eISSN: 1644-4124
ISSN: 1426-3912
Central European Journal of Immunology
Current issue Archive Manuscripts accepted About the journal Editorial board Abstracting and indexing Subscription Contact Instructions for authors Ethical standards and procedures
SCImago Journal & Country Rank
vol. 28

Mechanisms of allergic inflammation in bronchial asthma

Renata Jankowska

(Centr Eur J Immunol 2003; 28 (1): 36–40)
Online publish date: 2004/01/20
Article file
- Mechanisms.pdf  [0.22 MB]
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero
A very complex mechanisms depending on inflammatory mediators are the background of allergic inflammation in airways. This is manifested by several phenomena like transudate, mucosal edema, increased secretion of mucus, changed viscosity of discharge, impairment of cilliary transportation and contraction of smooth muscles of bronchi. The above symptoms and shedding of respiratory epithelium lead to the obturation of bronchi, i.e. to impaired ventilation of airways due to the constriction of their lumen.

One may distinguish two phases of allergic inflammation:
- immediate-type allergic reaction, in which coupling of allergen to specific IgE bound to the high affinity receptor (FcεRI) on membrane of mast cells leads to the release of mediators including histamine, leukotrienes, prostaglandins, platelet activating factor and eosinophil chemotactic factor;
- late reaction, in which an afflux of inflammatory cells to bronchi and infiltration of subepithelial mucosa with eosinophils, lymphocytes (predominantly Th2) and mastocytes occurr. This phenomenon takes place following prior activation of cells and their migration to the inflammation site that i.e. towards the highest concentration of chemotactic factors. In this phase the most significant part in development and intensity of inflammatory response have cytokines released from cells and inflammation mediators secreted secondarily uder influence of cytokines.

Lasting inflammatory process is responsible for characteristic to asthma bronchial hyperreactivity, that is an exaggerated tendency to react with bronchospasm under influence of different stimuli. Bronchial asthma, due to chronic allergic inflammation, leads to the structural changes within bronchial walls. This process, called remodeling, is based on accumulation of collagen III and V, fibronectin and tenascin [1] in subepithelial layer instead of typical proteins like collagen IV and laminin, on hyperplasia and hypertrophy of goblet cells, submucosal glands, smooth muscles and an increase in number and volume of blood vessels [2–4]. Numerous cytokines and growth factors participate in phenomenon of remodeling with recent attention turned to IL-1, IL-13 and epithelial growth factor (EGF) [5–7].
In consequence of this remodeling, due to thickening of bronchial walls and shortening of smooth muscles, an increase in partially irreversible bronchial hyperreactivity may develop. In addition, an increase in vascularization of airways, hypertrophy of goblet cells and mucus glands may lead to the formation of mucus casts blocking airways [8, 9].

Allergic inflammation is found on every degree of advancement of bronchial asthma, including epizodic one [10]. Histopathological examinations confirm infiltration of bronchi with eosinophils, mast cells or lymphocytes. The main effector cells are mastocytes and eosinophils, which under an influence of various factors release preformed in granules and newly synthetized mediators, leading to the development of chronic inflammation. Lymphocytes, macrophages and epithelial cells also participate in development of inflammatory process.

An initial stage of allergic inflammation occurring after first contact with an allergen is an uptake and processing of inhalatory allergens by antigen presenting cells (APC), which include macrophages, dendritic cells and B lymphocytes. APC have an essential part in emergence of inflammatory response, because T lymphocytes usually can not react to allergens without their help [11].

Antigen presentation consists of succession of phenomena of procession and proper recognition of an allergen associated with MHC particle on surface of APC. Processing of an external allergen consists of its degradation in cytoplasm by proteolytic enzymes to peptide fragments which bind to MHC II particles in cytoplasms and transportation of these class II complexes to a cell surface.
B lymphocytes function as APC through surface immunoglobulins, whereas macrophages through nonspecific receptors.

Dendritic cells appear to be the main APCs. They have permanent expression of MHC molecules and uptake an antigen by means of pinocytosis. They initiate proliferation of T lymphocytes causing an increase in number of antigen specific T cells. In lungs, dendritic cells are located above the basal membrane of respiratory epithelium, at the site where the contact with an inhaled allergen occurrs [12]. In patients with bronchial asthma the number of CD+1a and MHC II dendritic cells is higher than in healthy subjects [13]. It has been known recently that dendritic cells have a key part not only in the induction of primary immune response but also in development and maintenance of allergic inflammation [14, 15].
Epithelial cells, although usually do not function as APCs can be stimulated to an expression of MHC class II by IFN gamma and function as APCs [16]. These cells have also an expression of other molecules important for antigen presentation (CD40, B7 and ICAM-1) [17].
The phenomenon of an antigen presentation has a key importance to a character of late inflammatory response. In dependence on which cytokines released in the process have an influence on precursor T lymphocytes, antigen specific Th cells differentiate towards Th1 or Th2. The kind of cytokines released during presentation of an antigen may in part depend on its nature but the cause of differentiation of Th is not precisely known [15]. In healthy subjects, Th lymphocytes differentiate mainly towards Th1 whereas in atopics towards Th2. It was shown that for differentiation towards Th2, the IL-4 is necessary whereas the one towards Th1, requests IFNγ, IFNα and IL-12. The latter cytokines simultaneously inhibit development of Th2 lymphocytes. IFNγ and IL-12 are secreted by APCs and act directly on T lymphocytes and indirectly through stimulation of NK cells towards production of IFNγ.
It is considered recently that T lymphocytes have an essential part in the induction and maintenance of inflammatory state in bronchial asthma [18]. Majority of the functions of T cells depends on the production of different cytokines, chemokines and other mediators. Th1 cells produce IL-2, IL-12, IFNγ, IFNβ and Th2 – IL-4, IL-5, IL-6, IL-10, IL-13 and sometimes in a very small guantities IL-2 and IFN gamma. However, both types of cells synthetize IL-3, GMCSF and TNF alpha [16].
Th2 lymphocytes stimulate humoral response, because IL-4 and IL-13 are the main factors inducing an increase in production of IgE in response to allergen. For the synthesis of IgE, an interaction of CD 40 with a ligand of stimulated T cells is also necessary [19]. IL-4 is produced also by mast cells, NKs and basophils [20] whereas IL-13 by mastocytes and stimulated Th2 cells [21]. It has the capacity of switching the B cells towards production of IgE. Similarly to IL-4, IL-13 also increases an expression of CD23 and MHC II on B cells and monocytes. IL-13 ifluences, in a lesser degree, the trancription and switching the immunoglobulin production towards IgG4 and IgE [7]. Atopic subjects have a higher number of cells producing IgE than healthy ones. Moreover, an increase in IgE synthesis is influenced by IL-5 and IL-6 produced by Th2, whereas IL-12 produced by Th1 inhibits synthesis of IgE by peripheral blood mononuclears stimulated IL-4 [22]. The factors influencing the synthesis of IgE independently on T cells may be Epstein Barr, RSV, Parainfluenza and Influenza viruses which have the ability to direct B lymphocytes to the production of specific IgE antibodies [23]. Independently on viral infection, an increase in IgE concentration was found in serum and bronchoalveolar lavage (BAL) of allergic subjects [24].

Mastocyte is an effector cell in immediate allergic reaction. Mature mast cells are present only in tissues and are particularly numerous in those which come into contact with an external environment i.e. mucosa of airways. One may distinguish the two subpopulations of human mast cells: the one, containing tryptase, present mainly in mucous membranes, the other, containing tryptase and chymase, in connective tissue. Crosslinking of surface IgE by an allergen triggers a release of preformed mediators like histamine, synthesis of lipid mediators like leukotrienes (LTC4, LTD4, LTE4) and prostaglandins (PGD2). These mediators induce an early phase of allergy. Several hours later, cytokines (IL-4, IL-5, IL-6, IL-13, TNF alpha, GMCSF) and chemokines are released, enhancing an inflammatory reaction.

Histamine released from mast cell granules during immediate allergic reaction acts through their H1, H2 and H3 receptors. Stimulation of H1 recepors is instaneous and disappears early whereas H2 react more slowly and longer. In majority of proinflammatory activities of histamine participate H1 receptors causing the contraction of smooth muscles of bronchi, stimulation of afferent fibres of n. vagus and sensory fibres C. The result of these activities is bronchial hyperreactivity being not only bronchospasm but also the release of acetylcholine (increase in tonus of bronchial walls) and substance P (neurogenic inflammation). In addition, histamine through H1 receptors induces production and release of nitric oxide (NO), prostacycline PGI2, shrinking of endothelial cells leading to increased vascular permeability and edema. In allergic rhinitis, stimulation by histamine the sensory, afferent C fibres causes sneezing, pruritus and edema of nasal mucosa whereas stimulation of n. vagus – rhinorrhea.

Cysteine leukotrienes (LTD4 and LTE4) induce prolonged bronchospasm, increase vascular permeability and chemotaxis of inflammatory cells, mostly eosinophils (LTD4) and neutrophils (LTC4), towards an inflammation site. It was shown that positive provocation test with LTE4 caused an increase in number of eosinophils in biopsies of bronchial mucosa. One has to consider that leukotrienes are produced by different cells depending on the phase of an allergic reaction. At early one, their source are mast cells, later – eosinophils. This was confirmed by Smith, who found that antagonists of CysLT-1 inhibit both early and late phase of an allergic reaction [25].

The late phase of allergic reaction is the stage in which the main part have eosinophils accumulating at the site of inflammation and the active proteins produced by them (MBP, ECP, EDN, EPO). An appearance of inflammatory cells is preceded by the following phenomena [23, 26]:
- association of leukocytes with vascular endothelial cells,
- rolling of cells along a vessel walls with participation of E-selectins,
- adhesion and stimulation of leukocytes determined by the presence of α4β1 and α4β7 integrins,
- passing between endothelial cells and chemotaxis of leukocytes towards an inflammation site.

These sequential phenomena are the result cooperation between inflammatory and stimulated endothelial cells. Vascular endothelium, by the release of cytokines (IL-1, IL-8), leukotriene B4, PAT, NO and chemotactic factors, influences the activation of inflammatory cells and increases the expression of adhesion molecules [27].

Eosinophils are the main effector cells in allergic inflammation and determine the course of bronchial asthma [28, 29]. The increased accumulation of eosinophils in airways of asthmatics was shown following inhalatory allergen provocation or after innhalation of IL-5 [22, 29]. In mice genetically lacking IL-5, allergen provocation did not increase the number of eosinophils and hyperreactivity of bronchi to metacholine [30]. These results confirm the essential participation of eosinophils in development of bronchial reactivity [31], particularly that the experimental placing of MBP in bronchi led to their hyperreactivity and on the other hand the autopsy data of subjects who died due to asthma revealed MBP deposits in airways [32]. Concentration of MBP and EDN in bronchoalveolar lavage were higher in patients with symptomatic bronchial asthma than during remission of the disease. Busse et al. have shown that inflammation mediators, particularly MBP, can directly damage respiratory epithelium and in addition secondarily cause degranulation of mast cells [28, 33].
IL-5 is not the only factor stimulating an infiltration of airways. IL-1, TNF alpha and IL-4 binding to the surface receptors of endothelium induce the expression of adhesion molecules, necessary for infiltration with eosinophils.

Respiratory epithelium acts as a defence against an external environment. This include the production of mucus by goblet cells, production of surfactant, efficient cilliary transportation, production and release of inflammation mediators and expression of adhesion molecules participating in movement of inflammatory cells. It was found that the cells of respiratory epithelium of asthmatics during remission show an increased expression of surface ICAM-1 molecules in comparison to the epithelium of healthy subjects. This may explain the increased sensitivity of children with atopia to infections of upper airways, for it is known that ICAM-1 is the tissue receptor for rhinovirus [34, 35]. It has been shown recently that Th2 cytokines cause, in vitro, a marked increase in expression of surface ICAM-1. It has been also found that rhinoviruses cause further increase an expression of Th2-induced ICAM-1 molecules [36].
The airway epithelium exert effector functions, as epithelial cell synthesize and secrete mediators such as leukotriens (LTC4 and LTD4), prostanoids and cytokines (IL-α, IL-1β, IL-6, Il-8, TNFα, TNFβ, GM-CSF and Rantes) [37].
The presence of one of the isoforms of nitric oxide synthetase (iNOS) was detected on the surface of respiratory epithelium cells, smooth muscles, vascular endothelium and macrophages. It turned out that an increase in the expression of iNOS may appear after exposure to an allergen [38]. The expression of iNOS on bronchial mucous membrane is induced by proinflammatory cytokines (TNFα, IL-1β), manufactured by macrophages and IFN gamma, produced by Th1 lymphocytes [39]. In patients put through specific provocation test, after which late phase of allergic reaction occurred, an increased concentration of NO in exhaled air was observed, correlating with the decrease in FEV1 [38]. Action of NO depends on its concentration at the reaction site – in low concentrations it regulates the homeostasis of immunological, circulatory and respiratory system, in high – has proinflammatory and cytotoxic activity. NO can exacerbate innflammation through selective blocking of Th1 lymphocytes, shifting the Th1/Th2 balance and also acting directly or through toxic hydroxyl radicals, participating in shedding of epithelium in bronchial asthma [40].
In atopic asthma, Th2 are the main lymphocyte population in biopsy samples of bronchi and BALf [16]. Th2 cytokines promote allergy and the degree of activation of Th2, and in allergic asthma, directly correlate with the severity of symptoms [12].

In 2003, Willis-Karp et al. have published the hypothesis that IL-13, produced by Th lymphocytes, eosinophils and mastocytes, induces bronchial hyperreactivity via its direct action on bronchial epithelium and smooth muscles and not in dependence on IgE and eosinophils. According to the hypothesis, bronchial hyperreactivity develops on basis of following events caused by IL-13:
- influencing respiratory epithelial cell it increases mucus production and impaires cilliary transportation, leading to obturation of airways,
- induces secretion of TGF beta by epithelial cells which stimulates secretion of extracellular matrix components and the mediators influencing matrix in bronchial walls,
- decreases the production of NO by epithelial cells, what probably leads to an increase in bronchial smooth muscles tonus,
- can induce production of anaphylatoxin, the complement component paticipating in development of bronchial hyperreactivity,
- can directly damage beta adrenergic receptor responsible for relaxation of bronchial smooth muscles [7].

The presented data prove how complicated and dependent on various factors is allergic inflammation in bronchial asthma. As it is known, this process is a result of numerous interactions of leukocytes, epithelial and endothelial cells regulated by cytokines, adhesion molecules, chemotactic and growth factors. The results of many investigations have therapeutical implications. Employment of glucocorticosteroids, inhibitors of leukotriene receptor, inhibitors of phosphodiesterase controls several links of allergic inflammation and this way influences the decrease or withdrawal of disease symptoms. Nevertheless, none of these drugs is able to stop the emergence of IgE dependent allergic reaction and subsequent inflammation. Recently, obtaining monoclonal antibodies to IgE created the possibility of blocking this reaction by inhibiting the IgE synthesis. An attempts of employment of the ”humanized” anti IgE antibody (Omalizumab) to the therapy of allergic diseases showed the decrease in concentration of serum IgE, bronchial hyperreactivity and the number of eosinophils in sputum [41, 42]. However, this therpeutical approach still requires further observation.


1. Laitinen A, Altraja A, Kampe M, et al. (1997): Tenascin is increased in airway basement membrane of asthmatics and decreased by an inhaled steroid. Am J Respir Crit Care Med 156: 951-958.
2. Li X, Wilson JW (1997): Increased vascularity of the bronchial mucose in mild asthma. Am J Respir Crit Care Med 156: 229-233.
3. Kips JC, Pouwels RA (1999): Airway wall remodeling: does it occur and what does it mean? Clin Exp Allergy 29: 1457-1466.
4. Bousquet J, Jeffery PK, Busse WW, et al. (2000): Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 161: 1720-1745.
5. Tang W, Geba GP, Zheng T, et al. (1999): Targeted expression of IL-11 in the murine airway causes lymphocytic inflammation, bronchiale remodeling and airway obstruction. J Clin Invest 98: 2845-2853.
6. Takeyama K, Fahy JV, Nadel JA (2001): Relation of epidermal factor receptors to goblet cells production in human bronchi. Am J Respir Care Med 163: 511-516.
7. Wills-Karp M, Chiaramonte M (2003): Interleukin-13 in asthma. Curr Opin Pulm Med 9: 21-27.
8. Aikawa T, Shimura S, Sasaki H, et al. (1992): Market goblet cell hyperplasia with mucus accumulation in the airways of patients who died of severe acute asthma attack. Chest 101: 916-921.
9. Nadel JA, Takeyama K (1999): Mechanisms of hypersecretion in acute asthma, propose cause of death, and novel therapy. Pediatric Pulmonol 18: 54S-55S.
10. Holgate ST (1993): Asthma: past, present and future. Eur Respir J 6: 1507-1520.
11. Stirling RG, Chung KF (2000): New immunological approaches and cytokine targets in asthma and allergy. Eur Respir J 16: 1158-1174.
12. von Bubnoff D, Geiger E, Bieber T (2001): Antigen – presenting cells in allergy. J Allergy Clin Immunol 108: 329-39.
13. Moller GM, Overbeek SE, Van Helden-Meeuwsen CG, et al. (1996): Increased numbers of dendritic cells in the bronchial mucosa of atopic asthmatic patients: downregulation by inhaled corticosteroids. Clin Exp Allergy 26: 517-524.
14. Lambrecht BN, De Veermen M, Coyle AJ, et al. (2000): Myeloid dendritic cells induce Th2 responses to inhaled antigen leading to eosinophilic airway inflammation. J Clin Invest 106: 551-559.
15. Lambrecht BN, Hammad H (2003): The other cells in asthma dendritic cell and epithelial cell crosstalk. Curr Opin Pulm Med 9: 34-31.
16. Mazzarella G, Bianco A, Catena E, et al. (2000): Th1/Th2 lymphocyte polarization in asthma. Allergy 55: (suppl 61) 6-9.
17. Nakijama J, Ono M, Takeda M, et al. (1997): Role of costimulatory molecules on airway epithelial cells acting as alloantigen presenting cells. Transplant Proc 2297-2300.
18. Wills- Karp M (1999): Immunological basis of antigen – induced airway hyperresposiveness. Ann Rev Immunol 17: 225-281.
19. Barcharier LB, Geha RS (2000): Molecular mechanisms of IgE regulation. J Allergy Clin Immunol 105: 547-55.
20. Ryan JJ (1997): Interleukin-4 and its receptor: essential mediators of the allergic response. J Allergy Clin Immunol 99: 1-5.
21. Keegan AD, Neim SK, Wang LM, et al. (1994): Interleukin-4 receptor: signaling mechanism. Immunol Today 15: 423-532.
22. Broide DH (2001): Molecular and cellular mechanisms of allergic diseases. J Allergy Clin Immunol 108: S65-71.
23. Stokes PR, Harter TV (2000): Respiratory viruses and asthma. Curr Opin Pulm Med 6: 10-14.
24. Shi HZ, Xiao CQ, Zhong D, et al. (1998): Effect of inhaled interleukin-5 on airway hyperractivity and eosinophilia in asthmatics. Am J Respir Crit Care Med 157: 204-9.
25. Smith LJ (1998): The prospects for long-term intervention in asthma with antileukotrienes. Clin Exp Allergy 28: (suppl 5) 17-26.
26. Butley AM (1993): Expression of endothelial and leukocyte adhesion molecules intercellular adhesion molecule -1, E-selectin and vascular cell adhesion molecule -1 in the bronchial mucosa in steady state of allergen- induced asthma. J Allergy Clin Immunol 92: 857-868.
27. Montefort S, Holgate ST, Howorth PF (1993): Leukocyte -endothelial adhesion molecules and their role in bronchial asthma and allergic rhinitis. Eur Respir J 6: 1044-1054.
28. Venge P (1990): What is the role of eosinophil? Thorax 45: 161-163.
29. Habre W, Loh RKS, Isidoro A, et al. Eosinophil cationic protein and tryptase levels in bronchoalveolar lavage fluid of children with and without asthma: correlation with lung function. Eur Respir J 12: (suppl 28) S105.
30. Foster P, Hogan SP, Ramsay AJ, et al. (1996): Interleukin-5 deficiency abolished eosinophilia, airway heperreactivity and lung damage in a mouse asthma model. J Exp Med 183: 195-201.
31. Gleich GJ, Flavahan NA, Fujisawa T, et al. (1988): The eosinophil as a mediator of damage to respiratory epithelium: a model for bronchial hyperractivity. J Allergy Clin Immunol 81: 776-81.
32. Gleich GJ (2000): Mechanisms of eosinophil – associated inflammation. J Allergy Clin Immunol 105: 651-63.
33. Busse WW, Lemanske RFJ (2001): Asthma. N Engl J Med 344: 350-62.
34. Greve JM, Davis G, Mejer AM, et al. (1989): The major human rhinovirus receptor is ICAM-1. Cell 56: 839-47.
35. Pattemore PK, Johnston SL, Bardin PG (1995): Viruses as precipitant of asthmatic symptoms epidemiology. J Allergyy Clin Immunol 96: 971-979.
36. Bianco A, Sethi SK, Allen JT, et al. (1998): TH2 cytokines exert a dominant influence on epithelial cell expression of the major group human rihnovirus receptor, ICAM-1. Eur Respir J 12: 619-26.
37. Martin LD, Rochelle LG, Fisher BM, et al. (1997): Airway epithelium as an effector of inflammation molecular regulation of secondary mediators. Eur Respir J 10: 2139-2146.
38. Kharitonov SA, O, Connor BJ, Evans DJ, et al. (1995): Allergen – induced late asthmatic reactions are associated with elevation of exhaled nitric oxide. Am J Respir Crit Care Med 151: 1894-1899.
39. Donelly LE, Barnes PJ (2002): Expression and regulation of inducible nitric oxide synthase from human primary airway epithelial cells. Am J Respir Cell Mol Biol 26: 144-151.
40. Heiss LN (1994): Epithelial autotoxicity of nitric oxide. Role in respiratory cytopathology of nitric oxide. Proc Natl Acad Sci 91: 267 -271.
41. Fahy VJ, Fleming HE, Wong HH, et al. (1997): The effect of an anti-IgE monoclonal antibody on the early- and late- phase responses to allergen inhalation in asthmatic subjects. Am J Respi Crit Care 155: 1828-1834.
42. Milgrom H, Fick RBJ, Su JQ, et al. (1999): Treatment of allergic asthma with monoclonal anti-IgE antibody rhuMAB-E25 Study Group. N Engl J Med 341: 1966-1977.
Copyright: © 2004 Polish Society of Experimental and Clinical Immunology This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Quick links
© 2022 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.