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Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis. The relationship between allergen immunotherapy and omalizumab for treating asthma. 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 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 species 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.
Dendritic cells DCs are major antigen presenting cells APCs specialized in the uptake, processing and presentation of antigens to T cells Susceptibility to airway hyperresponsiveness is associated with preferential myeloid DCs allergen uptake and production of Thskewing cytokines IL-6 and IL IL-4 and IL play an important role in the pathogenesis of allergic diseases and are required for IgE production in B-cells However, Th2 cells are not the sole source of IL-4 and IL, other cell types, such as basophils 27 , mast cells 28 and epithelial cells 29 , release relatively large quantities of IL-4 and IL Indeed, allergic sensitization through the airway primes modest Th2 responses and strong Th17 responses that promote airway neutrophilia and acute allergen-induced airway hyperreactivity Through IL, these cells promote neutrophil recruitment and are involved in allergic asthma, where neutrophils contribute to inflammation more than eosinophils.
Moreover, atopy might aggravate nasal polyposis through the stimulation of the Th17 population and increased ILA production Studies have shown that the numbers or function of both subsets might be deficient in the patients with atopic allergic diseases 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 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 CD 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 cells 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 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 allergen 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 paper 6.
Although the clinical implications remain obscure, elevated levels of beta-lactoglobulin-specific serum IgA and IgG4 have been associated with cow's milk allergy Increased IgA levels have also been observed in the nasal lavage fluid of patients with allergic rhinitis Because these molecules are major mediators of allergy and asthma, IL-3 is likely to play a role in allergy.
Interestingly, mast cells secrete IL-3 47 , and mast cell-derived IL-3 selectively induces retinaldehyde dehydrogenase-II release from basophils via PI3-kinase and NF-kappaB pathways 48 , suggesting the self-amplification of mast cell activation and cross talk between mast cells and basophils. IL-4 and IL are key Th2 cytokines involved in allergy, providing the first crucial signal 49 for class switching in B cells for the production of allergen-specific IgE antibodies that bind to specific receptors on mast cells and basophils IL-4 production during antigen presentation to Th cells is critical for the development of Th2 cells 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.
IL-5 and IL-5R drive allergic and inflammatory immune responses IL promotes neutrophil recruitment to the airways in neutrophilic asthma 55 , whereas ILE also known as IL , produced in epithelial cells, eosinophils, basophils and mast cells, enhances Th2 cytokine production for the regulation of adaptive immunity Upregulated IL activity activates Th2 cells, mast cells, dendritic cells, eosinophils and basophils, leading to inflammatory processes that define allergic disease Anti-IL prevents the development of key features of asthma, suggesting the suppression of the Th2 response IL has recently been identified as a new member of the IL-6 family of cytokines.
The enhanced expression of IL has been associated with a number of diseases, including allergy and inflammatory bowel disease IL coordinates the interaction of T-cells, mast cells, and eosinophils with epithelial cells to release chemokines and other cytokines.
IL is primarily produced in Th2 60 and mast cells 61 , suggesting a role in allergic diseases. ST2 is stably expressed on mast and Th2 cells. IL induces Th2 cytokine release from mast cells and polarized mouse T cells, leading to pulmonary and mucosal inflammation.
IL 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. 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 disease TSLP is secreted from basophils 63 , mast cells 64 and DCs upon house dust mite exposure 21 , and the percentage of TSLP-positive mast cells in the total population of mast cells was significantly increased in asthmatic airways It played significant roles in the proliferation and differentiation of eosinophils in the bone marrow 68 , and the chemotaxis and activation of eosinophils Mast cells and basophils are the primary effector cells of allergies 70 , 71 , which directly respond to allergen challenge through immunoglobulin dependent or independent mechanisms Upon activation, mast cells and basophils release three major groups of proinflammatory mediators causing pathological damages 73 and clinical manifestations 74 , 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 mediators 76 , 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, and eotaxin These products greatly contribute to pathological damage in different tissues Table 2 79 , Histamine, apart from the induction of microvascular leakage 81 and vasodilation, polarizes human DCs into Th2 cell-promoting effector DCs 82 and induces eosinophil adhesion and accumulation Tryptase induces eosinophil and neutrophil accumulation 85 , promoting the release of eosinophil peroxidase and beta-hexosaminidase from peripheral blood eosinophils 86 , and stimulating human coronary artery endothelial cells to release arachidonic acid and platelet-activating factor PAF Chymase induces eosinophil migration 88 , which was mediated through the extracellular signal-regulated kinase pathway 89 , and stimulates mucin secretion from bronchial epithelial cells 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 toxins Heparin is a potent chemoattractant for neutrophils 92 , which increases vascular permeability through a heparin-initiated bradykinin formation mechanism 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 proteases MMP-9 is a potent chemoattractant for neutrophils, which might be responsible for the crosstalk between mast cells and neutrophils 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 bronchoconstriction 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 production As a potent phospholipid mediator involved in anaphylaxis, PAF activates platelets and induces bronchoconstriction, bronchial hyper-responsiveness 98 , and mast cell chemotaxis Interestingly, arachidonic acid products can be released alone from basophils without degranulation in response to allergen challenge The cytokines released from mast cells act as potent proinflammatory factors to contribute to the pathogenesis of allergy 6.
In the last two decades, for the identification of surface membrane activation markers for mast cells and basophils has made promising progress.
CD63 gp53, lysosomal-associated membrane protein has been identified as an activation marker for basophils and mast cells , which is employed in flow cytometric basophil activation tests BAT for the diagnosis of allergy CD63 expression is rapidly upregulated following allergen challenge and reaches a maximum after 20—30 min 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 neutrophils , DCs , T cells , and eosinophils Therefore, the identification of a constitutive and constant expression marker for basophils, regardless of activation status, is essential for the specificity of BAT.
Similarly, CD has been identified on plasmacytoid DCs and plasmacytoid monocytes ; thus, this protein is not a unique marker for basophils either. Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vivo and the IgE-mediated degranulation of mast cells in vitro , suggesting that CD63 is involved in the degranulation of mast cells in allergy. CDc has also been recognized as a more specific surface marker for basophils than CD63 The spontaneous expression of CDc 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 CDc is significantly increased in basophils during asthma exacerbation , suggesting that the increased expression of CDc, but not CD63, is associated with asthma exacerbation.
Nevertheless, BAT is a widely validated and reliable tool, particularly for the diagnosis of hymenoptera venom , nut , grass pollen and rare allergies such as drugs and exotic foods , and anaphylaxis and anaphylactoid reactions 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-up 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 monitoring In addition, BAT can be dissociated from basophil histamine release Cross-linking CDR3 with antibodies induced mast cells degranulation and IL-4 production in basophils in vitro In addition, CD c kit a receptor of SCF is expressed on the surface of all mast cells, independent of maturation and activation status , suggesting that this receptor has potential as a surface marker for mast cells and basophils.
However, the expression of CD on some hematopoietic stem cells, melanocytes, and Cajal cells of the gastrointestinal tract, and kit-positive tumors complicates the use of this receptor as a selection marker for mast cells and basophils. 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 IgG 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. 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 water Neuromuscular blocking agents remain the most frequently incriminated drugs.
Reactions involving antibiotics, dyes, or nonsteroidal anti-inflammatory agents have been reported with increasing frequency 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 low 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. Indeed, anaphylaxis and anaphylactoid reactions are clinically indistinguishable 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 crucial Allergic diseases include four subgroups: 1 IgE dependent; 2 other immunoglobulin dependent; 3 non-immunoglobulin mediated; and 4 mixture of the first three subgroups.
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. 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. 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.
However, SACTs should be conducted under the supervision of experienced physicians because these procedures might cause adverse reactions, such as anaphylaxis ; thus, these tests are not frequently used 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 test and BAT using flow cytometry 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. Main procedure and mechanism of the specific allergen challenge test.
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 worldwide 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.
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.
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 results 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. Proposed procedure for the laboratory diagnosis of allergy.
The gray arrows indicate the previous names of the diseases. With more than 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. Allergy practice worldwide: a report by the world allergy organization specialty and training council. Int Arch Allergy Immunol ; : — Barnes PJ. Pathophysiology of allergic inflammation.
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Curr Opin Allergy Clin Immunol ; 8 : —5. Allergy-like reactions to iodinated contrast agents. There are many critical factors involved in the current allergy epidemic, such as genetic predisposition, the intricate relationship between the immune system and pathogens, and environmental factors. The hygiene hypothesis proposes that diminished exposure to infectious agents during development is associated with susceptibility to allergic disease.
The proposed mechanism behind this hypothesis is the imbalance in the activation process of T helper Th 2 cells over Th1 cells. Th2 cells are the known culprit for the development of atopic disorders. This hypothesis was first proposed in through an epidemiological study of hay fever. The study revealed that the children who encountered fewer infectious agents as a result of changes in lifestyle, such as higher standards of personal hygiene, reduced family size, and upgraded amenities, were more susceptible to hay fever.
This suggests that allergic diseases might be prevented by early childhood infections. When expressed by immature dendritic cells and mononuclear phagocytic cells, Interleukin 10 IL plays a vital role in the stimulation and maintenance of tolerance to benign allergens.
But in allergic rhinitis and asthma, airway IL expression is reduced. This, in turn, results in inflammation, in response to non-harmful allergens. The counter-regulatory hypothesis suggests that infections lead to increased expression of IL, which lowers predisposition towards allergy.
The current lifestyle in Western countries has reduced exposure to infectious agents. This has diminished the benefits of this counter-regulatory feedback, making people more susceptible to atopic disorders. Granulocyte-macrophage colony-stimulating factor GM-CSF is produced by many cell types, including T cells, macrophages, and endothelial cells, following their activation. GM-CSF in turn stimulates the proliferation and activation of neutrophils, monocytes, lymphocytes, macrophages, and dendritic cells.
In allergic disorders, GM-CSF causes the continual survival of eosinophils by inhibiting their apoptosis. The hapten-atopy hypothesis proposes that high-level exposure to chemicals in the early stages of development is associated with increased allergic disorders.
Haptens are small molecules with low molecular weight less than Da that are typically not capable of generating an immune response but can bind to bigger molecules and turn them into allergens. Exposure to dietary haptens through processed food, formula milk, and oral medications has drastically increased in the past four decades. It is suggested that this rise in exposure has contributed to the increased prevalence of atopic disorders during this period.
There are two contradictory theories behind the role antioxidants play in atopic disease. Some studies propose that a low intake of antioxidants, such as green vegetables, and fresh fruits and fish, contributes to the increased prevalence of atopic disorders, while others suggest that increased antioxidant intake has caused the increase in allergic disorders. The consumption of foods containing n-3 polyunsaturated fat, found in tuna, herring, mackerel, salmon, sardines, and trout has reduced in the past few decades.
At the same time, there has been a rise in the consumption of processed foods that are rich in n-6 polyunsaturated fat, which presumably activates IgE production causing atopic disorders. This theory is defined as the lipid hypothesis. Vitamin D hypothesis proposes that the prevalence of allergic disorders is higher in patients who were supplemented with vitamin D as infants. IgE plays a vital role in allergic disorders by inducing immediate hypersensitivity reactions. The activation of Fc epsilon RI, located on the surface of mast cells, facilitates immediate hypersensitivity reactions that can manifest as sneezing, urticaria, acute bronchospasm, secretory diarrhea, cardiovascular collapse, or fatal systemic anaphylactic reactions.
Thus SYK is an ideal therapeutic target for inflammatory and allergic conditions. More than million people in the world suffer from allergic rhinitis AR , which is a chronic inflammatory disease.
The symptoms include sneezing, itching, rhinorrhea, nasal congestion. The pathophysiology of AR involves an immediate and late-phase response involving the nasal mucosa. The immediate response is IgE-mediated, whereas the late response is carried out by activated eosinophils and T cells that contribute to the chronic inflammatory process. The IgE that is synthesized in the local mucosa and IL-4 both help augment the Fc epsilon RI expression in the mast cells and basophils.
This increases mast cell sensitivity to the allergen, further enhancing the presence of cytokines and chemical mediators. Asthma affects approximately million people in the world and is caused by chronic, inflammation, hyperactivity, and reversible obstruction of the airway. It presents with shortness of breath, cough, and wheezing.
Non-allergic asthma, which is not associated with atopy, presents with negative skin tests to typical aeroallergens and tends to present with a later onset in life.
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