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Mast cells and basophils are essential for allergies: mechanisms of allergic inflammation and a proposed procedure for diagnosis

Abstract

The current definition of allergy is a group of IgE-mediated diseases. However, a large portion of patients with clinical manifestations of allergies do not exhibit elevated serum levels of IgE (sIgEs). In this article, three key factors, ie soluble allergens, sIgEs and mast cells or basophils, representing the causative factors, messengers and primary effector cells in allergic inflammation, respectively, were discussed. Based on current knowledge on allergic diseases, we propose that allergic diseases are a group of diseases mediated through activated mast cells and/or basophils in sensitive individuals, and allergic diseases include four subgroups: (1) IgE dependent; (2) other immunoglobulin dependent; (3) non-immunoglobulin mediated; (4) mixture of the first three subgroups. According to our proposed definition, pseudo-allergic-reactions, in which mast cell or basophil activation is not mediated via IgE, or to a lesser extent via IgG or IgM, should be non-IgE-mediated allergic diseases. Specific allergen challenge tests (SACTs) are gold standard tests for diagnosing allergies in vivo, but risky. The identification of surface membrane activation markers of mast cells and basophils (CD203c, CCR3, CD63, etc) has led to development of the basophil activation test (BAT), an in vitro specific allergen challenge test (SACT). Based on currently available laboratory allergy tests, we here propose a laboratory examination procedure for allergy.

Introduction

Allergic diseases, which include allergic rhinitis, allergic asthma, allergic dermatitis, allergic conjunctivitis, anaphylaxis, food or drug allergic reactions, are major diseases involving approximately 22% of the world population1. However, the current definition of allergic diseases is a group of diseases largely driven via immunoglobulin (IgE)-dependent mechanisms2, which is hardly applicable to the allergy patients in the 22% world population. Indeed, a majority of the allergy population has never undergone specific IgE (sIgE) testing. However, new terms, allergy-like reactions or pseudo-allergy, have been derived from allergy in the last two decades to describe a clinical syndrome much like allergy, with normal serum IgE levels3. Although these patients are not diagnosed as allergies, these individuals are treated in exactly the same manner as that for allergic patients. A majority of physicians prescribing anti-allergic medicine do not examine the serum IgE levels of these patients in daily clinical practice, suggesting that the term “allergy,” as a group of IgE-mediated diseases, might not cover all naturally occurring allergic disorders. Indeed, there might be some misunderstanding of allergy.

It has recently been reported that the diagnosis of immediate-type hypersensitivity begins with a thorough clinical history and physical examination, confirmed through an allergen extract skin prick and allergen sIgE measurement4. This testing is a routine procedure used for diagnosing allergic disorders over the last several decades, consistent with the current definition of allergic diseases. Based on this definition, special attention has to be paid to serum level of IgE (sIgE). However, there is a great clinical disagreement between clinical manifestation (including skin prick tests) and sIgE measurement. For example, the predictive utility of serologic measures of sIgE for food and drug allergies and asthma is relatively poor4. The consistency between the clinical manifestations of allergies and sIgE measurement was only 40% for 50 487 clinical cases from 2008–2010 in the Allergy Department of Beijing Union Hospital5. These clinical findings suggest that some patients with negative serologic levels of sIgE can still be diagnosed as an allergy.

According to the data from the Allergy Department of Beijing Union Hospital, 60% of patients with clinical manifestations of allergies do not have elevated serum sIgE levels. Thus, the current term “allergy” is not consistent with the understanding of millions of people, as allergists define “allergy” as a group of IgE-mediated diseases, which really should be considered as a subgroup of allergic diseases.

Basic pathogenesis of allergy

Allergic inflammation is a fundamental pathological change of an allergy, and type I hypersensitivity of the immune system is the basic mechanism of allergic inflammation2. There are two phases in the basic process of allergic inflammation, as we previously described6: the induction (sensitization) phase and the effector phase (Figure 1). The induction phase involves antigen presenting cells (APCs), T cells, Th2 cytokines, such as interleukin (IL)-4, IL-5 and IL-13, class switching of B cells, IgE secretion and binding to the high-affinity IgE receptor FcεRI on the membrane of mast cells and basophils, forming sensitized mast cells and basophils. The effector phase begins when same allergen cross-links two adjacent IgEs on sensitized mast cells or basophils; activated mast cells or basophils subsequently released proinflammatory mediators or cytokines, thereby causing the clinical manifestations of allergy. Soluble allergens, sIgEs and mast cells or basophils are three key factors in the pathophysiological process of allergic inflammation, representing causative factors, messengers and primary effector cells, respectively. In contrast to primary effector cells, eosinophils and neutrophils are secondary effector cells, which can be accumulated and activated through the mediators released from mast cells or basophils.

Figure 1
figure1

Classical pathophysiological process of allergic inflammation. MC, mast cell; DC, dendritic cell; Eos, eosinophil; sIgE, specific IgE; mIgE, membrane binding IgE; TCR, T cell receptor; MHC II, class II major histocompatibility complex; PGD, prostaglandin D; LTC, leukotriene C; IL, interleukin; MBP, major basic protein. Source of mast cell images: http://proteopedia.org/wiki/index.php/Phl_p_2 and http://findingtherootcause.blogspot.ca/2011/01/mast-cells.html

PowerPoint slide

Causative factors of allergies

Allergens are the causative factors of allergies. The current definition of aeroallergens is aerosols ranging from submicron particles to relatively larger pollen grains, fungal spores, animal emanations, and biogenic debris7.

Protein allergens

Based on the definition, multi-protein substances, including house dust mites, cat hair, Aspergillus fumigatus or short ragweed pollen, are called allergens. Accordingly, allergies caused by these substances are named after the allergic substance followed by the word “allergy.” For example, an allergy caused by house dust mite is called a house dust mite allergy.

However, since the identification of “the first indoor allergen” Fel d 1, purified from the cat (Felis domesticus)8, and “the first full sequence of allergen” Der p 19, more than 300 protein molecules have been identified as “allergens”. The novel names of these allergens (such as Fel d 1–Fel d 7 from the cat; Asp f 1-Asp f 27 from Aspergillus fumigatus; Der p 1-Der p 14 from the house dust mite) appear to be in conflict with the traditional names of allergens (such as cat allergen, Aspergillus fumigatus allergen, or house dust mite allergen). To distinguish the novel name of an allergen from the traditional name of an allergen, we propose naming traditional allergens as “allergenic species” and novel name of allergens as “allergen.” For example, there are 14 allergens in house dust mite species. Because it is relatively easy to detect proteins in extracts, reservoir dust samples, and air-borne particulates using antibody-based immunometric assays, a growing number of protein allergens have been identified. There are at least three subgroups of allergens in the protein allergen group, which activate mast cells through different receptors, including IgE10,11, IgG12,13, and complement C3a, C5a receptors14,15. However, not all allergens are antigens; for example, large numbers of low molecular weight allergenic substances do not have antigenic activity, but these substances activate mast cells or basophils through direct, non-receptor-mediated mechanisms6.

Low molecular weight molecules (LMWMs)

There are huge numbers of LMWMs that cause allergies in the body and environment. For example, heparin induces anaphylactic and anaphylactoid reactions16, sphingosine-1-phosphate is emerging as a novel mediator of anaphylaxis17, and iodinated contrast agents have been shown to induce allergy-like reactions18. These LMWMs should be included in the list of allergens. Therefore, the definition of allergens should include substances that cause allergy regardless of the antigen, ie, a hapten, which needs to be bound to larger molecules to enhance antigenicity, or a LMWM, which does not stimulate the immune system to produce specific antibodies. This is, allergenic activity does not equal to antigenic activity, as antigenic activity stimulates the production of antibodies, whereas allergenic activity includes both antigenic activity and LMWM induced direct, non-receptor-mediated mast cell or basophil degranulation mechanisms. Based on the molecular size of allergens, there should be at least two different groups of allergens: large molecule allergens (molecular weight >10 kDa), including protein and non-protein allergens, and low molecular weight allergens, including haptens and other small molecule allergens.

Transmitters or messengers of allergy

Based on the previous definition of allergy, the mechanisms of IgE-mediated allergic inflammation have been extensively studied. As shown in Figure 1, all key cells and molecules involved in transmitting the biological message of allergen to primary effector cells are transmitters or messengers of an allergy, representing the most complicated process of an allergy, whose underlying mechanisms remain unknown. However, allergic inflammation reflects a complex interplay between several inflammatory cells, including mast cells, basophils, lymphocytes, dendritic cells, eosinophils, and neutrophils. These cells produce multiple inflammatory mediators, including lipids, purines, cytokines, chemokines, and reactive oxygen species19. In the present review, the roles of some key cells and molecules in the transmission from biological messages of allergen to primary effector cells are summarized.

Cellular messengers of allergy

Dendritic cells (DCs) are major antigen presenting cells (APCs) specialized in the uptake, processing and presentation of antigens to T cells20. Following allergen exposure, DCs act as reporters of the microenvironment, subsequently migrate to draining lymph nodes21 to activate naïve T cells to produce T helper (Th)2 cytokines14. FcεRI-positive DCs are efficient stimulators of both primary and FcεRI/IgE-dependent secondary T-cell responses at low cell numbers22. Susceptibility to airway hyperresponsiveness is associated with preferential myeloid DCs allergen uptake and production of Th17-skewing cytokines (IL-6 and IL-23)23. Epidermal Langerhans cells (LCs) belong to the DCs family and represent the major APCs within the skin. The recruitment of CD1a+ LCs to the nasal mucosa during natural seasonal allergen exposure might contribute to local T-cell responses24. Inflammatory dendritic epidermal cell-like DCs are a group of FcεRI-bearing APCs which might regulate inflammatory processes through the production of Th1/Th2-polarizing signals, proinflammatory cytokines and chemokines25.

Following allergen exposure, the interaction of DCs with CD4(+) T cells leads to the production of Th2 cytokines IL-4, IL-5 and IL-13. IL-4 and IL-13 play an important role in the pathogenesis of allergic diseases and are required for IgE production in B-cells26. However, Th2 cells are not the sole source of IL-4 and IL-13, other cell types, such as basophils27, mast cells28 and epithelial cells29, release relatively large quantities of IL-4 and IL-13. Indeed, allergic sensitization through the airway primes modest Th2 responses and strong Th17 responses that promote airway neutrophilia and acute allergen-induced airway hyperreactivity30. Th17 cells are characterized by IL-17 (or IL-17A), IL-17F, IL-6, tumor necrosis factor, and IL-22 expression31. Through IL-17, these cells promote neutrophil recruitment and are involved in allergic asthma, where neutrophils contribute to inflammation more than eosinophils. The identification of Th17/Th2 cells, producing both IL-4 and IL-17, in allergic asthma is consistent with the observation that different clinical phenotypes coexist in the same patient32. Moreover, atopy might aggravate nasal polyposis through the stimulation of the Th17 population and increased IL-17A production33. Regulatory T cells (Tregs) develop in the thymus from CD4(+) T cells (natural Tregs) and in the periphery through the conversion of naïve CD4(+) T cells (induced Tregs)34.

CD4+CD25+FOXP3+ Tregs and IL-10-secreting inducible type 1 Tregs inhibit the development of allergy35,36. Studies have shown that the numbers or function of both subsets might be deficient in the patients with atopic allergic diseases37.

The differentiation of B-lymphocytes into IgE-expressing cells depends on three types of signals. The first signal is delivered through the B-cell antigen receptor and is pivotal in determining the antigenic specificity of the response. The second signal is primarily provided through cytokines derived from Th2 cells, such as IL-4 and IL-13. Under tight regulation, these cytokines stimulate transcription through Ig constant region genes. The third signal is provided via the interaction between the constitutively expressed CD40 molecule on B-lymphocytes and CD154 (CD40 ligand), a molecule expressed on activated T-lymphocytes. Thus, the elevated levels of IgE observed in atopic individuals might reflect the preferential activation of Th2 cells38.

Molecular messengers of allergy

As shown in Table 1, lists the key molecules associated with the transmission of biological messages of allergens to primary effector cells. Notably, some of these messengers have been used as diagnosing tools for allergies. Although it seems likely that cytokines are essential for sensitization, IgE or IgG remain the key messengers of allergies. IgE molecules bind to high-affinity receptors on the surface of mast cells and basophils and the subsequent cross-linking of these molecules with the allergen releases preformed and newly synthesized mediators, causing the bronchoconstriction, lung inflammation and airway hyperresponsiveness observed in asthma (effector phase)14. The antibody drug cetuximab, containing oligosaccharide, which stimulates the production of the oligosaccharide-specific IgE antibody, might serve as an emerging and clinically important IgE-mediated allergen39. Recently, IgG has emerged as a key messenger of allergy, and the influence of IgG on mast cells and basophils has been summarized in a previous paper6. Although the clinical implications remain obscure, elevated levels of beta-lactoglobulin-specific serum IgA and IgG4 have been associated with cow's milk allergy40. Increased IgA levels have also been observed in the nasal lavage fluid of patients with allergic rhinitis41.

Table 1 Key molecules related to transmission of biological messages of allergen to primary effector cells.

IL-3 stimulates the release of large quantities of histamine, LTC4, IL-4, and IL-13 from basophils42. Because these molecules are major mediators of allergy and asthma, IL-3 is likely to play a role in allergy. IL-3 also plays an important role in the rapid and specific expansion of basophils43 and the generation of mast cells from CD133(+) progenitor cells in cord or peripheral blood44. In the presence of stem cell factor (SCF) and IL-3, CD34(+)-enriched mononuclear cells from human blood are converted to FcεRI-expressing mast cells45, and rat bone marrow mononuclear cells (BMMCs) exhibit the characteristics of mucosal mast cells46. Interestingly, mast cells secrete IL-347, and mast cell-derived IL-3 selectively induces retinaldehyde dehydrogenase-II release from basophils via PI3-kinase and NF-kappaB pathways48, suggesting the self-amplification of mast cell activation and cross talk between mast cells and basophils.

IL-4 and IL-13 are key Th2 cytokines involved in allergy, providing the first crucial signal49 for class switching in B cells for the production of allergen-specific IgE antibodies that bind to specific receptors on mast cells and basophils31. IL-4 production during antigen presentation to Th cells is critical for the development of Th2 cells50. Th2 cells31, mast cells51,52 and basophils53, and EC29 release substantial quantities of IL-4 and IL-13.

IL-5 is a Th2 homodimeric cytokine involved in the differentiation, maturation, migration, development, survival, trafficking and effector functions of blood and local tissue eosinophils. The IL-5 receptor (IL-5R) consists of an IL-5-specific α subunit that interacts in conformationally dynamic ways with the βc subunit, an aggregate of domains that also have binding sites for IL-3 and GM-CSF. IL-5 and IL-5R drive allergic and inflammatory immune responses54.

IL-17 promotes neutrophil recruitment to the airways in neutrophilic asthma55, whereas IL-17E (also known as IL-25), produced in epithelial cells, eosinophils, basophils and mast cells, enhances Th2 cytokine production for the regulation of adaptive immunity56. Upregulated IL-25 activity activates Th2 cells, mast cells, dendritic cells, eosinophils and basophils, leading to inflammatory processes that define allergic disease57. Anti-IL-25 prevents the development of key features of asthma, suggesting the suppression of the Th2 response58.

IL-31 has recently been identified as a new member of the IL-6 family of cytokines. IL-31 signals through a heterodimeric receptor that stimulates JAK-STAT, RAS/ERK, and PI3K/AKT signal transduction pathways. The enhanced expression of IL-31 has been associated with a number of diseases, including allergy and inflammatory bowel disease59. IL-31 coordinates the interaction of T-cells, mast cells, and eosinophils with epithelial cells to release chemokines and other cytokines. IL-31 is primarily produced in Th260 and mast cells61, suggesting a role in allergic diseases.

IL-33 is an IL-1 family member, recently identified as the ligand for the ST2 receptor, a member of the IL-1 receptor family. ST2 is stably expressed on mast and Th2 cells. IL-33 induces Th2 cytokine release from mast cells and polarized mouse T cells, leading to pulmonary and mucosal inflammation. Human blood-derived basophils express high levels of ST2 receptor and respond to IL-33 by producing several pro-inflammatory cytokines, including IL-1beta, IL-4, IL-5, IL-6, IL-8, IL-13, and GM-CSF53. IL-33 also acts on the ubiquitously expressed IL-1 receptor accessory protein (ILRAcP) and might play a central role in allergic asthma, addressing various cascades of innate and adaptive immune responses in a unique fashion via basophils, mast cells, eosinophils and Th2 cells. DCs pre-treated with IL-33 were significantly more potent for the generation of allergen-specific Th2 cells with IL-5 and IL-13 production62.

TSLP (thymic stromal lymphopoietin), a member of the Th2 cytokine family, has recently emerged as an active participant in the pathogenesis of allergy. Unregulated TSLP activity activates Th2 cells, mast cells, DCs, eosinophils, and basophils, leading to inflammatory processes that define allergic disease57. TSLP is secreted from basophils63, mast cells64 and DCs upon house dust mite exposure21, and the percentage of TSLP-positive mast cells in the total population of mast cells was significantly increased in asthmatic airways64.

Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor produced in mast cells in response to IgE receptor-mediated activation65, epithelial cells upon house dust mite exposure21, basophils53 and Th2 cells66 for the induction of IL-4 release from mast cells67. It played significant roles in the proliferation and differentiation of eosinophils in the bone marrow68, and the chemotaxis and activation of eosinophils69.

Primary effector cells of allergy

Mast cells and basophils are the primary effector cells of allergies70,71, which directly respond to allergen challenge through immunoglobulin dependent or independent mechanisms72. Upon activation, mast cells and basophils release three major groups of proinflammatory mediators causing pathological damages73 and clinical manifestations74,75. Symptoms of allergies occur after the activation of mast cells or basophils. Theoretically, the degranulation of mast cells and basophils is the definitive event in allergy, whereas IgE only serves as one of the key messengers.

Although mast cells and basophils play a decisive role in allergy, the cell types involved in the sensitization of primary effector cells are also essential for the occurrence of allergy. For example, an individual allergic reaction to alcohol, grass pollen, or certain foods requires long process to obtain sensitization to that specific allergen and not other allergens. This natural phenomenon suggests that mast cells or basophils should be primed before activation, although the known activators are LMWMs.

Degranulated mast cells or basophils are definitely activated, but whether activated mast cells or basophils undergo the degranulation process remains unknown. Mast cells release three groups of mediators76, including preformed granule products, such as histamine, tryptase, chymase and heparin; newly synthesized arachidonic acid products, such as leukotriene C4 (LTC4) and prostaglandin D2 (PGD2)77; and cytokines, such as IL-4, IL-13, and eotaxin78. These products greatly contribute to pathological damage in different tissues (Table 2)79,80.

Table 2 Key proinflammatory actions of major mast cell products.

Preformed granule products of mast cells

Histamine, apart from the induction of microvascular leakage81 and vasodilation, polarizes human DCs into Th2 cell-promoting effector DCs82 and induces eosinophil adhesion and accumulation83. The activation of the histamine H4 receptor enhances LPS-induced IL-6 production in mast cells via ERK and PI3K activation84. Tryptase induces eosinophil and neutrophil accumulation85, promoting the release of eosinophil peroxidase and beta-hexosaminidase from peripheral blood eosinophils86, and stimulating human coronary artery endothelial cells to release arachidonic acid and platelet-activating factor (PAF)87. Chymase induces eosinophil migration88, which was mediated through the extracellular signal-regulated kinase pathway89, and stimulates mucin secretion from bronchial epithelial cells90. While the exact contribution of mast cell carboxypeptidase A (MC-CPA) to allergy is unclear, this protease plays a role in regulating innate immunity responses, including the degradation of harmful substances, such as the vasoconstrictive factor endothelin 1 and snake venom toxins91. Heparin is a potent chemoattractant for neutrophils92, which increases vascular permeability through a heparin-initiated bradykinin formation mechanism93. Heparin plays an essential role in promoting the storage of other granule-contained compounds, including bioactive monoamines and different mast cell-specific proteases, and regulating the enzymatic activities of mast cell proteases94. MMP-9 is a potent chemoattractant for neutrophils, which might be responsible for the crosstalk between mast cells and neutrophils95.

Newly synthesized arachidonic acid products of mast cells

LTC4 is an important mediator produced through the arachidonic acid pathway in the plasma membrane of mast cells and basophils via 5-lipoxygenase, which promotes inflammation processes, including eosinophil migration, increased vascular permeability and bronchoconstriction96. PGD2 is another major arachidonic acid product primarily produced in mast cells in allergic diseases, inducing vasodilatation, increased vascular permeability, inflammatory cell migration, and cytokine production97. As a potent phospholipid mediator involved in anaphylaxis, PAF activates platelets and induces bronchoconstriction, bronchial hyper-responsiveness98, and mast cell chemotaxis99. Interestingly, arachidonic acid products can be released alone from basophils without degranulation in response to allergen challenge100.

Mast cell-released cytokines

Cytokines, such as IL-4101, IL-6, vascular endothelial growth factor102, IL-13, and TNF103, are released from mast cells without causing degranulation. The cytokines released from mast cells act as potent proinflammatory factors to contribute to the pathogenesis of allergy6. For example, the interactions of eotaxin, RANTES and MCP-1 with CCR3 (CD193) are responsible for the recruitment of basophils, eosinophils and mast cells104. While IL-6105, IL-8106, and TNF107 stimulate mast cells migration108, and IL-29 induces mast cell infiltration via CD18- and intercellular adhesion molecule-1 (ICAM-1)-dependent mechanisms101.

Activation markers of mast cells and basophils

Mast cell-specific secretory products

Mast cell-specific secretory products, including histamine, tryptase, chymase, LTC4, PGD2 and beta-hexosaminidase, are activation markers for mast cells, and histamine, LTC4 and PGD2 are activation markers for basophils (Table 3). However, eosinophils release LTC4109 and DC secretes PGD2110. In the last two decades, for the identification of surface membrane activation markers for mast cells and basophils has made promising progress.

Table 3 Activation markers of mast cells and basophils.

Plasma membrane molecules

CD63 (gp53, lysosomal-associated membrane protein) has been identified as an activation marker for basophils111 and mast cells112, which is employed in flow cytometric basophil activation tests (BAT) for the diagnosis of allergy113. CD63 expression is rapidly upregulated following allergen challenge and reaches a maximum after 20–30 min114. However, as a lysosomal-associated membrane protein, CD63 is a non-specific marker of basophils, and the upregulated expression of this molecule has been observed in several other cell types, such as neutrophils115, DCs116, T cells117, and eosinophils118. Therefore, the identification of a constitutive and constant expression marker for basophils, regardless of activation status, is essential for the specificity of BAT. Thus, CCR3119 and CD123 (IL-3 receptor α chain)120 have been selected as constant expression and identification markers for basophils to distinguish these cells from CD63, the activation marker. Because CCR3 has also been observed on eosinophils121 and a small proportion of CD4+T cells122, this protein is not the unique marker for basophils. Similarly, CD123 has been identified on plasmacytoid DCs123 and plasmacytoid monocytes124; thus, this protein is not a unique marker for basophils either. However, DCs and monocytes, but not basophils, express human leukocyte antigen (HLA)-DR, which could distinguish CD123-positive basophils from DCs and monocytes. Thus, basophils in the BAT can be identified as CD123+/HLA-DR-cells in flow cytometry analysis125, and CD63+ basophils in whole blood are located in the CD123+ HLA-DR-cell population126.

Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vivo and the IgE-mediated degranulation of mast cells in vitro127, suggesting that CD63 is involved in the degranulation of mast cells in allergy. Cross-linking the IgE-receptors enhances the expression of both CD63 and CD203c (ectonucleotide pyrophosphatase/phosphodiesterase 3) on basophils128. CD203c has also been recognized as a more specific surface marker for basophils than CD63129. Basophil priming and degranulation-enhancing factors are not required for CD203c-based BAT114. The spontaneous expression of CD203c is significantly higher on basophils from patients with exacerbated asthma than on those from patients with stable asthma or healthy subjects. In contrast, no differences in the spontaneous expression of CD63 or CD69 were observed among the three groups. The anti-IgE-induced expression of CD203c is significantly increased in basophils during asthma exacerbation130, suggesting that the increased expression of CD203c, but not CD63, is associated with asthma exacerbation.

Nevertheless, BAT is a widely validated and reliable tool, particularly for the diagnosis of hymenoptera venom131, nut132, grass pollen133 and rare allergies (such as drugs and exotic foods)113, and anaphylaxis134 and anaphylactoid reactions120. BAT exhibited the highest sensitivity and specificity, with a significantly better ability than sIgE testing for the identification of Anisakis species in the patients with acute urticaria, potentially supplementing current standardized procedures in both diagnosis and follow-up135. Indeed, BAT has several advantages over the autologous serum skin test: no risk of accidental infection, no influence of antihistamines on the test results, quantifiable results, and potential for treatment monitoring136. In addition, BAT can be dissociated from basophil histamine release137. Nevertheless, there is currently no approach for mast cell and/or basophil marker testing or available optimal algorithm for the clinical application of this marker in allergy diagnosis.

The high-affinity IgE receptor FcεRI on the basophil membrane shows potential as a basophil activation marker. However, the IgE gating strategy has the highest variation, showing up to 80% of non-basophils in the selected gate in certain donors119. This variation might reflect the large proportion of CD1c+ DCs138 and eosinophils139 expressing surface FcεRI. CD200R3, as a disulfide-linked dimer, has been identified on mast cells and basophils primarily in association with the ITAM-bearing adaptor DAP12. Cross-linking CD200R3 with antibodies induced mast cells degranulation and IL-4 production in basophils in vitro140. In addition, CD117 (c kit) a receptor of SCF is expressed on the surface of all mast cells, independent of maturation and activation status141, suggesting that this receptor has potential as a surface marker for mast cells and basophils. However, the expression of CD117 on some hematopoietic stem cells, melanocytes, and Cajal cells of the gastrointestinal tract, and kit-positive tumors142 complicates the use of this receptor as a selection marker for mast cells and basophils. CD300a is expressed on human peripheral blood basophils and rapidly upregulated upon IgE/FcεRI cross-linking, showing potential as an activation marker for basophils143.

Properties and pathogenesis of pseudo-allergic reactions

Pseudo-allergic reactions are clinical manifestations, including urticaria, angioedema, conjunctivitis, rhinitis, asthma, and anaphylaxis, which mast cell or basophil activation is not mediated via IgE, or to a lesser extent via IgG144 or IgM. The main causes of pseudo-allergic reactions are food, additives and drugs. The diagnosis of pseudo-allergic reactions is characterized by the absence of sIgE for the suspected substances, and the treatment for this allergy is similar to that for allergic diseases, including antihistamine drugs, steroids, B2 agonists, and epinephrine (Table 4)3.

Table 4 Comparison of allergic and pseudo-allergic reactions.

Non-IgE-mediated pseudo-allergic reactions

Non-IgE-mediated pseudo-allergic reactions resulting from drugs are called drug-induced immediate hypersensitivity reactions (DIIHSRs), which does not fit in Gell and Coombs' Type I category of drug allergies. The DIIHSRs are primarily caused by (1) certain liposomal formulations of intravenous drugs and imaging agents, (2) infusion liquids containing micelle-forming amphiphilic lipids or synthetic block-copolymer emulsifiers and (3) iodinated radiocontrast media with limited solubility in water145. The mechanism of DIIHSRs involves the activation of the complement system to generate anaphylatoxins C3a and C5a, and the latter activates mast cells and/or basophils, suggesting a subdivision of Type I allergies. DIIHSRs are largely under-reported, with a significantly higher risk in adult women than in men. Neuromuscular blocking agents remain the most frequently incriminated drugs. Reactions involving antibiotics, dyes, or nonsteroidal anti-inflammatory agents have been reported with increasing frequency146.

Pseudo-allergic reactions might also occur following administration of iodinated contrast media. Positive skin tests to contrast media have been reported, but the affinity of IgE towards contrast media is low18.

Anaphylaxis and anaphylactoid reactions

Anaphylaxis is a life-threatening allergic reaction primarily mediated through IgE antibodies as well as IgG or IgM antibodies (immune complex anaphylaxis), which interact with mast cells, basophils, or the complement system to liberate vasoactive mediators and recruit other inflammatory cells. The most common elicitors of anaphylaxis are foods in childhood, insect stings and drugs. In clear-cut IgE-mediated anaphylaxis, allergen-specific immunotherapy is an effective causal treatment, with success rates of 90% in insect venom anaphylaxis147. Studies have reported cases with similar clinical symptomatology without detectable immunological sensitization, which were initially referred to as pseudo-allergic or anaphylactoid reactions, but are now called “non-immune anaphylaxis”, according to the World Allergy Organization (WAO). Indeed, anaphylaxis and anaphylactoid reactions are clinically indistinguishable18. However, the distinction of different pathophysiological processes is important because non-immune anaphylaxis cannot be detected using skin tests or in vitro allergy diagnostic procedures. Thus, history and provocation tests are crucial148.

If we consider allergies as a group of mast cell and/or basophil-mediated diseases, pseudo-allergic reactions should be included in the category of allergy, as a group of non-IgE-mediated allergic diseases. Thus, IgE-mediated allergy, as a subgroup of allergy, might be the largest subgroup, reflecting the fact that pseudo-allergic reactions are mediated through mast cells and/or basophils and the clinical symptomatology and treatment of these reactions are similar (if not the same) to those for allergic diseases.

Proposed definition and classification of allergic diseases

Allergic diseases are a group of diseases mediated through activated mast cells and/or basophils in sensitive populations. Allergic diseases include four subgroups: (1) IgE dependent; (2) other immunoglobulin dependent; (3) non-immunoglobulin mediated; and (4) mixture of the first three subgroups. Ideally, allergic diseases should include chronic allergic reactions, such as contact dermatitis, which most likely are not mast cell and/or basophil-mediated. Because the nature of allergy remains elusive, our proposal definitely requires further confirmation. Moreover, numerous issues, such as infection, autoimmune diseases, arthrosclerosis, which might involve mast cell or basophil activation agents, should be further considered. Moreover, whether these issues affect the progress of allergy should be addressed in the near future.

Diagnosis procedure of allergic diseases

As for any other types of diseases, the diagnostic procedure of allergy must be based upon its definition and classification, beginning with a thorough clinical history and physical examination.

Specific allergen challenge test (SACT)

Once symptoms compatible with an allergic disorder have been identified, the SACT should be applied to provide confirmation of sensitization. SACTs are the most reliable and gold standard tests for diagnosing allergy, which include in vivo tests, such as skin provocation tests for medications, oral challenge tests for food allergens and bronchial challenge tests for aerosol allergens. The main procedure for in vivo SACT is demonstrated in Figure 2. However, SACTs should be conducted under the supervision of experienced physicians because these procedures might cause adverse reactions, such as anaphylaxis149; thus, these tests are not frequently used in daily clinical practice. The skin prick test (SPT) and atopy skin patch test are in vivo SACTs, which are safely employed in daily clinical practice. However, because the testing allergens of SPT and the atopy skin patch test are primarily located in the epidermis and have limited contact with mast cells, these tests are not as reliable as the other SACTs described above. To achieve safe and more reliable testing results, in vitro SACTs have been developed. The specific allergen-induced basophil histamine release test149 and BAT using flow cytometry150 are two tests available for clinical practice. Once fully developed, these tests should more accurately and reliably determine allergens than any current in vitro tests.

Figure 2
figure2

Main procedure and mechanism of the specific allergen challenge test. PGD, prostaglandin D; LTC, leukotriene C.

PowerPoint slide

Allergen-specific immunoglobulin tests

Because the classical definition of allergy is a group of diseases largely driven through IgE-mediated mechanisms, allergen sIgE measurement has been the most popular allergy test used worldwide151. In the current review, IgE-mediated allergy is only considered as a subgroup of allergy, therefore other types of allergen-specific immunoglobulins, such as IgG, IgA, or IgM, should be determined following positive SACTs. Ultimately, the patient's clinical history remains the principal arbiter to determine the final diagnosis of allergic disease. Positive serum immunoglobulin tests provide further information concerning the types of allergens and allergies the patients suffer from, such as IgE-mediated or IgG-mediated allergies.

Proposed laboratory diagnosis procedure of allergic diseases

Based on the proposed definition, the ideal laboratory examination procedure for allergy should begin with allergen extract skin prick and skin patch (small molecules) tests according to clinical history and physical examination (Figure 3). The test results will limit the number of allergens needed for the basophil histamine release test and BAT. BAT is more sensitive and specific than any other in vitro diagnostic techniques in drug allergy. The sensitivity of BAT to different drugs ranges between 36% and 97.7%, with a specificity of approximately 93%150. There was a case that the SPT and serum sIgE to beef, pork and milk allergens showed negative results, but the BAT showed significant positive results152. The positive SACTs will confirm the diagnosis of allergy, and the substances that the patients are allergic to. Ideally, serum sIgE or specific IgG measurement should be performed after positive SACTs to determine the subtype of allergy that the patients suffer, and alternatively this measurement can be performed simultaneously with SACTs.

Figure 3
figure3

Proposed procedure for the laboratory diagnosis of allergy. Non-IgE/IgG dependent, IgE-dependent or IgG-dependent allergies have been proposed in the current review. The gray arrows indicate the previous names of the diseases.

PowerPoint slide

Future work

With more than 2000 years of clinical practice, we are coming increasingly closer to understanding the nature of allergic diseases, and mast cells and basophils are unarguably essential cells for allergy. Fortunately, the proper tools have been created to breakthrough the diagnosis of these diseases. To further understand the nature of allergic diseases and examine the laboratory diagnosis procedure, the following work should be performed: 1) Investigating non-IgE mediated sensitization processes of mast cells or basophils; 2) Understanding the reason why different types of allergens cause different subtypes of allergy; 3) Investigating sensitized mast cells or basophils respond to a single type allergen or several types of allergens; 4) Investigating the types of stimulation, the strength of stimulation and the mechanisms which cause mast cells selectively secrete different mediators; 5) Paying more attention to the LMWM-induced activation of mast cells or basophils; 6) Identifying the best antibody combination for BAT; 7) Developing a more reliable and low-cost allergen-specific basophil histamine release test; and 8) Characterizing other clinical conditions, such as infection, autoimmune diseases and arthrosclerosis, which might involve mast cell or basophil activation agents. Moreover, we should also investigate why these individuals do not suffer from allergies.

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Acknowledgements

This project was supported through grants from the Major State Basic Research Program of China (973 Program, No 2013CB530500); the National Natural Science Foundation of China (No 81030054, 81172836, 81241135, and 81060250); and the Key Project of the Natural Science Foundation of Jiangsu Province, China (No BK2010020).

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Correspondence to Shao-heng He or Hui-yun Zhang.

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He, Sh., Zhang, Hy., Zeng, Xn. et al. Mast cells and basophils are essential for allergies: mechanisms of allergic inflammation and a proposed procedure for diagnosis. Acta Pharmacol Sin 34, 1270–1283 (2013). https://doi.org/10.1038/aps.2013.88

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Keywords

  • allergy
  • mast cell
  • basophil
  • IgE
  • IgG
  • pseudo-allergic reaction
  • specific allergen challenge test
  • basophil activation test

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