Revista Societatii de Medicina Interna
Articolul face parte din revista :
Nr.1 din luna ianuarie 2017
Autor Elena Camelia Berghea, Ruxandra Ulmeanu, Claudia Lucia Toma
Titlu articolNEW CONSIDERATIONS ABOUT THE ROLE OF IGE IN ALLERGIC AND NONALLERGIC ASTHMA – SHORT REVIEW
Cuvinte cheieastm, imunoglobulină E, atopie
Articol
Asthma is a chronic inflammatory airway disease, which can be triggered by a variety of environmental factors, affecting about 300 million people worldwide(1). Although profound insights have been made into the pathophysiology of bronchial asthma and it is known that the typical symptoms of asthma (intermittent attacks of breathlessness, wheezing, cough) are caused by chronic inflammation and remodeling of the conducting airways, the exact mechanisms inducing and regulating the disease are still not fully understood. Allergic asthma is characterized by a TH2-dominated immune response associated with increased serum immunoglobulin E (IgE) levels in response to inhaled allergens. However, asthmatic patients with negative skin prick tests to common allergens, defined as nonatopic, usually characterized by a more severe and difficult-to-control disease, also have increased total IgE serum levels compared with those seen in healthy control subjects(2). It was demonstrated a direct correlation between asthma and the serum level of IgE, asthma prevalence increases linearly with the logarithm IgE values(3).
Immunoglobulin E synthesis, structure and receptors
Discovered in 1967(4), IgE is exclusively present in mammals(5). It was demonstrated that IgE has the ability to induce potent inflammatory immune responses with an essential role in allergic diseases. IgE is the immunoglobulin with a low plasma concentration (serum IgE levels are about 104 times lower than IgG concentrations in healthy individuals), with a short half-life (2.5 days), composed of two identical heavy chains which contains two regions, one variable and one constant and two identical light chains which contain one variable region and one constant domain(6). Variable regions of light and heavy chains create two identical antigen-binding sites. There are two forms of IgE: the secretory IgE and the membrane-bound form of IgE (mIgE) with an extracellular membrane proximal domain; a transmembrane sequence and a cytoplasmic tail are added to the last constant domain of the heavy chain(6). Surface forms of immunoglobulins are connected with two membrane proteins, Igα and Igβ, to form the B-cell antigen receptor with an important role in survival and development of the B cell(6).
The classic pathway of IgE synthesis requires interaction between mature naive B cells and dendritic cells which present the antigen into peripheral lymphoid organs. In an atopic millieu, dendritic cells will induce Th2 polarization; Th2 cells produce IL4, IL5, IL13, powerfull mediators of allergic inflammation and IgE synthesis(8).
The interaction between Th2 cells specific for a particular antigen, and B cells, induces a T-dependent antibody response. Activated B cells become short-lived plasma cells which produce specific antibodies, or stay in B-cell follicles and form germinal centers where undergo clonal expansion and selection and antibody affinity maturation(7). The class-switching to IgE synthesis requires two signals. One of them is provided by interleukins IL-4, IL-13 released by Th2 cells, the other one is supported by the interaction between CD40, protein receptor constitutively expressed on B cells, and CD40 ligand (CD40L) which is expressed on activated Th2 cells(2, 8). Mature B cells isotype-switched from germinal centers, become long-lived memory B cells or long-lived plasma cells which ensure humoral memory and react on antigen recall by increasing the immunoglobulins synthesis(2). It is also possible that synthesis of IgE to be induced by corticosteroids in the presence of IL4, by increasing CD40 expression, not requiring the interaction with T cells(3, 9); Epstein-Barr virus can nonspecifically induce IgE class-switching, probably due to the similarity between a virus-encoded latent membrane protein 1 and CD40 molecule(10); complement C4-binding protein, a regulatory protein of classical complement pathway, also mimic the CD40 ligand and in presence of IL4, interacts with CD40 ligand, inducing switch to IgE synthesis(11).
Synthesis of IgE is negatively regulated by cytokines such as interferon- and IL-2, various B cell receptors (BCR, CD45, and CD23) trough different mechanisms(3).
There are evidences that the synthesis of IgE may not only take place in germinal-centres of lymph nodes but also in local mucosal tissues. It was revealed local synthesis of IgE in nasal mucosa in allergic rhinitis and bronchial mucosa in asthma, including asthma patients classified as non-atopic ones(6, 12, 13).
IgE fulfills its functions through immunoglobulin receptors. There are two classic types of receptors: high-affinity receptors FcεRI and low-affinity receptors FcεRII, different as structure, function and location. It was found that other molecules can act as additional IgE receptors or co-receptors, like galectin-3 that can interact with IgE or IgE receptor FcεRI, or CD21, important co-receptor of FcεRII involved in IgE regulation(6). High affinity receptor FcεRI has a tetrameric structure comprising one α-, one β- and two γ-subunits (αβγ2) or a trimeric one (αγ2) depending of where it is located (mast cells, basophils or dendritic cells, monocytes, macrophages respectively)(6). FcεRIα is a member of immunoglobulins superfamily and it is the subunit responsible for binding of IgE molecule(14). The βγ2 or γ2 complexes are the FcεRI signaling components. Cross-linking of IgE molecules connected to FcεRI on mast cells and basophils surfaces, leads to activation of the receptor and the subsequent signal transduction, cells activation and release of mediators. FcεRII is represented by CD23 polypeptides. There were found two polypeptides that differ in amino acid sequence, named CD23a (constitutively expressed by B cells) and CD23b (induced by IL4 on the surface of B cells, T cells, eosinophils, dendritic cells or epithelial cells)(15). Cross-linking of CD23 is involved in regulating IgE synthesis(15).
IgE produced locally in the mucosa binds to its FcεRI and FcεRII receptors on cells of the airway mucosa. When an allergen binds this local IgE, starts the typical symptoms of immediate hypersensitivity due to synthesis of inflammatory mediators and cytokines and initiate also the late-phase inflammatory response characteristic for asthma and allergic diseases(3).
The role of IgE in asthma pathogenesis
IgE plays a crucial role in the allergic response. Bronchial allergen challenge test in a sensitized individual, induces an IgE mediated allergic reaction characterized by an early response observed in 15-30 minutes, followed by a late phase reaction that begins 3-6 hours after the challenge and can persist for several hours to days(16,17). This type of reaction is associated with bronchial hyper-responsiveness to different triggers. Chronic allergen exposure induces chronic airways inflammation involving T cells, eosinophils, mast cells(18). The absence of high affinity receptors FcεRI, α chain, experimentally induced, highlights the importance of IgE during late-phase reactions and later establishment of chronic allergic airway inflammation. It has been shown that in mice lacking the FcεRIα chain, airway inflammation in an asthma model is diminished compared to wild-type mice(19,20). Was identified also, a significant correlation between the level of specific IgE and skin sensitivity to an allergen and the provocative dose necessary to decrease the forced expiratory volume in 1 second (FEV1) with 20%(21). In a pediatric population followed for 16 years to asses IgE sensitizations to food and inhalant allergens, 51% of children developed specific sensitization and 77% of them experienced allergic asthma. The authors’ conclusion was that specific IgE is strongly associated with asthma development from an age of 4 years(22). There are data supporting allergen-specific IgE as an efficient predictor for asthma symptoms in adult asthma too(23, 24). The activation of allergic cascade by specific IgE cross-linking and the following chronic allergic inflammation at the airways level, have been directly associated with airway remodeling. IL4 and IL13, the major cytokines involved in IgE synthesis, increase production of α-smooth muscle actin and collagen III, promote mucus metaplasia, subepithelial fibrosis and airway remodeling(20, 25, 26, 27, 28). It was shown that human airway smooth muscle cells express high and low affinity IgE receptors through which IgE can modulate cellular contraction and inflammatory mediator synthesis(29). In addition, was recently demonstrated that IgE stimulation in vitro of human airway smooth muscle cells isolated from asthmatic patients, amplify cell proliferation and extracellular matrix and collagen deposition in a dose-dependent manner(20, 29, 30).
Thus, there is important evidence supporting the role of IgE in asthma, even in non-atopic asthmatics which manifest raised serum total IgE in addition to raised blood and airway eosinophilia(31). A recent study showed that eosinophilic asthma exhibit higher serum total IgE and severe asthma also has higher levels of IgE compared with mild-to-moderate asthma. The authors found that in neutrophilic asthma level of total IgE and IgE sensitization are similar with that seen in pauci-granulocytic asthma, higher than in general population suggesting that atopy is a risk factor for asthma in any phenotype of inflammation(32).
The diagnostic role of total IgE
Total IgE measurements are often used in clinical practice in order to identify the atopic patients but the information should be carefully interpreted due to a considerable overlap of values between atopic subjects, non-atopic subjects and healthy controls. There are studies which have been demonstrate that serum total IgE measurements cannot be used to efficiently rule out sensitization to common inhalant allergens in adult subjects with symptoms that might be allergic, thus total IgE is not useful as the first step in the diagnostic work up of patients with allergic disease(33). However, it is expected that higher values of total IgE to be associated with a high risk of sensitization in younger subjects but this has limited practical utility(33). After that, the identification of the sensitizing inhalant allergens requires additional allergological tests. Bousquet et al.(34) found that in the age group 13–76 years, 38% of subjects with allergic disease and 25% of subjects with nonallergic asthma, rhinitis or conjunctivitis had total IgE concentrations within a ‘normal’ range. Asthmatic patients had higher mean IgE levels than those who were suffering from either rhinitis or conjunctivitis(34). Some authors suggested that total IgE increases with the number of sensitization, so the value of total IgE could rather help to discriminate polisensitized patients than monsensitized from non-sensitized patients(33).
IgE as a therapeutic target
Central role of IgE in asthma and allergic diseases pathogenesis increased the scientist interest to identify agents able to block the synthesis or signaling pathway of IgE. There are few experimental molecules (lumiliximab, ligelizumab, monoclonal antibody-12) or already in use molecules (omalizumab) against IgE or IgE receptors that can modulate the IgE effects. The intrinsic mechanism of these antibodies is different. Lumiliximab acts against FcεRII, block IgE synthesis in human B-cells and reduce serum IgE levels; ligelizumab is a humanized monoclonal IgG1κ antibody with a high avidity for IgE; monoclonal antibody-12 is an anti-human IgE antibody that may prove useful for the extracorporeal depletion of IgE and IgE-bearing cells from peripheral blood(20). Omalizumab is known to bind the Fc region of serum IgE, inhibiting the binding of IgE to FcεRIα on the surface of mast cells and basophils and gradually downregulate FcεRI expression on basophils, mast cells, dendritic cells. It was recently shown that omalizumab can induce anergy of B cells bearing membrane-attached IgE and these cells become unresponsive to antigenic stimuli(35). Starting from the known role of IgE in non-atopic asthma, some studies have suggested beneficial effect of anti-IgE therapy in this type of asthma too, indicating the possible modulation of innate immunity(36). The ability of omalizumab to lower free IgE in serum depends on dose, the patients' body weight and baseline total serum IgE level. Monitoring the level of total IgE in patients receiving omalizumab is not a useful tool because commercially available assays quantify both free IgE and IgE molecules that are part of omalizumab-IgE-complexes. New assays were developed in order to monitor free serum IgE once omalizumab treatment is initiated. Monitoring free IgE and omalizumab serum concentrations in patients treated with omalizumab does not predict clinical response. However, routine measurements of free IgE may be clinically relevant to demonstrate an adequate reduction in free IgE in patients not responding to omalizumab therapy(37).
Conclusions
The role of immunoglobulin E (IgE) in allergic asthmatic disease is well established. Allergen-specific IgE binds to specific receptors, triggering a series of cellular events including presentation of antigen by dendritic cells and degranulation of mast cells and basophils to release numerous factors that play an integral part in potentiating the disease symptoms. Recent data suggests that local IgE production may occur in mucosal tissues and that locally significant concentrations of IgE, not reflected by serum IgE concentrations, indicate that it may play a role in non-atopic as well as atopic disease. Central role of IgE in asthma pathogenesis has led to the development of therapeutic agents which modulate the synthesis and/or signaling pathways of IgE in order to modulate the long-term evolution of the disease.
References:
1. Anandan C, Nurmatov U, van Schayck OCP, Sheikh A. Is the prevalence of asthma declining? Systematic review of epidemiological studies. Allergy 2010;65:152–167
2. Dullaers M, De Bruyne R, Ramadani F, Gould HJ, Hannah J et al. The who, where, and when of IgE in allergic airway disease. The Journal of Allergy and Clinical Immunology, 2012, Volume 129, Issue 3
3. Rosenwasser, L.J. Mechanisms of IgE Inflammation. Curr Allergy Asthma Rep, 2011, 11: 178
4. Ishizaka K, Ishizaka T. Identification of gamma E-antibodies as a carrier of reaginic activity. J Immunol. 1967;99:1187–98
5. Hellman L. Regulation of IgE homeostasis, and the identification of potential targets for therapeutic intervention. Biomed Pharmacother 2007; 61:34–49.
6. Potaczek DP, Kabesch M. Current concepts of IgE regulation and impact of genetic determinants. Clinica land Experimental Allergy, 2012. Volume 42, Issue 6, Pages 852–871
7. McHeyzer-Williams L.J., McHeyzer-Williams M.G. Antigen-specific memory B cell development. Annu Rev Immunol, 2005, 23, pp. 487–513
8. Platts-Mills TA. The role of immunoglobulin E in allergy and asthma. Am J Respir Crit Care Med. 2001 Oct 15;164(8 Pt 2):S1-5
9. Jabara HH, Brodeur SR, Geha RS. Glucocorticoids upregulate CD40 ligand expression and induce CD40L-dependent immunoglobulin isotype switching. J Clin Invest. 2001;107:371–8
10. Geha RS, Jabara HH, Brodeur SR. The regulation of immunoglobulin E class-switch recombination. Nat Rev Immunol. 2003;3:721–32
11. Gounni AS, Lamkhioued B, Delaporte E, et al. The high-affinity IgE receptor on eosinophils: from allergy to parasites or from parasites to allergy? J Allergy Clin Immunol. 1994;94:1214–6
12. Takhar P, Smurthwaite L, Coker HA, Fear DJ, Banfield GK, Carr VA et al. Allergen drives class switching to IgE in the nasal mucosa in allergic rhinitis. J Immunol 2005; 174:5024–32.
13. Snow RE, Djukanovic R, Stevenson FK. Analysis of immunoglobulin E VH transcripts in a bronchial biopsy of an asthmatic patient confirms bias towards VH5, and indicates local clonal expansion, somatic mutation and isotype switch events. Immunology 1999; 98:646–51.
14. Garman SC, Sechi S, Kinet JP, Jardetzky TS. The analysis of the human high affinity IgE receptor Fc epsilon Ri alpha from multiple crystal forms. J Mol Biol 2001; 311:1049–62
15. Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol 2008; 8:205–17.
16. Holgate ST, Robinson C, Church MK. Mediators of immediate hypersensitivity. In: Middleton E Jr, Reed CE, Regis EF et al., eds. Allergy Principles and Practice 4th edn. St Louis, Missouri: Mosby, 1993:267±30.
17. O'Byrne PM, Dolovich J, Hargreave FE. Late asthmatic responses. Am Rev Respir Dis 1987; 136:740±51
18. Arshad S. H. and Holgate S. The role of IgE in allergen-induced inflammation and the potential for intervention with a humanized monoclonal antiIgE antibody. Clinical and Experimental Allergy, 2001, Volume 31, pages 1344±1351
19. Mayr SI, Zuberi RI, Zhang M, et al. IgE-dependent mast cell activation potentiates airway responses in murine asthma models. J Immunol 2002; 169: 2061–2068.
20. Samitas K, Delimpoura V, Zervas E, Gaga M. Anti-IgE treatment, airway inflammation and remodelling in severe allergic asthma: current knowledge and future perspectives. Eur Respir Rev. 2015 Dec;24(138):594-601
21. Cockcroft DW, Murdock KY, Kirby J, Hargreave F. Prediction of airway responsiveness to allergen from skin sensitivity to allergen and airway responsiveness to histamine. Am Rev Respir Dis 1987; 135:264±7
22. Ballardini N, Bergstr€om A, Wahlgren C-F, van Hage M, Hallner E, Kull I et al. IgE antibodies in relation to prevalence and multimorbidity of eczema, asthma, and rhinitis from birth to adolescence. Allergy 2015;71:342-349
23. Olivieri M, Heinrich J, Schl€unssen V, Anto JM, Forsberg B, Janson C et al. The risk of respiratory symptoms on allergen exposure increases with increasing specific IgE levels. Allergy 2016; 71:859-868.
24. Vandenplas O, Froidure A, Meurer U, Rihs HP, Rifflart C, Soetaert S et al. The role of allergen components for the diagnosis of latex-induced occupational asthma. Allergy 2016;71:840-849
25. Batra V, Musani AI, Hastie AT, et al. Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)-β1, TGF-β2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on α-smooth muscle actin and collagen III synthesis by primary human lung fibroblasts. Clin Exp Allergy 2004; 34: 437-444
26. Novak N, Bieber T. Allergic and nonallergic forms of atopic diseases. J Allergy Clin Immunol 2003; 112: 252-262
27. Doherty T, Broide D. Cytokines and growth factors in airway remodeling in asthma. Curr Opin Immunol 2007; 19: 676-68
28. Zhu Z, Homer RJ, Wang Z, et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999; 103: 779-788
29. Roth M, Zhong J, Zumkeller C, et al. The role of IgE-receptors in IgE-dependent airway smooth muscle cell remodelling. PLoS One 2013; 8: e56015
30. Redhu NS, Gounni AS. The high affinity IgE receptor (FcεRI) expression and function in airway smooth muscle. Pulm Pharmacol Ther 2013; 26: 86-94
31. Bettiol J, Bartsch P, Louis R et al. Cytokine production from peripheral whole blood in atopic and nonatopic asthmatics: relationship with blood and sputum eosinophilia and serum IgE levels. Allergy 2000; 55:1134±41
32. Manise M, Bakayoko B, Schleich F, Corhay JL, Louis R. IgE mediated sensitisation to aeroallergens in an asthmatic cohort: relationship with inflammatory phenotypes and disease severity. Int J Clin Pract. 2016 Jul;70(7):596-605
33. Kerkhof M, Dubois A. E. J., Postma D. S., Schouten J. P., et al. Role and interpretation of total serum IgE measurements in the diagnosis of allergic airway disease in adults. Allergy, Volume 58, Issue 9, September 2003, Pages 905-911
34. Bousquet J, Coulomb Y, Arrrendal H, Robinet-Levy M, Michel FB. Total serum IgE concentrations in adolescents and adults using the Phadebas IgE PRIST technique. Allergy 1982;37: 397-406
35. Chan MA, Gigliotti NM, Dotson AL, et al. Omalizumab may decrease IgE synthesis by targeting membrane IgE+ human B cells. Clin Transl Allergy 2013; 3: 29
36. Lommatzsch M, Korn S, Buhl R, et al. Against all odds: anti-IgE for intrinsic asthma? Thorax 2014; 69: 94-96
37. Korn S, Haasler I, Fliedner F, Becher G, Strohner P et al. Monitoring free serum IgE in severe asthma patients treated with omalizumab. Respir Med. 2012 Nov;106(11):1494-500
Nr.1 din luna ianuarie 2017
Asthma is a chronic inflammatory airway disease, which can be triggered by a variety of environmental factors, affecting about 300 million people worldwide(1). Although profound insights have been made into the pathophysiology of bronchial asthma and it is known that the typical symptoms of asthma (intermittent attacks of breathlessness, wheezing, cough) are caused by chronic inflammation and remodeling of the conducting airways, the exact mechanisms inducing and regulating the disease are still not fully understood. Allergic asthma is characterized by a TH2-dominated immune response associated with increased serum immunoglobulin E (IgE) levels in response to inhaled allergens. However, asthmatic patients with negative skin prick tests to common allergens, defined as nonatopic, usually characterized by a more severe and difficult-to-control disease, also have increased total IgE serum levels compared with those seen in healthy control subjects(2). It was demonstrated a direct correlation between asthma and the serum level of IgE, asthma prevalence increases linearly with the logarithm IgE values(3).
Immunoglobulin E synthesis, structure and receptors
Discovered in 1967(4), IgE is exclusively present in mammals(5). It was demonstrated that IgE has the ability to induce potent inflammatory immune responses with an essential role in allergic diseases. IgE is the immunoglobulin with a low plasma concentration (serum IgE levels are about 104 times lower than IgG concentrations in healthy individuals), with a short half-life (2.5 days), composed of two identical heavy chains which contains two regions, one variable and one constant and two identical light chains which contain one variable region and one constant domain(6). Variable regions of light and heavy chains create two identical antigen-binding sites. There are two forms of IgE: the secretory IgE and the membrane-bound form of IgE (mIgE) with an extracellular membrane proximal domain; a transmembrane sequence and a cytoplasmic tail are added to the last constant domain of the heavy chain(6). Surface forms of immunoglobulins are connected with two membrane proteins, Igα and Igβ, to form the B-cell antigen receptor with an important role in survival and development of the B cell(6).
The classic pathway of IgE synthesis requires interaction between mature naive B cells and dendritic cells which present the antigen into peripheral lymphoid organs. In an atopic millieu, dendritic cells will induce Th2 polarization; Th2 cells produce IL4, IL5, IL13, powerfull mediators of allergic inflammation and IgE synthesis(8).
The interaction between Th2 cells specific for a particular antigen, and B cells, induces a T-dependent antibody response. Activated B cells become short-lived plasma cells which produce specific antibodies, or stay in B-cell follicles and form germinal centers where undergo clonal expansion and selection and antibody affinity maturation(7). The class-switching to IgE synthesis requires two signals. One of them is provided by interleukins IL-4, IL-13 released by Th2 cells, the other one is supported by the interaction between CD40, protein receptor constitutively expressed on B cells, and CD40 ligand (CD40L) which is expressed on activated Th2 cells(2, 8). Mature B cells isotype-switched from germinal centers, become long-lived memory B cells or long-lived plasma cells which ensure humoral memory and react on antigen recall by increasing the immunoglobulins synthesis(2). It is also possible that synthesis of IgE to be induced by corticosteroids in the presence of IL4, by increasing CD40 expression, not requiring the interaction with T cells(3, 9); Epstein-Barr virus can nonspecifically induce IgE class-switching, probably due to the similarity between a virus-encoded latent membrane protein 1 and CD40 molecule(10); complement C4-binding protein, a regulatory protein of classical complement pathway, also mimic the CD40 ligand and in presence of IL4, interacts with CD40 ligand, inducing switch to IgE synthesis(11).
Synthesis of IgE is negatively regulated by cytokines such as interferon- and IL-2, various B cell receptors (BCR, CD45, and CD23) trough different mechanisms(3).
There are evidences that the synthesis of IgE may not only take place in germinal-centres of lymph nodes but also in local mucosal tissues. It was revealed local synthesis of IgE in nasal mucosa in allergic rhinitis and bronchial mucosa in asthma, including asthma patients classified as non-atopic ones(6, 12, 13).
IgE fulfills its functions through immunoglobulin receptors. There are two classic types of receptors: high-affinity receptors FcεRI and low-affinity receptors FcεRII, different as structure, function and location. It was found that other molecules can act as additional IgE receptors or co-receptors, like galectin-3 that can interact with IgE or IgE receptor FcεRI, or CD21, important co-receptor of FcεRII involved in IgE regulation(6). High affinity receptor FcεRI has a tetrameric structure comprising one α-, one β- and two γ-subunits (αβγ2) or a trimeric one (αγ2) depending of where it is located (mast cells, basophils or dendritic cells, monocytes, macrophages respectively)(6). FcεRIα is a member of immunoglobulins superfamily and it is the subunit responsible for binding of IgE molecule(14). The βγ2 or γ2 complexes are the FcεRI signaling components. Cross-linking of IgE molecules connected to FcεRI on mast cells and basophils surfaces, leads to activation of the receptor and the subsequent signal transduction, cells activation and release of mediators. FcεRII is represented by CD23 polypeptides. There were found two polypeptides that differ in amino acid sequence, named CD23a (constitutively expressed by B cells) and CD23b (induced by IL4 on the surface of B cells, T cells, eosinophils, dendritic cells or epithelial cells)(15). Cross-linking of CD23 is involved in regulating IgE synthesis(15).
IgE produced locally in the mucosa binds to its FcεRI and FcεRII receptors on cells of the airway mucosa. When an allergen binds this local IgE, starts the typical symptoms of immediate hypersensitivity due to synthesis of inflammatory mediators and cytokines and initiate also the late-phase inflammatory response characteristic for asthma and allergic diseases(3).
The role of IgE in asthma pathogenesis
IgE plays a crucial role in the allergic response. Bronchial allergen challenge test in a sensitized individual, induces an IgE mediated allergic reaction characterized by an early response observed in 15-30 minutes, followed by a late phase reaction that begins 3-6 hours after the challenge and can persist for several hours to days(16,17). This type of reaction is associated with bronchial hyper-responsiveness to different triggers. Chronic allergen exposure induces chronic airways inflammation involving T cells, eosinophils, mast cells(18). The absence of high affinity receptors FcεRI, α chain, experimentally induced, highlights the importance of IgE during late-phase reactions and later establishment of chronic allergic airway inflammation. It has been shown that in mice lacking the FcεRIα chain, airway inflammation in an asthma model is diminished compared to wild-type mice(19,20). Was identified also, a significant correlation between the level of specific IgE and skin sensitivity to an allergen and the provocative dose necessary to decrease the forced expiratory volume in 1 second (FEV1) with 20%(21). In a pediatric population followed for 16 years to asses IgE sensitizations to food and inhalant allergens, 51% of children developed specific sensitization and 77% of them experienced allergic asthma. The authors’ conclusion was that specific IgE is strongly associated with asthma development from an age of 4 years(22). There are data supporting allergen-specific IgE as an efficient predictor for asthma symptoms in adult asthma too(23, 24). The activation of allergic cascade by specific IgE cross-linking and the following chronic allergic inflammation at the airways level, have been directly associated with airway remodeling. IL4 and IL13, the major cytokines involved in IgE synthesis, increase production of α-smooth muscle actin and collagen III, promote mucus metaplasia, subepithelial fibrosis and airway remodeling(20, 25, 26, 27, 28). It was shown that human airway smooth muscle cells express high and low affinity IgE receptors through which IgE can modulate cellular contraction and inflammatory mediator synthesis(29). In addition, was recently demonstrated that IgE stimulation in vitro of human airway smooth muscle cells isolated from asthmatic patients, amplify cell proliferation and extracellular matrix and collagen deposition in a dose-dependent manner(20, 29, 30).
Thus, there is important evidence supporting the role of IgE in asthma, even in non-atopic asthmatics which manifest raised serum total IgE in addition to raised blood and airway eosinophilia(31). A recent study showed that eosinophilic asthma exhibit higher serum total IgE and severe asthma also has higher levels of IgE compared with mild-to-moderate asthma. The authors found that in neutrophilic asthma level of total IgE and IgE sensitization are similar with that seen in pauci-granulocytic asthma, higher than in general population suggesting that atopy is a risk factor for asthma in any phenotype of inflammation(32).
The diagnostic role of total IgE
Total IgE measurements are often used in clinical practice in order to identify the atopic patients but the information should be carefully interpreted due to a considerable overlap of values between atopic subjects, non-atopic subjects and healthy controls. There are studies which have been demonstrate that serum total IgE measurements cannot be used to efficiently rule out sensitization to common inhalant allergens in adult subjects with symptoms that might be allergic, thus total IgE is not useful as the first step in the diagnostic work up of patients with allergic disease(33). However, it is expected that higher values of total IgE to be associated with a high risk of sensitization in younger subjects but this has limited practical utility(33). After that, the identification of the sensitizing inhalant allergens requires additional allergological tests. Bousquet et al.(34) found that in the age group 13–76 years, 38% of subjects with allergic disease and 25% of subjects with nonallergic asthma, rhinitis or conjunctivitis had total IgE concentrations within a ‘normal’ range. Asthmatic patients had higher mean IgE levels than those who were suffering from either rhinitis or conjunctivitis(34). Some authors suggested that total IgE increases with the number of sensitization, so the value of total IgE could rather help to discriminate polisensitized patients than monsensitized from non-sensitized patients(33).
IgE as a therapeutic target
Central role of IgE in asthma and allergic diseases pathogenesis increased the scientist interest to identify agents able to block the synthesis or signaling pathway of IgE. There are few experimental molecules (lumiliximab, ligelizumab, monoclonal antibody-12) or already in use molecules (omalizumab) against IgE or IgE receptors that can modulate the IgE effects. The intrinsic mechanism of these antibodies is different. Lumiliximab acts against FcεRII, block IgE synthesis in human B-cells and reduce serum IgE levels; ligelizumab is a humanized monoclonal IgG1κ antibody with a high avidity for IgE; monoclonal antibody-12 is an anti-human IgE antibody that may prove useful for the extracorporeal depletion of IgE and IgE-bearing cells from peripheral blood(20). Omalizumab is known to bind the Fc region of serum IgE, inhibiting the binding of IgE to FcεRIα on the surface of mast cells and basophils and gradually downregulate FcεRI expression on basophils, mast cells, dendritic cells. It was recently shown that omalizumab can induce anergy of B cells bearing membrane-attached IgE and these cells become unresponsive to antigenic stimuli(35). Starting from the known role of IgE in non-atopic asthma, some studies have suggested beneficial effect of anti-IgE therapy in this type of asthma too, indicating the possible modulation of innate immunity(36). The ability of omalizumab to lower free IgE in serum depends on dose, the patients' body weight and baseline total serum IgE level. Monitoring the level of total IgE in patients receiving omalizumab is not a useful tool because commercially available assays quantify both free IgE and IgE molecules that are part of omalizumab-IgE-complexes. New assays were developed in order to monitor free serum IgE once omalizumab treatment is initiated. Monitoring free IgE and omalizumab serum concentrations in patients treated with omalizumab does not predict clinical response. However, routine measurements of free IgE may be clinically relevant to demonstrate an adequate reduction in free IgE in patients not responding to omalizumab therapy(37).
Conclusions
The role of immunoglobulin E (IgE) in allergic asthmatic disease is well established. Allergen-specific IgE binds to specific receptors, triggering a series of cellular events including presentation of antigen by dendritic cells and degranulation of mast cells and basophils to release numerous factors that play an integral part in potentiating the disease symptoms. Recent data suggests that local IgE production may occur in mucosal tissues and that locally significant concentrations of IgE, not reflected by serum IgE concentrations, indicate that it may play a role in non-atopic as well as atopic disease. Central role of IgE in asthma pathogenesis has led to the development of therapeutic agents which modulate the synthesis and/or signaling pathways of IgE in order to modulate the long-term evolution of the disease.
References:
1. Anandan C, Nurmatov U, van Schayck OCP, Sheikh A. Is the prevalence of asthma declining? Systematic review of epidemiological studies. Allergy 2010;65:152–167
2. Dullaers M, De Bruyne R, Ramadani F, Gould HJ, Hannah J et al. The who, where, and when of IgE in allergic airway disease. The Journal of Allergy and Clinical Immunology, 2012, Volume 129, Issue 3
3. Rosenwasser, L.J. Mechanisms of IgE Inflammation. Curr Allergy Asthma Rep, 2011, 11: 178
4. Ishizaka K, Ishizaka T. Identification of gamma E-antibodies as a carrier of reaginic activity. J Immunol. 1967;99:1187–98
5. Hellman L. Regulation of IgE homeostasis, and the identification of potential targets for therapeutic intervention. Biomed Pharmacother 2007; 61:34–49.
6. Potaczek DP, Kabesch M. Current concepts of IgE regulation and impact of genetic determinants. Clinica land Experimental Allergy, 2012. Volume 42, Issue 6, Pages 852–871
7. McHeyzer-Williams L.J., McHeyzer-Williams M.G. Antigen-specific memory B cell development. Annu Rev Immunol, 2005, 23, pp. 487–513
8. Platts-Mills TA. The role of immunoglobulin E in allergy and asthma. Am J Respir Crit Care Med. 2001 Oct 15;164(8 Pt 2):S1-5
9. Jabara HH, Brodeur SR, Geha RS. Glucocorticoids upregulate CD40 ligand expression and induce CD40L-dependent immunoglobulin isotype switching. J Clin Invest. 2001;107:371–8
10. Geha RS, Jabara HH, Brodeur SR. The regulation of immunoglobulin E class-switch recombination. Nat Rev Immunol. 2003;3:721–32
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