ACP medicine, 3rd Edition


Allergic Response

Pamela J. Daffern M.D.1

Lawrence B. Schwartz M.D., PH.D.2

1Assistant Professor of Internal Medicine, Division of Reumatology, Allergy, and Immunology, Medical College of Virginia at Virginia Commonwealth University

2Professor of Internal Medicine, Division of Rheumatology, Allergy, and Immunology, Medical College of Virginia at the Virginia Commonwealth University

Pamela J. Daffern, M.D., has no commercial relationships with manufacturers of products or providers of services discussed in this subsection.

Lawrence B. Schwartz, M.D., Ph.D., has a licensing agreement with the Pharmacia Corporation for a tryptase assay kit.

February 2003

Definition of Allergic Response

The word anaphylaxis was coined in 1902 by Charles Richet, in order to contrast the condition with prophylaxis. Richet described anaphylaxis as “the peculiar attribute which certain poisons possess of increasing instead of diminishing the sensitivity of an organism to their action.…”1 One hundred years later, we understand anaphylaxis as the extreme of a spectrum of events mediated by immunoglobulin E (IgE). Persons with IgE-mediated disorders have a genetic propensity to form IgE antibodies against otherwise innocuous environmental antigens (allergens); this propensity is termed atopy (from the Greek atopos, meaning “out of place”). In atopic persons, IgE mediates a wide range of reactions, including dermatitis, rhinitis, asthma, urticaria, angioedema, and anaphylaxis.

Confusion arises over the misapplication of the term allergy to describe any untoward reaction to food or medications or to perceived environmental exposures. This confusion is further complicated by the fact that both IgE-mediated and non-IgE-mediated forms of rhinitis, asthma, and atopic dermatitis occur, often in the same person.

In the nonatopic person, exposure to allergen results in immunologic tolerance or neglect, whereas in atopic persons, exposure results in sensitization. On reexposure to the allergen, atopic persons mount an immunologically mediated inflammatory response in the target organ. Other environmental factors—such as tobacco smoke, air pollution, respiratory virus infection, and lack of exposure to certain microbes in childhood—may also promote an allergic inflammatory response.

Epidemiology of Atopic Disorders

Up to 30% of the United States population may be affected by allergic rhinoconjunctivitis, asthma, or atopic dermatitis. This high incidence of atopic disease may reflect societal factors. Fetal development takes place in an intrauterine environment that favors atopic sensitization2; the maternal immune system suppresses cell-mediated immune responses in order to prevent rejection of the fetus. Thus, the neonate may enter the world with T cells that are already primed by common environmental and food allergens that have crossed the placenta. It has been proposed that microbial exposure and infections during infancy shift the immune response away from the allergic pattern to a protective immune response.3 Specifically, after macrophages or dendritic cells ingest microbes, T cells produce cytokines that promote non-IgE responses by B cells. Therefore, the increasing prevalence of atopic disorders in countries that have adopted a Western lifestyle, including overuse of antibiotics, has been attributed to a lack of microbial antigen stimulation.

Humoral and Cellular Mechanisms of Allergic Inflammation Associated with Immediate Hypersensitivity


All persons encounter environmental antigens that are capable of inducing an allergic response. Soluble antigens, such as allergens, undergo endocytosis by professional antigen-presenting cells (APCs), which include dendritic cells, such as epidermal Langerhans cells; macrophages; and B cells.4 However, only dendritic cells and Langerhans cells are able to prime naive T cells and thus are responsible for the sensitization phase.5,6 Once primary sensitization has been achieved, monocytes and B cells amplify the process. B cells bind allergen through immunoglobulin receptors specific for the allergen, as opposed to nonspecific endocytic pathways used by other APCs. The internalization of antigen results in two processes. The first is general activation of the APC: this includes upregulation of major histocompatibility complex (MHC) and accessory molecules. The second process is fusion of the endocytic vesicle with lysosomes, which results in the formation of specialized antigen-processing vesicles in which antigens are hydrolyzed into protein fragments. The linear peptides that result are incorporated into the antigen-binding groove of a class II human lymphocyte antigen (HLA) molecule during its transport to the cell surface.

In general, APCs will co-express a heterogeneous assortment of allergen-derived peptides and HLA class II molecules on their surface. The efficiency with which processed allergen peptides bind to the HLA class II molecules presumably depends on variations in the HLA loci; these variations are genetically determined. The binding efficiency in turn influences the predisposition of the person to develop allergy to or tolerance of a particular antigen. The APC loaded with processed antigen/HLA class II complexes presents this complex to CD4+,CD8- helper T cells. The genetically determined binding efficiency of an HLA-derived molecule to an antigen also may influence how T cells develop when exposed to that complex.7 In addition, the quantity of interleukin-12 (IL-12) produced by APCs also influences the type of T cell response.5


The helper T cell response is influenced not only by APCs but also by the age of the person and by the amount, type, duration, and route of allergen exposure.7,8 Also, the cytokine milieu during lymphocyte differentiation determines the type of effector function of the helper T cell [see Table 1].

Table 1 Cytokines Involved in IgE-Mediated Allergic Inflammation





TH2 cells,* mast cells, basophils, eosinophils

Promotes granulocyte and macropage maturation; eosinophil activation and survival


TH2 cells,* mast cells, basophils

Promotes differentiation of TH0 to TH2 cells; antagonizes differentiation of TH0 to TH1 cells; IgE isotype switching


TH2 cells,* mast cells, eosinophils

Promotes eosinophil development, activation, and survival


TH2 cells,* mast cells, basophils

IgE isotype switching, eosinophil activation


TH2 cells and activated macrophages,* endothelial and epithelial cells

Promotes granulocyte and macrophage maturation, eosinophil activation, and survival


Monocytes/macrophages,* mast cells

Promotes chemotaxis and activation of leukocytes and vascular endothelium

*Major source.
GM-CSF—granulocyte-macrophage colony-stimulating factor IL—interleukin TNF—tumor necrosis factor

For example, bacterial DNA sequences have immunostimulatory regions containing deoxycytidine-phosphate-deoxyguanosine (CpG) repeats. CpG repeats are recognized as foreign by pattern recognition receptors called Toll-like receptor-9 (TLR-9) on APCs.9,10 These CpG repeats stimulate macrophages and dendritic cells to secrete inflammatory cytokines, including IL-12 and IL-18. These cytokines then induce T cells and natural killer (NK) cells to produce interferon gamma (IFN-γ), a cytokine known to promote nonallergic, protective responses. This pattern of response by helper T cells is termed a TH1 response, because it is associated with differentiation of naive helper T (TH0) cells into mature TH1 cells. Similarly, the helper T cells of persons without atopy respond to presentation of potentially allergenic peptides by ignoring them or by producing IFN-γ and directing the production of allergen-specific IgG1 and IgG4 antibodies.11

In contrast, helper T cells of atopic persons respond to processed aeroallergens by forming IL-4, IL-5, and IL-13 and by directing the production of allergen-specific IgE antibodies. This type of helper T cell response is termed a TH2 response. IL-4 and IL-13 share a number of functions, because both cytokines signal through the IL-4Rα/IL-13Rα heterodimer.12 However, only IL-4 is able to induce the differentiation of TH0 cells to TH2 cells and to antagonize the differentiation of TH0 cells to TH1 cells, resulting in IgE-mediated allergic inflammation. In contrast, both IL-12 and IFN-γ induce the differentiation to TH1 cells; TH2 cell differentiation is inhibited by IFN-γ. Differentiation to TH1 cells results in cell-mediated immunity and inflammation.13 Therefore, the differentiation of TH0 cells to either TH1cells or TH2 cells appears to be the crucial event that determines which type of immune response will follow.


Research has begun to identify specific genetic variants that contribute to the development of the atopic state. For example, a mutation of the IL-12R beta2-chain gene has recently been shown to impair signaling through IL-12. Because IL-12 is a potent inducer of IFN-γ production and because IFN-γ downregulates IgE production (see above), this mutation results in increased IgE production in atopic persons.14 Polymorphisms in the gene for STAT-6, a transcription factor selectively regulated by IL-4 and IL-13 (cytokines that upregulate IgE production), have also been described.15 These genetic variations in STAT-6 also appear to be associated with a predisposition to atopy. Finally, an asthma gene (ADAM-33) associated with bronchial hyperresponsiveness but not atopy was recently defined by genetic-linkage analysis of affected sibling pairs. The ADAM-33 gene product, a membrane metalloprotease, may function to modulate the response to cytokines in the lung by solubilizing cytokine membrane receptors, but its precise role still needs to be determined.16 Like other allergies, however, asthma involves environmental factors. For example, the predisposition to asthma is modified by the presence of allergens and endotoxins.17


Once allergen is processed by APCs and presented to TH2 cells, a specific sequence of events must follow for IgE production by B cells to occur [see Figure 1]. The switch from IgM or IgG production to IgE production by B cells occurs in the genome and requires two signals.18The first signal is delivered through the IL-4Rα chain by either IL-4 or IL-13.12 Signaling through these cytokine receptors initiates transcription from the germline promoter site of the constant portion of the heavy chain of IgE. The IgE heavy-chain gene is located downstream of the IgG and IgM heavy-chain genes and replaces IgG or IgM on the immunoglobulin molecule. The second signal is delivered through activation of the cluster differentiation 40 (CD40) receptor on B cells.19 Signaling through CD40 activates the recombinases necessary to remove the upstream IgG or IgM heavy-chain constant region and replace it with the corresponding region of IgE. This process switches the type of antibody being produced without altering its antigenic specificity. Stimulation of B cells through CD40 also stimulates growth, differentiation, and survival of these cells.20


Figure 1. Inflammatory Mechanisms in Allergic Inflammation

Antigen is taken up by antigen-presenting cells (APCs), processed, and then presented to CD4+ helper T cells (TH). The strength of interactions between APCs and helper T cells and the quantity of antigen present determine the type of T cell response. Production of interferon gamma (IFN-γ) during TH1 responses downregulates TH2 responses, whereas interleukin-4 (IL-4) production by TH2 inhibits TH1 responses. IL-4 is also critical for switching B cell antibody production to IgE. Signaling through cluster differentiation 40 (CD40) on the B cell is also required for IgE production. Other TH2 cytokines, such as IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) lead to eosinophil (Eos) and basophil (Baso) production and activation. IgE binds to high-affinity receptors on basophils and mast cells (FcεRI); cross-linking by allergen initiates mediator release. (CpG—deoxycytidine-phosphate-deoxyguanosine; LTC4—leukotriene C4; PAF—platelet-activating factor; PGD2—prostaglandin D2)

The ligand for CD40 (CD154, CD40L) is expressed not only on T cells but also on mast cells and basophils. Importantly, all of these cells also secrete IL-4, IL-13, or both, and therefore could potentially play a role in directing B cell production of IgE. However, it seems likely that T cells are responsible for initiating the switch to antigen-specific IgE production. Mast cells and basophils may then amplify deviation of immune responses toward IgE production after the primary IgE sensitization has occurred.19 It seems likely that binding to CD40 on B cells by mast cells and basophils would enhance polyclonal (i.e., not antigen-dependent or specific) IgE production by B cells, because mast cells and basophils are not dedicated APCs. IgE antibody secreted by B cells circulates briefly, having a serum half-life of 2 to 3 days, before binding to IgE receptors.


Receptors for IgE (FcεR) are expressed on various cells.21 The high-affinity receptor for IgE, FcεRI, has two forms that differ by the presence or absence of a beta chain. The beta chain is present in the high-affinity receptor found on mast cells and basophils.19 The presence of the beta chain amplifies the cellular signaling that occurs when IgE bound to FcεRI is cross-linked by allergen. Its presence also increases the amount of IgE receptor on the surfaces of mast cells and basophils by up to sixfold.22 Levels of FcεRI on the surface of basophils have been shown to correlate with serum IgE levels in various IgE-associated diseases.23,24 The high-affinity receptor lacking the beta chain is also expressed on monocytes, Langerhans cells, dendritic cells (i.e., APCs other than B cells), activated eosinophils, and epithelial cells.

The low-affinity IgE receptor, FcεRII, bears structural homology to C-type lectins, but not to FcεRI. (Lectin receptors recognize pathogens and also function as adhesion receptors and signaling molecules.) FcεRII, also known as CD23, is expressed on B and T cells, monocytes, eosinophils, and platelets.25 CD23 expression is increased by IL-4 and IL-13, and increased CD23 expression would presumably facilitate allergen uptake and presentation to T cells by APCs.26 Furthermore, B cells from allergic asthmatic patients exposed to allergen have increased CD23 expression.27 Whether allergic inflammation is initiated when IgE is bound to FcεRII is not clear. However, the solubilized form of CD23 may play a regulatory role in IgE synthesis.26,28

When a sensitized individual is exposed to allergen, the allergen binds to IgE receptors on mast cells and basophils. If multivalent, the allergen will cross-link a critical number of cell-bound IgE receptors, leading to cellular activation, secretion of mediators, and production of the symptoms characteristic of early-phase allergic responses.28

Clearly, treatment that interferes with IgE activation of mast cells and basophils may be beneficial. Omalizumab, a recombinant, humanized monoclonal antibody directed against the Fcε portion of IgE, has recently been developed.29 Important features of this anti-IgE molecule are (1) it does not bind IgE already attached to FcεRI, and therefore does not cause anaphylaxis; (2) it does not activate complement; and (3) it has a much longer half-life than IgE. In phase III trials, omalizumab was administered by subcutaneous injections given every 2 or 4 weeks to patients with allergic rhinitis or with allergic asthma of varying severity.30,31 All studies showed dramatic reductions in free IgE levels that were dependent on omalizumab dose as well as baseline IgE levels.32 As levels of serum IgE decreased, so did surface expression of FcεRI on basophils. Moreover, the posttreatment level of free IgE directly correlated with reduced symptom scores, reduced use of rescue medication, and improved quality of life. For asthma, significant reductions in asthma exacerbations, in hospitalizations for asthma, and in the dose of inhaled or oral steroids were also found. A recent phase II trial of omalizumab in peanut-sensitive children showed a decreased sensitivity to oral peanut challenges.


Eosinophils share a common origin with basophils: a single bone-marrow-derived myeloid progenitor cell has the capacity to give rise to a mixed colony of eosinophils and basophils or to pure colonies of either cell type.33 A common origin for eosinophils and basophils is further supported by the presence of Charcot-Leyden crystal (CLC) protein and major basic protein (MBP) in both cell types. Eosinophil development is uniquely dependent on the presence of IL-5, a cytokine whose chief source is the TH2 helper cell.34 Along with IL-5, other T cell cytokines—IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF)—promote maturation, activation, and prolonged survival of eosinophils.33 However, only IL-5 potently stimulates the bone marrow to produce eosinophils. In vitro, a low dose of IL-3 favors the development of basophils from progenitors, whereas a high dose of IL-3 favors the development of eosinophils. In contrast, other cytokines may inhibit the growth of eosinophil progenitors. Transforming growth factor-β (TGF-β) contributes to eosinophil apoptosis in vitro and influences progenitor development toward the basophil pathway.35 IFN-α inhibits progenitor cells in vitro and has been used for treatment of certain patients with eosinophilia refractory to treatment with prednisone.36

Eosinophils dwell primarily in tissue. Circulating eosinophils have a short half-life and represent only about 1% of the total number of eosinophils in the body. Epithelial surfaces of mucosal tissues that are exposed to the external environment are heavily inhabited by eosinophils, whereas other tissues are normally devoid of eosinophils.33 The epithelial tissues of the respiratory tract produce GM-CSF, which is capable of prolonging eosinophil survival in vitro for up to 14 days.

Cell Surface Receptors

Two overlapping populations of circulating eosinophils are thought to represent differing states of eosinophil activation.37 Nonallergic individuals have greater numbers of eosinophils of normal density and fewer numbers of low-density activated eosinophils. The reverse is true for patients with disorders leading to eosinophilia. This heterogeneity suggests that priming of eosinophils by various cytokines may lead to changes in expression of surface receptors and mediator release [see Table 2]. For example, both high-affinity receptors (FcεRI) and low-affinity receptors (FcεRII) for IgE have been found on peripheral blood eosinophils from patients with hypereosinophilic syndrome. However, eosinophils derived from normal donors or from patients with allergy fail to stain with a panel of monoclonal antibodies directed against IgE receptors.38 Similar differences have been observed for IgG receptors (FcγR) on eosinophils. Freshly isolated eosinophils express FcγRIIb, a low-affinity IgG receptor that may inhibit mediator release when cross-linked.34 Both FcγRI and FcγRIII can be induced on eosinophils in vitro when these cells are cultured with IFN-γ, which, in contrast to FcγRIIb, may result in activation. Sera from patients with hay fever contain allergen-specific IgG1 and IgG3, which cause eosinophils to degranulate in vitro in an allergen-dependent manner.39Surface receptors for IgA are also present on eosinophils and provide a potent stimulus for release of granule proteins in vitro. The presence of secretory IgA (sIgA) together with eosinophils at mucosal surfaces suggests that IgA-dependent activation also occurs in vivo.40

Table 2 Receptors on Eosinophils

IgE receptors
   FcεRI (high affinity)
   FcεRII (low affinity)
IgA receptor
Complement receptors
Lipid-mediator receptors
   Leukotriene (LT) receptors
   Platelet-activating factor (PAF)
Chemokine receptors

Receptors for complement (C3a and C5a); the lipid mediators platelet-activating factor (PAF), leukotriene C4 (LTC4), and LTB4; and numerous cytokines and chemokines bind to and activate eosinophils.33,34 Chemokines of the C-C family play an important chemotactic role for eosinophils. Chemokines of this large family have adjacent cysteine residues (C-C) and have the same receptors. A particular C-C chemokine receptor, CCR3, is found abundantly on eosinophils but not on neutrophils.41 CCR3 binds at least four chemokines that play crucial roles in the homing of eosinophils to epithelial tissues and that activate eosinophils to release mediators. Another mechanism, which leads to preferential accumulation of eosinophils rather than neutrophils at sites of allergic inflammation, relates to differences in expression of surface adhesion molecules. Eosinophils and neutrophils share several selectins and integrins that initiate the rolling of circulating cells along the endothelium, as well as the subsequent firm adhesion, diapedesis, and transmigration of these cells through the vessel wall. However, eosinophils—but not neutrophils—express an integrin, very late antigen (VLA)-4, whose ligand on endothelial cells (VCAM-1) is upregulated by IL-4 and IL-13, cytokines that are present during TH2 responses; consequently, these cytokines promote adherence of eosinophils, but not neutrophils, to endothelium.42


An array of inflammatory mediators are produced when eosinophils are activated. Preformed mediators are stored in granules and rapidly released once eosinophils are activated. Major basic protein (MBP) is the principal constituent of the granule proteins.43 Other granule proteins include eosinophil peroxidase (EPO), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP). MBP, ECP, and EPO have been shown to damage parasites in vitro; in patients with eosinophil-associated diseases, these proteins are present in high concentrations that can cause toxicity to autologous cells and tissues. Unfortunately, MBP and EPO cause ciliostasis and detachment of respiratory epithelial cells in vitro, and they may contribute to epithelial damage and inflammation in allergic respiratory disorders.43However, in one study, treatment of asthmatic patients with anti-IL-5 monoclonal antibody resulted in the selective elimination of eosinophils from the airway, but airway hyperreactivity or the airway response to inhaled allergen were not affected. This leaves open the question of the precise role that eosinophils play in the pathogenesis of atopic asthma.44 Proteases present in the eosinophils may contribute to airway damage by degrading collagen.45

Lipid mediators are rapidly generated by eosinophils after appropriate stimulation. PAF production may lead to activation of platelets, neutrophils, and smooth muscle cells, and thereby induce bronchoconstriction and amplify inflammation. The major eicosanoid product of eosinophils is LTC4, from which LTD4 and LTE4 are derived. These sulfidopeptides are extremely potent at contracting airway smooth muscle, stimulating mucus production, causing capillary leakage, and promoting chemotaxis of eosinophils.

Numerous cytokines have been identified as potential eosinophil products. Some may function in an autocrine or paracrine manner to activate or prime eosinophils. Others enhance eosinophil development and survival. In addition, eosinophils produce cytokines that regulate immune responses. However, eosinophils elaborate a considerably smaller quantity of cytokines than do lymphocytes. Therefore, the importance of the eosinophil-derived cytokines to allergic inflammation is unclear. Some cytokines that have been demonstrated in vitro have been confirmed in vivo by identifying the protein product in eosinophils infiltrating affected tissues. For example, eosinophils from nasal polyp tissue stain for TGF-β1 and could contribute to the structural pathology.46 Exposure of allergic patients to allergen revealed eosinophils in nasal mucosal tissues that stain for IL-5 protein; however, much larger contributions of IL-5 are anticipated from T cells in the same tissue.47


Microscopy of mast cells and basophils reveals intensely staining metachromatic granules [see Figure 2a and 2b]. Other common features shared by these cells include the presence of high-affinity receptors for IgE, the release of histamine after cross-linking of the FcεRI by allergen, and common intracellular signaling pathways.48 There are also numerous differences between the two cell types. Basophils generally complete their maturation in the bone marrow, circulate in the blood, and then are recruited to sites of inflammation.49 Mast cells that complete their maturation in the bone marrow appear to remain there, whereas those found in peripheral tissues develop from progenitor cells that seed these tissues. Mature mast cells in peripheral tissues may reside there for many months, retaining antigen-specific IgE for periods that exceed the lifespan of IgE in the circulation. Mast cells are strategically distributed in tissues or at mucosal surfaces that interface with the external environment; they are also in proximity to blood vessels and nerves.50


Figure 2a. Mast Cell Before Introduction of Antigen

Before introduction of antigen, a sensitized mast cell contains many osmotic granules.


Figure 2b. Mast Cell after Introduction of Antigen

(b) Sixty seconds after treatment with antigen, the peripheral granules have enlarged, neighboring granules have fused, and expulsion of granules from the mast cell has begun.

All mast cells contain tryptase in their granules; its release is characteristic of mast cell degranulation. However, several additional features further distinguish two types of mast cells [see Figure 3]. 51 Mast cells of the T type (MCT cells) are normally the predominant type of mast cell found in the mucosa of the small intestine and in the alveolar wall and epithelium of the respiratory tract. MCT cells are identified morphologically by a scroll-rich granule structure; they contain tryptase but not chymase, cathepsin G, or mast cell carboxypeptidase. The numbers of MCT cells in respiratory epithelium are increased in allergic airway inflammation, making them more accessible to inhaled allergens. In a study in asthmatics, increased mast cells predominantly of the MCTC type were localized to the airway smooth muscles but were not present in control subjects or in patients with eosinophilic bronchitis.52


Figure 3. Mediators Released by Mast Cells and Basophils

Mediators released by activated basophils and by the T type and TC type of mast cells (MCT and MCTC, respectively). (Baso—basophil; IL—interleukin; LTC4—leukotriene C4; MC—mast cell; PGD2—prostaglandin D2; TNF-α—tumor necrosis factor-α)

In contrast, the MCTC type of mast cell is the dominant type of mast cell in the dermis, conjunctiva, blood vessel walls, and small-intestinal submucosa. Morphologically, MCTC cells display a lattice/grating, scroll-poor granule structure. In addition to tryptase, TC-type mast cells contain chymase, cathepsin G, and mast cell carboxypeptidase. The development of both mast cell types requires stem cell factor (SCF), the ligand for the Kit (tyrosine kinase) receptor. Factors that regulate the recruitment, development, or survival of one mast cell type over the other are not known. Lineage-committing growth factors such as GM-CSF may divert hematopoietic progenitor cells that are capable of forming mast cells when exposed to SCF alone to non-mast cell lineages.53


Mast cells and basophils form histamine by decarboxylation of histidine. They then store the histamine in their granules. Degranulation releases the histamine, which then interacts with histamine receptors on various tissues. Histamine induces smooth-muscle contraction, increases mucous secretion in the airway, and stimulates nerve fibers. In addition, it enhances vascular permeability and dilates blood vessels, which results in hypotension if a critical number of cells degranulate. Chondroitin sulfates are proteoglycans that are present in the granules of both basophils and mast cells; heparin proteoglycan is stored exclusively in all mast-cell secretory granules. Both chondroitin sulfate and heparin proteoglycans play a role in packaging of histamine, proteases, and carboxypeptidases in the granules.54 Heparin is also involved in the processing of chymase and tryptase to catalytically active enzymes. Neutralization of the acidic granule pH during degranulation facilitates the dissociation of histamine from the protease-proteoglycan macromolecular complex.55 Consequently, histamine appears in the serum within minutes of induction of systemic anaphylaxis by allergen-dependent cross-linking of IgE on mast cells and basophils. Not surprisingly, peak plasma levels of histamine occur 5 minutes after insect-sting-induced anaphylaxis begins and decline to baseline within 20 minutes. Because they are relatively transient, these elevations in histamine levels in plasma are difficult to utilize for the clinical determination of anaphylaxis as a cause of hypotension. However, tryptase diffuses into, and is removed from, the circulation more slowly than histamine. Tryptase levels peak in the circulation 15 minutes to 2 hours after mast-cell degranulation and decline with a half-life of about 2 hours. Peak levels during insect-sting-induced anaphylaxis correlate closely to the drop in mean arterial blood pressure, which is an important measure of clinical severity. For that reason, serum or plasma tryptase levels have recently been recognized as a clinically useful marker for the diagnosis of systemic anaphylaxis.55

Prostaglandin D2 (PGD2) is a newly synthesized cyclooxygenase product of arachidonic acid produced by MCT and MCTC cells, but not by basophils. PGD2 causes airway smooth muscle to contract, blood vessels to dilate, and platelets to remain unaggregated. In one study of patients with systemic mastocytosis and recurrent episodes of cardiovascular collapse that did not respond to antihistamines, therapeutic success was achieved with cyclooxgenase inhibition that diminished PGD2 production.56 LTC4 is produced by both mast cells and basophils, as well as by eosinophils, and it is a potent mediator of airway smooth muscle contraction and mucus secretion. Effects of LTC4 are blocked by 5-lipoxygenase inhibition and by leukotriene receptor antagonists.

Mast cells secrete a diverse array of cytokines, including TNF-α, GM-CSF, SCF, and interleukins 3, 4, 5, 6, 10, 13, and 16.50 TNF-α can reside preformed in mast cell granules and is also synthesized and secreted after mast cell activation. TNF-α causes chemotaxis and activation of many leukocytes, as well as activation of vascular endothelium. IL-4 and IL-13 are central to TH2 differentiation, IgE isotype switching, and induction of the adhesion receptors VCAM-1 on endothelium and VLA-4 on eosinophils. Basophils do not synthesize TNF-α and generally produce fewer cytokines than do mast cells. However, activated basophils synthesize more IL-4 and IL-13 on a per-cell basis than any other cell type. In tissues with allergic inflammation that are challenged with allergen, basophils appear to be the predominant source of antigen-specific production of IL-4 and IL-13.49

As with eosinophils, a subpopulation of low-density (so-called hypodense) basophils can be detected in peripheral blood samples. This subpopulation is more sensitive to the effects of glucocorticoids than the higher-density basophils. However, functional differences in the hypodense basophils have not been characterized, as they have for eosinophils. Recently, basophil-specific markers have been developed.57The monoclonal antibodies named 2D7 and BB1 detect basophil-specific antigens in secretory granules and should prove useful for more precise assessment of basophil involvement in human allergic diseases. For example, substantial numbers of basophils can now be detected in skin and respiratory tissues during the late-phase response to an allergen challenge, and these cells account for a major portion of the IL-4-containing cells in such tissues. Basophils appear to be similar to eosinophils in expression of numerous cytokines and chemokine receptors, including CCR3. Exposure of basophils to most CC chemokines leads to histamine release.


Figures 1 and 3 Seward Hung.


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Editors: Dale, David C.; Federman, Daniel D.