Effector mechanisms in allergic reactions (2024)

12-5. Most IgE is cell-bound and engages effector mechanisms of the immune systemby different pathways from other antibody isotypes

Most antibodies are found in body fluids and engage effector cells, throughreceptors specific for the Fc constant regions, only after binding specificantigen through the antibody variable regions. IgE, however, is an exception asit is captured by the high-affinity Fcε receptor in the absence of boundantigen. This means that IgE is mostly found fixed in the tissues on mast cellsthat bear this receptor, as well as on circulating basophils and activatedeosinophils. The ligation of cell-bound IgE antibody by specific antigentriggers activation of these cells at the site of antigen entry into thetissues. The release of inflammatory lipid mediators, cytokines, and chemokinesat sites of IgE-triggered reactions results in the recruitment of eosinophilsand basophils to augment the type I response.

There are two types of IgE-binding Fc receptor. The first, FcεRI, is ahigh-affinity receptor of the immunoglobulin superfamily that binds IgE on mastcells, basophils, and activated eosinophils (see Section 9-22). When the cell-bound IgE antibody iscross-linked by a specific antigen, FcεRI transduces an activating signal. Highlevels of IgE, such as those that exist in subjects with allergic diseases orparasite infections, can result in a marked increase in FcεRI on the surface ofmast cells, enhanced sensitivity of such cells to activation by lowconcentrations of specific antigen, and markedly increased IgE-dependent releaseof chemical mediators and cytokines.

The second IgE receptor, FcεRII, usually known as CD23, is a C-type lectin and is structurally unrelated toFcεRI; it binds IgE with low affinity. CD23 is present on many different celltypes, including B cells, activated T cells, monocytes, eosinophils, platelets,follicular dendritic cells, and some thymic epithelial cells. This receptor wasthought to be crucial for the regulation of IgE antibody levels; however,knockout mouse strains lacking the CD23 gene show no major abnormality in thedevelopment of polyclonal IgE responses. However the CD23 knockout mice havedemonstrated a role for CD23 in enhancing the antibody response to a specificantigen in the presence of that same antigen complexed with IgE. Thisantigen-specific, IgE-mediated enhancement of antibody responses fails to occurin mice lacking the CD23 gene. This demonstrates a role for CD23 onantigen-presenting cells in the capture of antigen by specific IgE.

12-6. Mast cells reside in tissues and orchestrate allergic reactions

Mast cells were described by Ehrlich in the mesentery of rabbits and namedMastzellen (‘fattened cells’). Like basophils, mast cellscontain granules rich in acidic proteoglycans that take up basic dyes. However,in spite of this resemblance, and the similar range of mediators stored in thesebasophilic granules, mast cells are derived from a different myeloid lineagethan basophils and eosinophils. Mast cells are highly specialized cells, and areprominent residents of mucosal and epithelial tissues in the vicinity of smallblood vessels and postcapillary venules, where they are well placed to guardagainst invading pathogens (see Sections9-20 and 9-21). Mast cellsare also found in subendothelial connective tissue. They home to tissues asagranular cells; their final differentiation, accompanied by granule formation,occurs after they have arrived in the tissues. The major growth factor for mastcells is stem-cell factor (SCF), which acts on the cell-surface receptor c-Kit(see Section 7-2). Mice with defectivec-Kit lack differentiated mast cells and cannot make IgE-mediated inflammatoryresponses. This shows that such responses depend almost exclusively on mastcells.

Mast cells express FcεRI constitutively on their surface and are activated whenantigens cross-link IgE bound to these receptors (see Fig. 9.35). Degranulation occurs within seconds,releasing a variety of preformed inflammatory mediators (Fig. 12.10). Among these are histamine—a short-lived vasoactive amine that causes animmediate increase in local blood flow and vessel permeability—and enzymes suchas mast-cell chymase, tryptase, and serine esterases. These enzymes can in turnactivate matrix metalloproteinases, which break down tissue matrix proteins,causing tissue destruction. Large amounts of tumor necrosis factor (TNF)-α arealso released by mast cells after activation. Some comes from stores inmast-cell granules; some is newly synthesized by the activated mast cellsthemselves. TNF-α activates endothelial cells, causing increased expression ofadhesion molecules, which promotes the influx of inflammatory leukocytes andlymphocytes into tissues (see Section2-22).

On activation, mast cells synthesize and release chemokines, lipid mediators suchas leukotrienes and platelet-activating factor (PAF), and additional cytokinessuch as IL-4 and IL-13 which perpetuate the T_H2 response. Thesemediators contribute to both the acute and the chronic inflammatory responses.The lipid mediators, in particular, act rapidly to cause smooth musclecontraction, increased vascular permeability, and mucus secretion, and alsoinduce the influx and activation of leukocytes, which contribute to thelate-phase response. The lipid mediators derive from membrane phospholipids,which are cleaved to release the precursor molecule arachidonic acid. Thismolecule can be modified by two pathways to give rise to prostaglandins,thromboxanes, and leukotrienes. The leukotrienes, especially C4, D4, and E4, areimportant in sustaining inflammatory responses in the tissues. Manyanti-inflammatory drugs are inhibitors of arachidonic acid metabolism. Aspirin,for example, is an inhibitor of the enzyme cyclooxygenase and blocks theproduction of prostaglandins.

IgE-mediated activation of mast cells thus orchestrates an important inflammatorycascade that is amplified by the recruitment of eosinophils, basophils, andT_H2 lymphocytes. The physiological importance of this reaction isas a defense mechanism against certain types of infection (see Section 9-23). In allergy, however, theacute and chronic inflammatory reactions triggered by mast-cell activation haveimportant pathophysiological consequences, as seen in the diseases associatedwith allergic responses to environmental antigens.

12-7. Eosinophils are normally under tight control to prevent inappropriate toxicresponses

Eosinophils are granulocytic leukocytes that originate in bone marrow. They areso called because their granules, which contain arginine-rich basic proteins,are colored bright orange by the acidic stain eosin (Fig. 12.11). Only very small numbers of these cells arenormally present in the circulation; most eosinophils are found in tissues,especially in the connective tissue immediately underneath respiratory, gut, andurogenital epithelium, implying a likely role for these cells in defense againstinvading organisms. Eosinophils have two kinds of effector function. First, onactivation they release highly toxic granule proteins and free radicals, whichcan kill microorganisms and parasites but can also cause significant tissuedamage in allergic reactions. Second, activation induces the synthesis ofchemical mediators such as prostaglandins, leukotrienes, and cytokines, whichamplify the inflammatory response by activating epithelial cells, and recruitingand activating more eosinophils and leukocytes (Fig. 12.12).

The activation and degranulation of eosinophils is strictly regulated, as theirinappropriate activation would be very harmful to the host. The first level ofcontrol acts on the production of eosinophils by the bone marrow. Feweosinophils are produced in the absence of infection or other immunestimulation. But when T_H2 cells are activated, cytokines such as IL-5are released that increase the production of eosinophils in the bone marrow andtheir release into the circulation. However, transgenic animals overexpressingIL-5 have increased numbers of eosinophils (eosinophilia) in thecirculation but not in their tissues, indicating that migration of eosinophilsfrom the circulation into tissues is regulated separately, by a second set ofcontrols. The key molecules in this case are CC chemokines (see Section 2-20). Most of these causechemotaxis of several types of leukocyte, but two are specific for eosinophilsand have been named eotaxin 1 and eotaxin 2.

The eotaxin receptor on eosinophils, CCR3, is a member of the chemokine family ofreceptors (see Section 6-16). Thisreceptor also binds the CC chemokines MCP-3, MCP-4, and RANTES, which alsoinduce eosinophil chemotaxis. The eotaxins and these other CC chemokines alsoactivate eosinophils. Identical or similar chemokines also stimulate mast cellsand basophils. For example, eotaxin attracts basophils and causes theirdegranulation, and MCP-1, which binds to CCR2, similarly activates mast cells inboth the presence or absence of antigen. MCP-1 can also promote thedifferentiation of naive T_H0 cells to T_H2 cells;T_H2 cells also carry CCR3 and migrate toward eotaxin. Thesefindings show that families of chemokines, as well as cytokines, can coordinatecertain kinds of immune response.

A third set of controls regulates the state of eosinophil activation. In theirnonactivated state, eosinophils do not express high-affinity IgE receptors andhave a high threshold for release of their granule contents. After activation bycytokines and chemokines, this threshold drops, FcεRI is expressed, and thenumber of Fcγ receptors and complement receptors on the cell surface alsoincreases. The eosinophil is now primed to carry out its effector activity, forexample degranulation in response to antigen that cross-links specific IgE boundto FcεRI on the eosinophil surface.

The potential of eosinophils to cause tissue injury is illustrated by raresyndromes due to abnormally large numbers of eosinophils in the blood (hypereosinophilia). These syndromesare sometimes seen in association with T-cell lymphomas, in which unregulatedIL-5 secretion drives a marked increase in the numbers of circulatingeosinophils. The clinical manifestations of hypereosinophilia are damage to theendocardium (Fig. 12.13) and to nerves,leading to heart failure and neuropathy, both thought to be caused by the toxiceffects of eosinophil granule proteins.

12-8. Eosinophils and basophils cause inflammation and tissue damage in allergicreactions

In a local allergic reaction, mast-cell degranulation and T_H2activation cause eosinophils to accumulate in large numbers and to becomeactivated. Their continued presence is characteristic of chronic allergicinflammation and they are thought to be major contributors to tissue damage.

Basophils are also present at the site of an inflammatory reaction. Basophilsshare a common stem-cell precursor with eosinophils; growth factors forbasophils are very similar to those for eosinophils and include IL-3, IL-5, andGM-CSF. There is evidence for reciprocal control of the maturation of thestem-cell population into basophils or eosinophils. For example, transforminggrowth factor (TGF)-β in the presence of IL-3 suppresses eosinophildifferentiation and enhances that of basophils. Basophils are normally presentin very low numbers in the circulation and seem to have a similar role toeosinophils in defense against pathogens. Like eosinophils, they are recruitedto the sites of allergic reactions. Basophils express FcεRI on the cell surfaceand, on activation by cytokines or antigen, they release histamine and IL-4 fromthe basophilic granules after which they are named.

Eosinophils, mast cells, and basophils can interact with each other. Eosinophildegranulation releases major basicprotein, which in turn causes degranulation of mast cells andbasophils. This effect is augmented by any of the cytokines that affecteosinophil and basophil growth, differentiation, and activation, such as IL-3,IL-5, and GM-CSF.

12-9. An allergic reaction is divided into an immediate response and a late-phaseresponse

The inflammatory response after IgE-mediated mast-cell activation occurs as animmediate reaction, starting within seconds, and a late reaction, which takes upto 8–12 hours to develop. These reactions can be distinguished clinically (Fig. 12.14). The immediate reaction is due to the activity of histamine,prostaglandins, and other preformed or rapidly synthesized mediators that causea rapid increase in vascular permeability and the contraction of smooth muscle.The late-phase reaction is causedby the induced synthesis and release of mediators including leukotrienes,chemokines, and cytokines from the activated mast cells (see Fig. 12.10). These recruit otherleukocytes, including eosinophils and T_H2 lymphocytes, to the site ofinflammation. Although the late-phase reaction is clinically less marked thanthe immediate response, it is associated with a second phase of smooth musclecontraction, sustained edema, and the development of one of the cardinalfeatures of allergic asthma: airway hyperreactivity to nonspecificbronchoconstrictor stimuli such as histamine and methacholine.

The late-phase reaction is an important cause of much serious long-term illness,as for example in chronic asthma. This is because the late reaction induces therecruitment of inflammatory leukocytes, especially eosinophils andT_H2 lymphocytes, to the site of the allergen-triggered mast-cellresponse. This late response can easily convert into a chronic inflammatoryresponse if antigen persists and stimulates allergen-specific T_H2cells, which in turn promote eosinophilia and further IgE production.

12-10. The clinical effects of allergic reactions vary according to the site ofmast-cell activation

When reexposure to allergen triggers an allergic reaction, the effects arefocused on the site at which mast-cell degranulation occurs. In the immediateresponse, the preformed mediators released are short-lived, and their potenteffects on blood vessels and smooth muscles are therefore confined to thevicinity of the activated mast cell. The more sustained effects of thelate-phase response are also focused on the site of initial allergen-triggeredactivation, and the particular anatomy of this site may determine how readilythe inflammation can be resolved. Thus, the clinical syndrome produced by anallergic reaction depends critically on three variables: the amount ofallergen-specific IgE present; the route by which the allergen is introduced;and the dose of allergen (Fig.12.15).

If an allergen is introduced directly into the bloodstream or is rapidly absorbedfrom the gut, the connective tissue mast cells associated with all blood vesselscan become activated. This activation causes a very dangerous syndrome calledsystemic anaphylaxis (Acute Systemic Anaphylaxis, inCase Studies in Immunology, see Preface for details).Disseminated mast-cell activation has a variety of potentially fatal effects:the widespread increase in vascular permeability leads to a catastrophic loss ofblood pressure; airways constrict, causing difficulty in breathing; and swellingof the epiglottis can cause suffocation. This potentially fatal syndrome iscalled anaphylactic shock. It canoccur if drugs are administered to people who have IgE specific for that drug,or after an insect bite in individuals allergic to insect venom. Some foods, forexample peanuts or brazil nuts, can cause systemic anaphylaxis in susceptibleindividuals. This syndrome can be rapidly fatal but can usually be controlled bythe immediate injection of epinephrine, which relaxes the smooth muscle andinhibits the cardiovascular effects of anaphylaxis.

The most frequent allergic reactions to drugs occur with penicillin and itsrelatives. In people with IgE antibodies against penicillin, administration ofthe drug by injection can cause anaphylaxis and even death. Great care should betaken to avoid giving a drug to patients with a past history of allergy to thatdrug or one that is closely related structurally. Penicillin acts as a hapten(see Section 9-2); it is a smallmolecule with a highly reactive β-lactam ring that is crucial for itsantibacterial activity. This ring reacts with amino groups on host proteins toform covalent conjugates. When penicillin is ingested or injected, it formsconjugates with self proteins, and the penicillin-modified self peptides canprovoke a T_H2 response in some individuals. These T_H2cells then activate penicillin-binding B cells to produce IgE antibody to thepenicillin hapten. Thus, penicillin acts both as the B-cell antigen and, bymodifying self peptides, as the T-cell antigen. When penicillin is injectedintravenously into an allergic individual, the penicillin-modified proteins cancross-link IgE molecules on the mast cells and cause anaphylaxis.

12-11. Allergen inhalation is associated with the development of rhinitis andasthma

Inhalation is the most common route of allergen entry. Many people have mildallergies to inhaled antigens, manifesting as sneezing and a runny nose. This iscalled allergic rhinitis, andresults from the activation of mucosal mast cells beneath the nasal epitheliumby allergens such as pollens that release their protein contents, which can thendiffuse across the mucus membranes of the nasal passages. Allergic rhinitis ischaracterized by intense itching and sneezing, local edema leading to blockednasal passages, a nasal discharge, which is typically rich in eosinophils, andirritation of the nose as a result of histamine release. A similar reaction toairborne allergens deposited on the conjunctiva of the eye is called allergic conjunctivitis. Allergicrhinitis and conjunctivitis are commonly caused by environmental allergens thatare only present during certain seasons of the year. For example, hay fever iscaused by a variety of allergens, including certain grass and tree pollens.Autumnal symptoms may be caused by weed pollen, such as that of ragweed. Thesereactions are annoying but cause little lasting damage.

A more serious syndrome is allergicasthma, which is triggered by allergen-induced activation ofsubmucosal mast cells in the lower airways (Fig. 12.16). This leads within seconds to bronchial constriction andincreased secretion of fluid and mucus, making breathing more difficult bytrapping inhaled air in the lungs. Patients with allergic asthma often needtreatment, and asthmatic attacks can be life-threatening. An important featureof asthma is chronic inflammation of the airways, which is characterized by thecontinued presence of increased numbers of T_H2 lymphocytes,eosinophils, neutrophils, and other leukocytes (Fig. 12.17).

Although allergic asthma is initially driven by a response to a specificallergen, the subsequent chronic inflammation seems to be perpetuated even inthe apparent absence of further exposure to allergen. The airways becomecharacteristically hyperreactive and factors other than reexposure to antigencan trigger asthma attacks. For example, the airways of asthmaticscharacteristically show hyperresponsiveness to environmental chemical irritantssuch as cigarette smoke and sulfur dioxide; viral or, to a lesser extent,bacterial respiratory tract infections can exacerbate the disease by inducing aT_H2-dominated local response.

12-12. Skin allergy is manifest as urticaria or chronic eczema

The same dichotomy between immediate and delayed responses is seen in cutaneousallergic responses. The skin forms an effective barrier to the entry of mostallergens but it can be breached by local injection of small amounts ofallergen, for example by a stinging insect. The entry of allergen into theepidermis or dermis causes a localized allergic reaction. Local mast-cellactivation in the skin leads immediately to a local increase in vascularpermeability, which causes extravasation of fluid and swelling. Mast-cellactivation also stimulates the release of chemicals from local nerve endings bya nerve axon reflex, causing the vasodilation of surrounding cutaneous bloodvessels, which causes redness of the surrounding skin. The resulting skin lesionis called a wheal-and-flarereaction. About 8 hours later, a more widespread and sustainededematous response appears in some individuals as a consequence of thelate-phase response (see Fig. 12.14). Adisseminated form of the wheal-and-flare reaction, known as urticaria or hives, sometimes appearswhen ingested allergens enter the bloodstream and reach the skin. Histaminereleased by mast cells activated by allergen in the skin causes large, itchy,red swellings of the skin.

Allergists take advantage of the immediate response to test for allergy byinjecting minute amounts of potential allergens into the epidermal layer of theskin. Although the reaction after the administration of antigen byintraepidermal injection is usually very localized, there is a small risk ofinducing systemic anaphylaxis. Another standard test for allergy is to measurelevels of IgE antibody specific for a particular allergen in a sandwich ELISA(see Appendix I, Section A-6).

Although acute urticaria is commonly caused by allergens, the causes of chronicurticaria, in which the urticarial rash can recur over long periods, are lesswell understood. In up to a third of cases, it seems likely that chronicurticaria is an autoimmune disease caused by autoantibodies against the α chainof FcεRI. This is an example of a type II hypersensitivity reaction in which anautoantibody against a cellular receptor triggers cellular activation, in thiscase causing mast-cell degranulation with resulting urticaria.

A more prolonged inflammatory response is sometimes seen in the skin, most oftenin atopic children. They develop a persistent skin rash called eczema or atopic dermatitis (Atopic Dermatitis, inCase Studies in Immunology, see Preface for details), due to achronic inflammatory response similar to that seen in the bronchial walls ofpatients with asthma. The etiology of eczema is not well understood.T_H2 cells and IgE are involved, and it usually clears inadolescence, unlike rhinitis and asthma, which can persist throughout life.

12-13. Allergy to foods causes symptoms limited to the gut and systemicreactions

When an allergen is eaten, two types of allergic response are seen. Activation ofmucosal mast cells associated with the gastrointestinal tract leads totransepithelial fluid loss and smooth muscle contraction, causing diarrhea andvomiting. For reasons that are not understood, connective tissue mast cells inthe dermis and subcutaneous tissues can also be activated after ingestion ofallergen, presumably by allergen that has been absorbed into the bloodstream,and this results in urticaria. Urticaria is a common reaction when penicillin isgiven orally to a patient who already has penicillin-specific IgE antibodies.Ingestion of food allergens can also lead to the development of generalizedanaphylaxis, accompanied by cardiovascular collapse and acute asthmaticsymptoms. Certain foods, most importantly peanuts, tree nuts, and shellfish, areparticularly associated with this type of life-threatening response.

12-14. Allergy can be treated by inhibiting either IgE production or the effectorpathways activated by cross-linking of cell-surface IgE

The approaches to the treatment and prevention of allergy are set out in Fig. 12.18. Two treatments are commonlyused in clinical practice—one is desensitization and the other is blockade ofthe effector pathways. There are also several approaches still in theexperimental stage. In desensitization the aim is to shift the antibody response away fromone dominated by IgE toward one dominated by IgG; the latter can bind to theallergen and thus prevent it from activating IgE-mediated effector pathways.Patients are injected with escalating doses of allergen, starting with tinyamounts. This injection schedule gradually diverts the IgE-dominated response,driven by T_H2 cells, to one driven by T_H1 cells, with theconsequent downregulation of IgE production. Recent evidence shows thatdesensitization is also associated with a reduction in the numbers of late-phaseinflammatory cells at the site of the allergic reaction. A potentialcomplication of the desensitization approach is the risk of inducingIgE-mediated allergic responses.

An alternative, and still experimental, approach to desensitization isvaccination with peptides derived from common allergens. This procedure inducesT-cell anergy (see Section 8-11), whichis associated with multiple changes in the T-cell phenotype, includingdownregulation of cytokine production and reduced expression of the CD3:T-cellreceptor complex. IgE-mediated responses are not induced by the peptides becauseIgE, in contrast to T cells, can only recognize the intact antigen. A majordifficulty with this approach is that an individual's responses to peptides arerestricted by their MHC class II alleles (see Section 5-12); therefore, patients with different MHC class IImolecules respond to different allergen-derived peptides. As the humanpopulation is outbred and expresses a wide variety of MHC class II alleles, thenumber of peptides required to treat all allergic individuals might be verylarge.

Another vaccination strategy that shows promise in experimental models of allergyis the use of oligodeoxynucleotides rich in unmethylated cytosine guaninedinucleotides (CpG) as adjuvants (see Section14-19) for desensitization regimes. These oligonucleotides mimicbacterial DNA sequences known as CpG motifs and strongly promote T_H1responses. Their mechanism of action is discussed in Sections 14-19 and 8-6 and Appendix I, SectionA-4.

The signaling pathways that enhance the IgE response in allergic disease are alsopotential targets for therapy. Inhibitors of IL-4, IL-5, and IL-13 would bepredicted to reduce IgE responses, but redundancy between some of the activitiesof these cytokines might make this approach difficult to implement in practice.A second approach to manipulating the response is to give cytokines that promoteT_H1-type responses. IFN-γ, IFN-α, IL-10, IL-12, and TGF-β haveeach been shown to reduce IL-4-stimulated IgE synthesis invitro, and IFN-γ and IFN-α have been shown to reduce IgE synthesisin vivo.

Another target for therapeutic intervention might be the high-affinity IgEreceptor. An effective competitor for IgE at this receptor could prevent thebinding of IgE to the surfaces of mast cells, basophils, and eosinophils.Candidate competitors include humanized anti-IgE monoclonal antibodies, whichbind to IgE and block its binding to the receptor, and modified IgE Fcconstructs that bind to the receptor but lack variable regions and thus cannotbind antigen. Yet another approach would be to block the recruitment ofeosinophils to sites of allergic inflammation. The eotaxin receptor CCR3 is apotential target for this type of therapy. The production of eosinophils in bonemarrow and their exit into the circulation might also be reduced by a blockadeof IL-5 action.

The mainstays of therapy at present, however, are drugs that treat the symptomsof allergic disease and limit the inflammatory response. Anaphylactic reactionsare treated with epinephrine, which stimulates the reformation of endothelialtight junctions, promotes the relaxation of constricted bronchial smooth muscle,and also stimulates the heart. Inhaled bronchodilators that act on β-adrenergicreceptors to relax constricted muscle are also used to relieve acute asthmaattacks. Antihistamines that block the histamine H₁ receptor reducethe urticaria that follows histamine release from mast cells and eosinophils.Relevant H₁ receptors include those on blood vessels that causeincreased permeability of the vessel wall, and those on unmyelinated nervefibers that are thought to mediate the itching sensation. In chronic allergicdisease it is extremely important to treat and prevent the chronic inflammatorytissue injury. Topical or systemic corticosteroids (see Section 14-1) are used to suppress the chronicinflammatory changes seen in asthma, rhinitis, and eczema. However, what isreally needed is a means of converting the T-cell response to the allergenicpeptide antigen from predominantly T_H2 to predominantlyT_H1. This topic is also discussed in Chapter 14.

Summary

The allergic response to innocuous antigens reflects the pathophysiologicalaspects of a defensive immune response whose physiological role is to protectagainst helminthic parasites. It is triggered by antigen binding to IgEantibodies bound to the high-affinity IgE receptor FcεRI on mast cells. Mastcells are strategically distributed beneath the mucosal surfaces of the body andin connective tissue. Antigen cross-linking the IgE on their surface causes themto release large amounts of inflammatory mediators. The resulting inflammationcan be divided into early events, characterized by short-lived mediators such ashistamine, and later events that involve leukotrienes, cytokines, andchemokines, which recruit and activate eosinophils and basophils. The late phaseof this response can evolve into chronic inflammation, characterized by thepresence of effector T cells and eosinophils, which is most clearly seen inchronic allergic asthma.