOH S domains S Proteolytic γ Extracellular S β γ cleavage H2N NH2 space S S Plasma membrane Cytoplasm ITAM COOH COOH NH2 NH2 COOH COOH FIGURE 15-3 Schematic diagrams of the high-affinity Fc␧RI and low-affinity Fc␧RII receptors that bind the Fc region of IgE. (a) Fc␧RI consists of a ␣ chain that binds IgE, a ␤ chain that participates in signaling, and two disulfide-linked ␥ chains that are the most important component in signal transduction. The ␤ and ␥ chains contain a cytoplasmic ITAM, a motif also present in the Ig␣/Ig␤ (CD79␣/␤) heterodimer of the B-cell receptor and in the T-cell receptor complex. (b) The single-chain Fc␧RII is unusual because it is a type II transmembrane protein, oriented in the membrane with its NH2-terminus directed toward the cell interior and its COOH-terminus directed toward the extracellular space. 490  Allergy, Hypersensitivities, and Chronic Inflammation | CHAPTER 15 491 Ag noreceptor tyrosine inhibitory motifs (ITIMs as distinct from IgE ITAMs) (see Figure 13-3). Cross-linking of these receptors leads to inhibition, rather than to activation of cellular FcεRI responses. Interestingly, mast cells express both the activating γ γ β α α β γ γ Fc␧RI and inhibiting Fc␥RIIB. Therefore, if an allergen binds both IgG and IgE molecules, it will trigger signals through Lyn Lyn both Fc receptors. The inhibitory signal dominates. This phe- Adaptors nomenon is part of the reason that eliciting IgG antibodies against common allergens through desensitization therapies can help atopic patients. The more anti-allergen IgG they have, the higher the probability that allergens will co-cluster Fc␧RI receptors with inhibitory Fc␥RIIB receptors. PKC MAPK Inhibition of Downstream Signaling Molecules PLD NF-κB PLA Because many of the reactions in the activation pathway downstream from the Fc␧RI pathways are phosphorylations, multiple phosphatases, such as SHPs, SHIPs, and PTEN, play Degranulation Cytokines Leukotrienes, prostaglandins an important role in dampening receptor signaling. In addi- tion, the tyrosine kinase, Lyn, can play a negative as well as a FIGURE 15-4 Signaling pathways initiated by IgE allergen positive role in Fc␧RI signaling by phosphorylating and acti- cross-linking. By cross-linking Fc␧ receptors, IgE initiates signals that vating the inhibitory Fc␥RIIB. Finally, Fc␧RI signaling lead to mast cell degranulation, cytokine expression, and leukotriene through Lyn and Syk kinases also activates E3 ubiquitin and prostaglandin generation. The signaling cascades initiated by the ligases, including c-Cbl. Cbl ubiquitinylates Lyn and Syk, as Fc␧RI are similar to those initiated by antigen receptors (see Chap- well as Fc␧RI itself, triggering their degradation. Thus, Fc␧RI ter 3). This figure illustrates only a few of the players in the complex activity contributes to its own demise. signaling network. Briefly, cross-linking of Fc␧RI activates tyrosine kinases, including Lyn, which phosphorylate adaptor molecules, which organize signaling responses that lead to activation of multiple Innate Immune Cells Produce Molecules kinases, including protein kinase C (PKC) and various mitogen-activated Responsible for Type I Hypersensitivity protein kinases (MAPKs). These, in turn, activate transcription fac- Symptoms tors (e.g., NF␬B) that regulate cytokine production. They also activate The molecules released in response to Fc␧RI cross-linking by lipases, including phospholipase D (PLD), which regulates degranula- mast cells, basophils, and eosinophils are responsible for the tion, and phospholipase A (PLA), which regulates the metabolism of clinical manifestations of type I hypersensitivity. These the leukotriene and prostaglandin precursor arachidonic acid. [K. Roth, inflammatory mediators act on local tissues as well as on W. M. Chen, and T. J. Lin, 2008, Positive and negative regulatory mechanisms in populations of secondary effector cells, including other high-affinity IgE receptor-mediated mast cell activation, Archivum immunolo- eosinophils, neutrophils, T lymphocytes, monocytes, and giae et therapiae experimentalis 56:385–399.] platelets. or membrane-bound molecule. For example, when solu- When generated in response to parasitic infection, these ble CD23 (sCD23) binds to CD21 on the surface of IgE- mediators initiate beneficial defense processes, including synthesizing B cells, IgE synthesis is increased. However, vasodilation and increased vascular permeability, which when membrane-bound CD23 binds to soluble IgE, further brings an influx of plasma and inflammatory cells to attack IgE synthesis is suppressed. Atopic individuals express rela- the pathogen. They also inflict direct damage on the parasite. tively high levels of surface and soluble CD23. In contrast, mediator release induced by allergens results in unnecessary increases in vascular permeability and inflam- mation that lead to tissue damage with little benefit. IgE Receptor Signaling Is Tightly Regulated The molecular mediators can be classified as either pri- Given the powerful nature of the molecular mediators mary or secondary (Table 15-2). Primary mediators are released by mast cells, basophils, and eosinophils following preformed and stored in granules prior to cell activation, Fc␧RI signaling, it should come as no surprise that the whereas secondary mediators are either synthesized after responses are subject to complex systems of regulation. target-cell activation or released by the breakdown of mem- Below we offer just a few examples of ways in which signal- brane phospholipids during the degranulation process. The ing through the Fc␧RI receptor can be inhibited. most significant primary mediators are histamine, proteases, eosinophil chemotactic factor (ECF), neutrophil chemotac- Co-Clustering with Inhibitory Receptors tic factor (NCF), and heparin. Secondary mediators include Recall from earlier chapters that the intracellular regions of platelet-activating factor (PAF), leukotrienes, prostaglan- some lymphocyte receptors, including Fc␥RIIB, bear immu- dins, bradykinins, and various cytokines and chemokines. 492 PA R T V I | The Immune System in Health and Disease (a) (b) Cytoplasmic granules Mast cell activation Cytokines, chemokines, growth factors, lipid mediators, granule-associated mediators Cellular targets Stromal and Nerves Vascular Hematopoietic cells Epithelial muscle cells endothelial cells cells Tissue changes Acute changes Inflammation and remodeling in function Days-weeks Hours-days FIGURE 15-5 Mast cell activity. (a) A mast cell in the process These mediators act on different cell types, and have both acute of degranulating (colorized EM image of mast cell membrane). and chronic effects. When produced over long periods of time, mast (b) Mast cell mediators and their effects. Different stimuli activate cell mediators have a significant influence on tissue structure by en- mast cells to secrete different amounts and/or types of products. hancing proliferation of fibroblasts and epithelial cells, increasing Activated mast cells immediately release preformed, granule- production and deposition of collagen and other connective tissue associated inflammatory mediators (including histamine, proteases, proteins, stimulating the generation of blood vessels, and more. and heparin) and are induced to generate lipid mediators (such [(a) http://t3.gstatic.com/images?q⫽tbn:ANd9GcQh3-PP1n1mbEiIsiHmciOq- as leukotrienes and prostaglandins), chemokines, cytokines, and eniEL5D-iMw3HTWlbVZsQ-TW0QPbQ. (b) Figure 1 in Galli, S. J., and S. Nakae. growth factors (some of which can also be packaged in granules). (2003). Mast Cells to the Defense. Nature Immunology 4:1160–1162.] c15Allergy,Hypersensitivities,andChronicInflammation.indd Page 493 12/20/12 5:39 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Allergy, Hypersensitivities, and Chronic Inflammation | CHAPTER 15 493 TABLE 15-2 Principal mediators involved in type I hypersensitivity. Mediator Effects Primary Histamine, heparin Increased vascular permeability; smooth muscle contraction Serotonin (rodents) Increased vascular permeability; smooth muscle contraction Eosinophil chemotactic factor (ECF-A) Eosinophil chemotaxis Neutrophil chemotactic factor (NCF-A) Neutrophil chemotaxis Proteases (tryptase, chymase) Bronchial mucus secretion; degradation of blood vessel basement membrane; generation of complement split products Secondary Platelet-activating factor Platelet aggregation and degranulation; contraction of pulmonary smooth muscles Leukotrienes (slow reactive substance Increased vascular permeability; contraction of pulmonary smooth muscles of anaphylaxis, SRS-A) Prostaglandins Vasodilation; contraction of pulmonary smooth muscles; platelet aggregation Bradykinin Increased vascular permeability; smooth muscle contraction Cytokines IL-1 and TNF-␣ Systemic anaphylaxis; increased expression of adhesion molecules on venular endothelial cells IL-4 and IL-13 Increased IgE production IL-3, IL-5, IL-6, IL-10, TGF-␤, and GM-CSF Various effects (see text) The varying manifestations of type I hypersensitivity in dif- Leukotrienes and Prostaglandins ferent tissues and species reflect variations in the primary As secondary mediators, the leukotrienes and prostaglandins and secondary mediators present. Below we briefly describe are not formed until the mast cell undergoes degranulation and the main biological effects of several key mediators. phospholipase signaling initiates the enzymatic breakdown of phospholipids in the plasma membrane. An ensuing enzymatic Histamine cascade generates the prostaglandins and the leukotrienes. Histamine, which is formed by decarboxylation of the amino In a type I hypersensitivity-mediated asthmatic response, acid histidine, is a major component of mast-cell granules, the initial contraction of human bronchial and tracheal accounting for about 10% of granule weight. Its biological smooth muscles is at first mediated by histamine; however, effects are observed within minutes of mast-cell activation. within 30 to 60 seconds, further contraction is signaled by Once released from mast cells, histamine binds one of four dif- leukotrienes and prostaglandins. Active at nanomole levels, ferent histamine receptors, designated H1, H2, H3, and H4. the leukotrienes are approximately 1000 times more effective These receptors have different tissue distributions and mediate at mediating bronchoconstriction than is histamine, and different effects on histamine binding. Serotonin is also present they are also more potent stimulators of vascular permeabil- in the mast cells of rodents and has effects similar to histamine. ity and mucus secretion. In humans, the leukotrienes are Most of the biologic effects of histamine in allergic reac- thought to contribute significantly to the prolonged bron- tions are mediated by the binding of histamine to H1 recep- chospasm and buildup of mucus seen in asthmatics. tors. This binding induces contraction of intestinal and bronchial smooth muscles, increased permeability of venules Cytokines and Chemokines (small veins), and increased mucous secretion. Interaction of Adding to the complexity of the type I reaction is the variety histamine with H2 receptors increases vasopermeability (due of cytokines released from mast cells and basophils. Mast to contraction of endothelial cells) and vasodilation (by relax- cells, basophils, and eosinophils secrete several interleukins, ing the smooth muscle of blood vessels), stimulates exocrine including IL-4, IL-5, IL-8, IL-13, GM-CSF, and TNF-␣. glands, and increases the release of acid in the stomach. Bind- These cytokines alter the local microenvironment and lead ing of histamine to H2 receptors on mast cells and basophils to the recruitment of inflammatory cells such as neutrophils suppresses degranulation; thus, histamine ultimately exerts and eosinophils. For instance, IL-4 and IL-13 stimulate a negative feedback on the further release of mediators. TH2 response and thus increase IgE production by B cells. 494 PA R T V I | The Immune System in Health and Disease IL-5 is especially important in the recruitment and activation how multiple granulocyte subsets can cooperate in the of eosinophils. The high concentrations of TNF-␣ secreted induction of chronic allergic inflammation. by mast cells may contribute to shock in systemic anaphy- laxis. IL-8 acts as a chemotactic factor, and attracts further There Are Several Categories of Type I neutrophils, basophils, and various subsets of T cells to the site of the hypersensitivity response. GM-CSF stimulates the Hypersensitivity Reactions production and activation of myeloid cells, including granu- The clinical manifestations of type I reactions can range locytes and macrophages. from life-threatening conditions, such as systemic anaphy- laxis and severe asthma, to localized reactions, such as hay Type I Hypersensitivities Are Characterized fever and eczema. The nature of the clinical symptoms depends on the route by which the allergen enters the body, by Both Early and Late Responses as well as on its concentration and on the prior allergen Type I hypersensitivity responses are divided into an imme- exposure of the host. In this section, we describe the pathol- diate early response and one or more late phase responses ogy of the various type I hypersensitivity reactions. (Figure 15-6). The early response occurs within minutes of allergen exposure and, as described above, results from the Systemic Anaphylaxis release of histamine, leukotrienes, and prostaglandins from Systemic anaphylaxis is a shocklike and often fatal state that local mast cells. occurs within minutes of exposure to an allergen. It is usually However, hours after the immediate phase of a type I initiated by an allergen introduced directly into the blood- hypersensitivity reaction begins to subside, mediators released stream or absorbed from the gut or skin. Symptoms include during the course of the reaction induce localized inflamma- labored respiration, a precipitous drop in blood pressure lead- tion, called the late-phase reaction. Cytokines released from ing to anaphylactic shock, followed by contraction of smooth mast cells, particularly TNF-␣ and IL-1, increase the expres- muscles leading to defecation, urination, and bronchiolar sion of cell adhesion molecules on venular endothelial cells, constriction. This leads to asphyxiation, which can lead to thus facilitating the influx of neutrophils, eosinophils, and death within 2 to 4 minutes of exposure to the allergen. These TH2 cells that characterizes this phase of the response. symptoms are all due to rapid antibody-mediated degranula- Eosinophils play a principal role in the late-phase reac- tion of mast cells and the systemic effects of their contents. tion. Eosinophil chemotactic factor, released by mast cells A wide range of antigens has been shown to trigger this during the initial reaction, attracts large numbers of eosino- reaction in susceptible humans, including the venom from phils to the affected site. Cytokines released at the site, bee, wasp, hornet, and ant stings; drugs such as penicillin, including IL-3, IL-5, and GM-CSF, contribute to the growth insulin, and antitoxins; and foods such as seafood and nuts. and differentiation of these cells, which are then activated by If not treated quickly, these reactions can be fatal. Epineph- binding of antibody-coated antigen. This leads to degranula- rine, the drug of choice for treating systemic anaphylactic tion and further release of inflammatory mediators that reactions, counteracts the effects of mediators such as hista- contribute to the extensive tissue damage typical of the late- mine and the leukotrienes, relaxing the smooth muscles of phase reaction. Neutrophils, another major participant in the airways and reducing vascular permeability. Epinephrine late-phase reactions, are attracted to the site of an ongoing also improves cardiac output, which is necessary to prevent type I reaction by neutrophil chemotactic factor released vascular collapse during an anaphylactic reaction. from degranulating mast cells. Once activated, the neutro- phils release their granule contents, including lytic enzymes, Localized Hypersensitivity Reactions platelet-activating factor, and leukotrienes. In localized hypersensitivity reactions (atopy), the pathology Recently, a third phase of type I hypersensitivity has is limited to a specific target tissue or organ, and often occurs been described in models of type I hypersensitivity reac- at the epithelial surfaces first exposed to allergens. Atopic tions in the skin. This third phase starts around 3 days post allergies include a wide range of IgE-mediated disorders, antigen challenge and peaks at day 4. It is also character- such as allergic rhinitis (hay fever), asthma, atopic dermatitis ized by massive eosinophil infiltration but, in contrast to (eczema), and food allergies. the second phase, requires the presence of basophils. As The most common atopic disorder, affecting almost 50% shown in Figure 15-7, which illustrates an example of the of the U.S. population, is allergic rhinitis or hay fever. Symp- late-phase responses in the mouse ear, cytokines and pro- toms result from the inhalation of common airborne aller- teases released from basophils act on tissue-resident cells gens (pollens, dust, viral antigens), which react with IgE such as fibroblasts. These fibroblasts then secrete chemo- molecules bound to sensitized mast cells in the conjunctivae kines that are responsible for the recruitment of larger and nasal mucosa. Cross-linking of IgE receptors induces the numbers of eosinophils and neutrophils to the skin lesion. release of histamine and heparin from mast cells, which then Subsequent degranulation of the eosinophils and neutro- cause vasodilation, increased capillary permeability, and pro- phils adds to the considerable tissue damage at the site of duction of exudates in the eyes and respiratory tract. Tearing, the initial allergen contact. These experiments illustrate runny nose, sneezing, and coughing are the main symptoms. c15Allergy,Hypersensitivities,andChronicInflammation.indd Page 495 12/20/12 5:39 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Allergy, Hypersensitivities, and Chronic Inflammation | CHAPTER 15 495 EARLY RESPONSE LATE RESPONSE IL-4 PAF TH 2 Mast cell IL-4 APC IL-5 ECF Histamine NCF Leukotrienes TNF-α Prostaglandins Leukotrienes Vasodilation Recruitment of inflammatory cells Mucus secretion Inflammatory Mucous Broncho- cells (eosinophils; glands constriction neutrophils) Epithelial injury Late response Early response Eosinophils Blood vessel Thickened basement membrane Curschmann's spirals EARLY RESPONSE (minutes) LATE RESPONSE (hours) Histamine Vasodilation IL-4, TNF-α, LTC4 Increased endothelial cell adhesion Prostaglandins Bronchoconstriction PAF, IL-5, ECF Leukocyte migration Leukotrienes Mucus secretion IL-4, IL-5 Leukocyte activation FIGURE 15-6 The early and late inflammatory responses in asthma. The immune cells involved in the early and late responses are represented at the top. The effects of various mediators on an airway, represented in cross-section, are illustrated in the center and also described in the text. c15Allergy,Hypersensitivities,andChronicInflammation.indd Page 496 12/20/12 5:39 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 496 PA R T V I | The Immune System in Health and Disease Antigen Epidermis Dermis 3 2 Cytokines 4 Chemokines Other factors 5 Blood vessel 1 IgE FcεRI Basophils Eosinophils Neutrophils FIGURE 15-7 Multiple innate immune cells are involved (3) that stimulate stromal cells (e.g., fibroblasts) to release chemokines in the chronic type 1 hypersensitivity response in a mouse (4), which attract other granulocytes, including eosinophils and ear-swelling model. Late in a type I response, basophils migrate neutrophils to the tissue, contributing to a chronic inflammation and into the dermis of the ear (1) and are activated by IgE/antigen com- tissue damage. [Adapted from H. Karasuyama et al., 2011, Nonredundant plexes (2). They release cytokines and other inflammatory mediators roles of basophils in immunity, Annual Review of Immunology 29:45–69.] Alternatively, an asthma attack can be induced by exercise or for more anaphylactic responses than any other type of cold, apparently independently of allergen stimulation allergy. They are highest in frequency among infants and (intrinsic asthma). toddlers (6%–8%) and decrease slightly with maturity. Like hay fever, allergic asthma is triggered by activation and Approximately 4% of adults display reproducible allergic degranulation of mast cells, with subsequent release of inflam- reactions to food. matory mediators, but instead of occurring in the nasal The most common food allergens for children are found mucosa, the reaction develops deeper in the lower respiratory in cow’s milk, eggs, peanuts, tree nuts, soy, wheat, fish, and tract. Contraction of the bronchial smooth muscles, mucus shellfish. Among adults, nuts, fish, and shellfish are the pre- secretion, and swelling of the tissues surrounding the airway all dominant culprits. Most major food allergens are water-soluble contribute to bronchial constriction and airway obstruction. glycoproteins that are relatively stable to heat, acid, and pro- Asthmatic patients may be genetically predisposed to teases and, therefore, digest slowly. Some food allergens atopic responses. Some, for instance, have abnormal levels of (e.g., the major glycoprotein in peanuts, Ara h 1) are also receptors for neuropeptides (substance P) that contract capable of acting directly as an adjuvant and promoting a smooth muscles and decreased expression of receptors for TH2 response and IgE production in susceptible individuals. vasoactive intestinal peptide, which relaxes smooth muscles. Allergen cross-linking of IgE on mast cells along the upper Atopic dermatitis (allergic eczema) is an inflammatory or lower gastrointestinal tract can induce localized smooth disease of skin and another example of an atopic condition. muscle contraction and vasodilation and thus such symp- It is observed most frequently in young children, often toms as vomiting or diarrhea. Mast-cell degranulation along developing during infancy. Serum IgE levels are usually ele- the gut can increase the permeability of mucous membranes, vated. The affected individual develops erythematous (red) so that the allergen enters the bloodstream. Basophils also skin eruptions that fill with pus if there is an accompanying play a significant role in acute food allergy symptoms. bacterial infection. Unlike a DTH reaction, which involves Several hypotheses have been advanced to explain why TH1 cells (see below), the skin lesions in atopic dermatitis some individuals become sensitive to antigens that are well contain TH2 cells and an increased number of eosinophils. tolerated by the rest of the population. One possibility is that a temporary viral or bacterial infection may lead to a short- Food Allergies: A Common Type of Atopy on the Rise lived increase in the permeability of the gut surface, allowing Food allergies, whose incidence is on the rise, are another increased absorption of allergenic antigens and sensitization. common type of atopy. In children, food allergies account Alternatively, sensitization may occur via the respiratory  Allergy, Hypersensitivities, and Chronic Inflammation | CHAPTER 15 497 TABLE 15-3 Immune basis for some food allergies Disorder Symptoms Common trigger Notes about mechanism IgE mediated (acute) Hives (urticaria) Wheal and flare swellings Multiple foods triggered by ingestion or skin contact Oral allergy Itchiness, swelling of mouth Fruits, vegetables Due to sensitization by inhaled pollens, producing IgE that cross-reacts with food proteins Asthma, rhinitis Respiratory distress Inhalation of aerosolized food Mast-cell mediated proteins Anaphylaxis Rapid, multiorgan inflamma- Peanuts, tree nuts, fish, shell- tion that can result in cardio- fish, milk, etc. vascular failure Exercise-induced anaphylaxis As above, but occurs when Wheat, shellfish, celery (may one exercises after eating be due to changes in gut trigger foods absorption associated with exercise) IgE and cell mediated (chronic) Atopic dermatitis Rash (often in children) Egg, milk, wheat, soy, etc. May be skin T cell mediated Gastrointestinal inflammation Pain, weight loss, edema, Multiple foods Eosinophil mediated and/or obstruction Cell mediated (chronic) Intestinal inflammation Most often seen in infants: Cow’s milk (directly or via TNF-␣ mediated brought about by dietary pro- diarrhea, poor growth, and/or breast milk), soy, grains tein (e.g., enterocolitis, proctitis) bloody stools Adapted from S. H. Sicherer and H. A. Sampson, 2009, Food allergy, Annual Review of Medicine 60:261–277. route or via absorption of allergens through the skin. This is develop asthmatic attacks after ingesting certain foods. Oth- thought to be the case for one type of allergic reaction to ers develop atopic urticaria, commonly known as hives, apple proteins. Exposure to birch pollen can induce respira- when a food allergen is carried to sensitized mast cells in the tory type I hypersensitivity, and the IgE that is generated skin, causing swollen (edematous), erythematous eruptions. cross-reacts to a protein from apples, leading to a severe digestive allergic response. Finally, various dietary condi- There Is a Genetic Basis for tions may bias an individual’s responses in the direction of TH2 generation. These include reduced dietary antioxidants, Type I Hypersensitivity altered fat consumption, and over- or under-provision of The susceptibility of individuals to atopic responses has a Vitamin D. Table 15-3 lists various immune mechanisms strong genetic component that has been mapped to several that play a role in food allergy. Note that although most are possible loci by candidate gene association studies, genome- IgE mediated, some are mediated by T cells. wide linkage analyses, and genome expression studies (see The efficiency of the gut barrier improves with maturity, Clinical Focus Box 15-2). As might be expected from the and the food allergies of many infants resolve without treat- pathogenesis of allergy and asthma, many of the associated ment as they grow, even though allergen-specific IgE can still gene loci encode proteins involved in the generation and be detected in their blood. However, resolution is not always regulation of immune responsiveness (e.g., innate immune achieved, and in some cases the continuation of the allergic receptors, cytokines and chemokines and their receptors, state reflects a reduced frequency of regulatory T cells in MHC proteins) as well as with airway remodeling (e.g., allergic versus nonallergic individuals. growth factors and proteolytic enzymes). Other proteins that Depending on where the allergen is deposited, patients have been implicated in the hereditary predisposition to with atopic dermatitis and food hypersensitivity can also allergy and asthma include transcription factors and pro- exhibit other symptoms. For example, some individuals teins that regulate epigenetic modifications.  498 PA R T V I | The Immune System in Health and Disease CLINICAL FOCUS The Genetics of Asthma and Allergy It has long been appreciated that a exhibit polymorphisms in structural or sequences until a gene of interest is iden- predisposition to asthma and allergic regulatory regions of the IL-4 gene, tified. This technique is referred to as responses runs strongly in families, sug- leading to unusually high levels of IL-4 positional cloning, and several genes gesting the presence of an hereditary production. important in asthma and atopy have been component. In addition, twin studies in Using this theoretical framework, identified in this way. humans and mice have implicated both geneticists selected a region on human Figure 1 illustrates some of the prod- environmental and epigenetic, as well as chromosome 5, 5q31-33, for detailed ucts of genes already identified as having genetic, factors in determining the sus- analysis. This region contains a cluster of polymorphisms relevant to the develop- ceptibility of an individual to hypersensi- cytokine genes, among which are the ment of asthma or atopy. However, this tivity responses. With this degree of genes for IL-3, IL-4, IL-5, IL-9, and IL-13, as investigation is far from complete. Some- complexity, it is not surprising that the well as the gene encoding granulocyte- times the same SNP has been shown to identification of the genes involved in macrophage colony stimulating factor. have different effects in various racial or controlling an individual’s vulnerability to Careful study of this region revealed a ethnic populations, illustrating the com- hypersensitivity responses has proven to polymorphism associated with the pre- plexity of such disease-associated genetic be a difficult task. However, since the late disposition to asthma that maps to the studies. 1980s, the geneticist’s toolkit has mark- promoter region of IL-4—a confirmation edly expanded with the availability of of the hypothesis advanced above. In genome wide sequence information in addition, two alleles of IL-9 associated addition to libraries of single nucleotide with a predisposition to atopy were also polymorphisms (SNPs). These tools, identified. along with more classical genetic A second approach starts with a statis- approaches have been used to map tically based search for genes associated hypersensitivity susceptibility genes. with particular disease states and is One approach to determining which referred to as a genome wide associa- genes are associated with a particular tion survey (GWAS). The genomes of pathological state is to use knowledge of individuals who do and those who do not the disease to develop and then geneti- have the disease in question are mapped cally test an hypothesis regarding poten- with respect to the presence of SNPs. Sta- tial candidate genes (i.e. “educated tistically significant association of disease guesses”). For example, we know that with a particular polymorphism then pro- asthma is associated with high numbers vides the motivation for detailed sequence of differentiated TH2 cells, and high levels analysis in the region of the SNP, and a of IL-4 expression introduce a bias in the search for likely candidate genes. Cloning differentiation of activated CD4 T cells of genes begins in the region identified by toward the TH2 state. We can therefore the candidate SNP and then proceeds by hypothesize that asthma sufferers may a sequential search of contiguous Diagnostic Tests and Treatments Are Available (the result of local mast cell degranulation) indicate an aller- for Type I Hypersensitivity Reactions gic response (Figure 15-8). Less commonly, physicians may elect to measure the serum levels of either total or allergen- Type I hypersensitivity is commonly assessed by skin testing, specific IgE using ELISA or Western blot technologies (see an inexpensive and relatively safe diagnostic approach that Chapter 20). allows screening of a wide range of antigens at once. Small Treatment of type I hypersensitivity reactions always amounts of potential allergens are introduced at specific skin begins with measures to avoid the causative agents. How- sites (e.g., the forearm or back), either by intradermal injec- ever, no one can avoid contact with aeroallergens such as tion or by dropping onto a site of a superficial scratch. Thirty pollen, and a number of immunological and pharmaceutical minutes later, the sites are reexamined. Redness and swelling interventions are now available. c15Allergy,Hypersensitivities,andChronicInflammation.indd Page 499 12/20/12 5:39 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Allergy, Hypersensitivities, and Chronic Inflammation | CHAPTER 15 499 BOX 15-2 TLR Prostaglandin E2 receptor Microbial product Pollen Defensin-β1 CC16 Epithelial cell STAT6 IL-4Rα IL-5Rα Eosinophil Dendritic cell STAT3 IL-4Rα IL-13 TLR Soluble mediators IL-5 MHC class II TREG cell FcεRIB Antigen CCL5 IL-10 IL-4 TCR TGF-β1 IL-13 IL-4 IgE IL-12β GATA3 IL-13 T-Bet STAT6 STAT6 Allergic Inflammation TH1 cell Precursor TH cell TH2 cell B cell IL-4 IL-13 FcεRIB FcεRIB Basophil Mast cell FIGURE 1 Products of genes that exhibit polymorphisms associated with predisposition to allergy. The genes coding for the products shown have been discovered by multiple genome wide survey techniques. They can be divided into three broad categories. One group of genes codes for proteins that trigger an immune response. These include pattern recognition receptors (TLR2, TLR4, TLR6), pollen receptors (Prostaglandin E2 receptor), and inhibitory cytokines (IL-10, TGF␤), as well as genes coding for proteins that regulate antigen presentation (MHC class II). Another group of genes codes for proteins that regulate TH2 differentiation and innate immune cell responses. These include polarizing cytokines (IL-4, IL-12), signaling and transcriptional regulators (STAT6, T-bet GATA3), Fc␧ receptors, effector cytokines (IL-4, IL-5, and IL-13), and cytokine receptors (IL-4R, IL-5R, IL-13R). Another group of genes is expressed by epithelial cells and smooth muscle cells and codes for proteins that regulate the tissue response. These include chemokines (CCL6), defensins (Defensin ␤2), and other signaling molecules. [Vercelli, D. Discovering susceptibility genes for asthma and allergy. Nature Reviews. Immunology 8:169–182.] Hyposensitization How does hyposensitization work? Two main mecha- For many years, physicians have been treating allergic nisms have been proposed (Figure 15-9). Repeated exposure patients with repeated exposure (via ingestion or injection) to low doses of allergen may induce an increase in regulatory to increasing doses of allergens, in a regimen termed hypo- T cells producing the immunosuppressive cytokines TGF-␤ sensitization or immunotherapy. This mode of treatment and/or IL-10 (a form of tolerance). It may also induce an attacks the disease mechanism of the allergic individual at increase in noninflammatory IgG (specifically IgG4) anti- the source and, when it works, is by far the most effective bodies specific for the allergens (desensitization). These way to manage allergies. Hyposensitization can reduce or antibodies either competitively inhibit IgE binding or induce even eliminate symptoms for months or years after the co-clustering of antigen with inhibitory Fc receptors as desensitization course is complete. described above. Regardless of mechanism, hyposensitization 500 PA R T V I | The Immune System in Health and Disease Hyposensitization (immunotherapy) Allergens Sheep wool Dog Horse Cat Histamine Feather APC Naïve CD4+ T cell Daisy Alternaria Birch Grass pollen (mould) TGF-β Plane Negative pollen pollen IL-10 pollen control FoxP3 FIGURE 15-8 Skin testing for hypersensitivity. This photo- graph shows an example of a skin test for a variety of antigens. These TREG cell were introduced by superficial injection and read after 30 minutes. The positive control for a response is histamine; the negative control Desensitization Tolerance Increased IgG4 Increased FoxP3+ TREGs is typically just saline. This individual is clearly atopic; the skin test re- Decreased IgE Increased IFN-γ, IL-10, TNF-α veals responses to multiple animal and plant allergens. [Southern Illinois Decreased basophil reactivity University/Getty Images] Decreased mast cell reactivity FIGURE 15-9 Mechanisms underlying hyposensitization results in a reduction of allergen-specific TH2 cells, and a treatment for type I allergy. This figure illustrates two major concomitant decrease in eosinophils, basophils, mast cells, mechanisms that are likely to contribute to successful hyposensiti- and neutrophils in the target organs. zation treatment (immunotherapy). Repeated injection or inges- Although often strikingly successful, hyposensitization tion of low doses of antigen may lead to immune tolerance via the does not work in every individual for every allergen. Patients induction of regulatory T cells that quell the immune response to the whose disease is refractory to hyposensitization, or who allergen. Alternatively or in addition, it may induce the generation of choose not to use it, can try other therapeutic strategies that IgG antibodies (specifically IgG4), which either compete with IgE for have taken advantage of our growing knowledge of mecha- binding to antigen or induce co-clustering of Fc␧RI with inhibitory nisms behind mast cell degranulation and the activity of Fc␥RII receptors (see chapter text). This inhibits basophil and mast cell hypersensitivity mediators. activity, reducing symptoms (desensitization). [A. M. Scurlock, B. P. Vick- ery, J. O’B. Hourihane, and A. W. Burks, 2010, Pediatric food allergy and mucosal Antihistamines, Leukotriene Antagonists, tolerance, Mucosal Immunology 3(4):345–354, www.nature.com/mi/journal/ and Inhalation Corticosteroids v3/n4/fig_tab/mi201021f1.html.] For many years now, antihistamines have been the most useful drugs for the treatment of allergic rhinitis. These drugs inhibit histamine activity by binding and blocking parable in effectiveness to antihistamines. Finally, inhalation histamine receptors on target cells. The H1 receptors are therapy with low-dose corticosteroids reduces inflammation blocked by the first-generation antihistamines such as by inhibiting innate immune cell activity and has been used diphenhydramine and chlorpheniramine, which are quite successfully to reduce frequency and severity of asthma effective in controlling the symptoms of allergic rhinitis. attacks. Unfortunately, since they are capable of crossing the blood-brain barrier, they also act on H1 receptors in the Immunotherapeutics nervous system and have multiple side effects. Because Therapeutic anti-IgE antibodies have been developed; one these first-generation drugs bind to muscarinic acetylcho- such antibody, omalizumab, has been approved by the FDA line receptors, they can also induce dry mouth, urinary and is available as a pharmacological agent. Omalizumab retention, constipation, slow heartbeat, and se