Abstract
Bronchial asthma is a common immune-mediated disorder characterized by reversible airway inflammation, mucus production, and variable airflow obstruction with airway hyperresponsiveness. Allergen exposure results in the activation of numerous cells of the immune system, of which dendritic cells (DCs) and Th2 lymphocytes are of paramount importance. Although the epithelium was initially considered to function solely as a physical barrier, it is now evident that it plays a central role in the Th2-cell sensitization process due to its ability to activate DCs. Cytokines are inevitable factors in driving immune responses. To the list of numerous cytokines already known to be involved in the regulation of allergic reactions, new cytokines were added, such as TSLP, IL-25, and IL-33. IgE is also a central player in the allergic response. The activity of IgE is associated with a network of proteins, especially with its high- and low-affinity Fc receptors. Understanding the cellular and molecular mechanisms of allergic reactions helps us not only to understand the mechanisms of current treatments, but is also important for the identification of new targets for biological intervention. An IgE-specific monoclonal antibody, omalizumab, has already reached the clinic and similar biological agents will surely follow.
Similar content being viewed by others
References
(1991) Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute. National Asthma Education Program. Expert Panel Report. J Allergy Clin Immunol 88:425–534
Adcock IM, Caramori G, Chung KF (2008) New targets for drug development in asthma. Lancet 372: 1073–1087
Akbari O, Faul JL, Hoyte EG et al (2006) CD4+ invariant T–cell-receptor+ natural killer T cells in bronchial asthma. N Engl J Med 354: 1117–1129
Anderson GP (2008) Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 372: 1107–1119
Antony AB, Tepper RS, Mohammed KA (2002) Cockroach extract antigen increases bronchial airway epithelial permeability. J Allergy Clin Immunol 110: 589–595
Aubry JP, Pochon S, Gauchat JF et al (1994) CD23 interacts with a new functional extracytoplasmic domain involving N–linked oligosaccharides on CD21. J Immunol 152: 5806–5813
Barbato A, Turato G, Baraldo S et al (2006) Epithelial damage and angiogenesis in the airways of children with asthma. Am J Respir Crit Care Med 174: 975–981
Barnes PJ (2006a) Drugs for asthma. Br J Pharmacol 147: S297–303
Barnes PJ (2006b) How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 148: 245–254
Barnes PJ (2008a) Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 8: 183–192
Barnes PJ (2008b) Role of GATA-3 in allergic diseases. Curr Mol Med 8: 330–334
Berger P, Perng DW, Thabrew H et al (2001) Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells. J Appl Physiol 91: 1372–1379
Berry MA, Hargadon B, Shelley M et al (2006) Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 354: 697–708
Bleck B, Tse DB, Jaspers I et al (2006) Diesel exhaust particle–exposed human bronchial epithelial cells induce dendritic cell maturation. J Immunol 176: 7431–7437
Bochner BS, Busse WW (2005) Allergy and asthma. J Allergy Clin Immunol 115: 953–959
Borish LC, Nelson HS, Lanz MJ et al (1999) Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med 160: 1816–1823
Bullens DM, Truyen E, Coteur L et al (2006) IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir Res 7: 135
Burgess JK, Blake AE, Boustany S et al (2005) CD40 and OX40 ligand are increased on stimulated asthmatic airway smooth muscle. J Allergy Clin Immunol 115: 302–308
Cahalan MD, Parker I (2006) Imaging the choreography of lymphocyte trafficking and the immune response. Curr Opin Immunol 18: 476–482
Casalino-Matsuda SM, Monzon ME, Forteza RM (2006) Epidermal growth factor receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium. Am J Respir Cell Mol Biol 34: 581–591
Comhair SA, Xu W, Ghosh S et al (2005) Superoxide dismutase inactivation in pathophysiology of asthmatic airway remodeling and reactivity. Am J Pathol 166: 663–674
Cosio BG, Tsaprouni L, Ito K et al (2004) Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 200: 689–695
Creticos PS, Chen YH, Schroeder JT (2004) New approaches in immunotherapy: allergen vaccination with immunostimulatory DNA. Immunol Allergy Clin North Am 24: 569–581
Durham SR, Walker SM, Varga EM et al (1999) Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 341: 468–475
Evans DJ, Cullinan P, Geddes DM (2001) Cyclosporin as an oral corticosteroid sparing agent in stable asthma. Cochrane database of systematic reviews (Online), CD002993
Finkelman FD, Urban JF Jr (1992) Cytokines: making the right choice. Parasitol Today 8: 311–314
Flood-Page P, Swenson C, Faiferman I et al (2007) A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 176: 1062–1071
Flood-Page PT, Kay AB, Kay AB, Kay AB et al (2003) Eosinophil’s role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 167: 199–204
Foley SC, Mogas AK, Olivenstein R et al (2007) Increased expression of ADAM33 and ADAM8 with disease progression in asthma. J Allergy Clin Immunol 119: 863–871
Gaga M, Zervas E, Grivas S et al (2007) Evaluation and management of severe asthma. Curr Med Chem 14: 1049–1059
Goleva E, Li LB, Eves PT et al (2006) Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. Am J Respir Crit Care Med 173: 607–616
Gould HJ, Sutton BJ (2008) IgE in allergy and asthma today. Nat Rev Immunol 8: 205–217
Green RH, Brightling CE, Woltmann G et al (2002) Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 57: 875–879
Hamilton LM, Torres-Lozano C, Puddicombe SM et al (2003) The role of the epidermal growth factor receptor in sustaining neutrophil inflammation in severe asthma. Clin Exp Allergy 33: 233–240
Hammad H, Lambrecht BN (2008) Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat Rev Immunol 8: 193–204
Hart TK, Blackburn MN, Brigham-Burke M et al (2002) Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma. Clin Exp Immunol 130: 93–100
Hart TK, Cook RM, Zia-Amirhosseini P et al (2001) Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys. J Allergy Clin Immunol 108: 250–257
Hibbert RG, Teriete P, Grundy GJ et al (2005) The structure of human CD23 and its interactions with IgE and CD21. J Exp Med 202: 751–760
Hintzen G, Ohl L, del Rio ML et al (2006) Induction of tolerance to innocuous inhaled antigen relies on a CCR7-dependent dendritic cell-mediated antigen transport to the bronchial lymph node. J Immunol 177: 7346–7354
Holgate ST (2008) Pathogenesis of asthma. Clin Exp Allergy 38: 872–897
Holgate ST, Casale T, Casale T, Casale T et al (2005) Anti–immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy. Clin Exp Allergy 35: 408–416
Holgate ST, Polosa R (2006) The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 368: 780–793
Holgate ST, Polosa R (2008) Treatment strategies for allergy and asthma. Nat Rev Immunol 8: 218–230
Holgate ST, Yang Y, Haitchi HM et al (2006) The genetics of asthma: ADAM33 as an example of a susceptibility gene. Proc Am Thorac Soc 3: 440–443
Howarth PH, Babu KS, Arshad HS et al (2005) Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 60: 1012–1018
Humbert M, Menz G, Ying S et al (1999) The immunopathology of extrinsic (atopic) and intrinsic (non-atopic) asthma: more similarities than differences. Immunol Today 20: 528–533
Idzko M, Hammad H, van Nimwegen M et al (2006) Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function. J Clin Invest 116: 2935–2944
Ito K, Lim S, Caramori G et al (2002) A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Nat Acad Sci USA 99: 8921–8926
Ito T, Wang YH, Duramad O et al (2005) TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med 202: 1213–1223
Jahnsen FL, Strickland DH, Thomas JA et al (2006) Accelerated antigen sampling and transport by airway mucosal dendritic cells following inhalation of a bacterial stimulus. J Immunol 177: 5861–5867
Jinquan T, Li W, Yuling H et al (2006) All roads lead to Rome: pathways of NKT cells promoting asthma. Arch Immunol Ther Exp 54: 335–340
Karagiannis SN, Warrack JK, Jennings KH et al (2001) Endocytosis and recycling of the complex between CD23 and HLA-DR in human B cells. Immunology 103: 319–331
Kaur D, Saunders R, Berger P et al (2006) Airway smooth muscle and mast cell-derived CC chemokine ligand 19 mediate airway smooth muscle migration in asthma. Am J Respir Crit Care Med 174: 1179–1188
Kay AB (2006) The role of T lymphocytes in asthma. Chem Immunol Allergy 91: 59–75
Keatings VM, Collins PD., Scott DM et al (1996) Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 153: 530–534
Kiss A, Montes M, Susarla S et al (2007) A new mechanism regulating the initiation of allergic airway inflammation. J Allergy Clin Immunol 120: 334–342
Komai-Koma M, Xu D, Li Y et al (2007) IL-33 is a chemoattractant for human Th2 cells. Eur J Immunol 37: 2779–2786
Kondo Y, Yoshimoto T, Yasuda K et al (2008) Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int Immunol 20: 791–800
Kurowska-Stolarska M, Kewin P, Murphy G et al (2008) IL-33 induces antigen-specific IL-5+ T cells and promotes allergic-induced airway inflammation independent of IL-4. J Immunol 181: 4780–4790
Lamers MC, Yu P (1995) Regulation of IgE synthesis. Lessons from the study of IgE transgenic and CD23-deficient mice. Immunol Rev 147: 71–95
Leckie MJ, ten Brinke A, Khan J et al (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356: 2144–2148
Lee JH, Yu HH, Wang LC et al (2007) The levels of CD4+CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma. Clin Exp Immunol 148: 53–63
Lex C, Zacharasiewicz A, Payne DN et al (2006) Exhaled breath condensate cysteinyl leukotrienes and airway remodeling in childhood asthma: a pilot study. Respir Res 7: 6
Liu FT (2005) Regulatory roles of galectins in the immune response. Int Arch Allergy Immunol 136: 385–400
Liu YJ (2006) Thymic stromal lymphopoietin: master switch for allergic inflammation. J Exp Med 203: 269–273
Livingston E, Chaudhuri R, McMahon AD et al (2007) Systemic sensitivity to corticosteroids in smokers with asthma. Eur Respir J 29: 64–71
Loke TK, Mallett KH, Ratoff J et al (2006) Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients. J Allergy Clin Immunol 118: 368–375
Lukacs NW, Berlin AA, Franz-Bacon K et al (2008) CRTH2 antagonism significantly ameliorates airway hyperreactivity and downregulates inflammation-induced genes in a mouse model of airway inflammation. Am J Physiol 295: L767–779
Lund L, Henmar H, Wurtzen PA et al (2007) Comparison of allergenicity and immunogenicity of an intact allergen vaccine and commercially available allergoid products for birch pollen immunotherapy. Clin Exp Allergy 37: 564–571
MacGlashan D Jr (2008) IgE receptor and signal transduction in mast cells and basophils. Curr Opin Immunol 20: 717–723
Min B (2008) Basophils: what they ‘can do’ versus what they ‘actually do’. Nat Immunol 9: 1333–1339
Min B, Paul WE (2008) Basophils: in the spotlight at last. Nat Immunol 9: 223–225
Montagnac G, Molla-Herman A, Bouchet J et al (2005) Intracellular trafficking of CD23: differential regulation in humans and mice by both extracellular and intracellular exons. J Immunol 174: 5562–5572
Mudde GC, Bheekha R, Bruijnzeel-Koomen CA (1995) Consequences of IgE/CD23-mediated antigen presentation in allergy. Immunol Today 16: 380–383
Neefjes JJ (1996) Antigen presentation by MHC class I and II molecules. Immunobiology 195: 456–460
Omori M, Ziegler S (2007) Induction of IL-4 expression in CD4(+) T cells by thymic stromal lymphopoietin. J Immunol 178: 1396–1404
Paganin F, Seneterre E, Chanez P et al (1996) Computed tomography of the lungs in asthma: influence of disease severity and etiology. Am J Respir Crit Care Med 153: 110–114
Pajno GB (2007) Sublingual immunotherapy: the optimism and the issues. J Allergy Clin Immunol 119: 796–801
Perez-Vilar J (2007) Mucin granule intraluminal organization. Am J Respir Cell Mol Biol 36: 183–190
Pizzichini E, Leff JA, Reiss TF et al (1999) Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J 14: 12–18
Rahman I (2002) Oxidative stress and gene transcription in asthma and chronic obstructive pulmonary disease: antioxidant therapeutic targets. Curr Drug Targets 1: 291–315
Reise Sousa C (2006) Dendritic cells in a mature age. Nat Rev Immunol 6: 476–483
Rivera J, Fierro NA, Olivera A et al (2008) New insights on mast cell activation via the high affinity receptor for IgE. Adv Immunol 98: 85–120
Rosenwasser LJ, Meng J (2005) Anti-CD23. Clin Rev Allergy Immunol 29: 61–72
Runswick S, Mitchell T, Davies P et al (2007) Pollen proteolytic enzymes degrade tight junctions. Respirology 12: 834–842
Russo C, Polosa R (2005) TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis. Clin Sci 109: 135–142
Sandor F, Buc M (2005a) Toll-like receptors. I. Structure, function and their ligands. Folia Biol 51: 148–157
Sandor F, Buc M (2005b) Toll-like receptors. II. Distribution and pathways involved in TLR signalling. Folia Biol 51: 188–197
Sandor F, Buc M (2005c) Toll-like receptors. III. Biological significance and impact for human medicine. Folia Biol 51: 198–203
Sano Y, Yamada H (2007) Progress in suplatast tosilate research. Clin Exp Allergy 37: 970–972
Sehmi R, Dorman S, Baatjes A et al (2003) Allergen-induced fluctuation in CC chemokine receptor 3 expression on bone marrow CD34+ cells from asthmatic subjects: significance for mobilization of haemopoietic progenitor cells in allergic inflammation. Immunology 109: 536–546
Shakib F, Ghaemmaghami AM, Sewell HF (2008) The molecular basis of allergenicity. Trends Immunol 29: 633–642
Shakib F, Schulz O, Sewell H (1998) A mite subversive: cleavage of CD23 and CD25 by Der p 1 enhances allergenicity. Immunol Today 19: 313–316
Simpson JL, Scott R, Boyle MJ et al (2006) Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology 11: 54–61
Simpson JL, Scott RJ, Boyle MJ et al (2005) Differential proteolytic enzyme activity in eosinophilic and neutrophilic asthma. Am J Respir Crit Care Med 172: 559–565
Sokol CL, Barton GM, Farr AG et al (2008) A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol 9: 310–318
Soler P, Moreau A, Basset F et al (1989) Cigarette smoking-induced changes in the number and differentiated state of pulmonary dendritic cells/Langerhans cells. Am Rev Respir Dis 139: 1112–1117
Spolski R, Leonard WJ (2008) Interleukin-21: basic biology and implications for cancer and autoimmunity. Ann Rev Immunol 26: 57–79
Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 19: 281–286
Suarez CJ, Parker NJ, Finn PW (2008) Innate immune mechanism in allergic asthma. Curr Allergy Asthma Rep 8: 451–459
Tanaka A, Minoguchi K, Samson KT et al (2007) Inhibitory effects of suplatast tosilate on the differentiation and function of monocyte-derived dendritic cells from patients with asthma. Clin Exp Allergy 37: 1083–1089
Thai P, Chen Y, Dolganov G et al (2005) Differential regulation of MUC5AC/Muc5ac and hCLCA-1/mGob-5 expression in airway epithelium. Am J Respir Cell Mol Biol 33: 523–530
Trompette A, Divanovic S, Visintin A et al (2009) Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature 457: 585–588
Veldhoen M, Uyttenhove C, van Snick J et al (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9: 1341–1346
Vijayanand P, Seumois G, Pickard C et al (2007) Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N Engl J Med 356: 1410–1422
Viriyakosol S, Kirkland T, Soldau K et al (2000) MD-2 binds to bacterial lipopolysaccharide. J Endotoxin Res 6: 489–491
Wang YH, Angkasekwinai P, Lu N et al (2007) IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J Exp Med 204: 1837–1847
Wang YH, Ito T, Wang YH et al (2006) Maintenance and polarization of human TH2 central memory T cells by thymic stromal lymphopoietin-activated dendritic cells. Immunity 24: 827–838
Wang YH, Liu YJ (2008) The IL-17 cytokine family and their role in allergic inflammation. Curr Opin Immunol 20: 697–702
Wark PA, Johnston SL, Bucchieri F et al (2005) Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med 201: 937–947
Weaver CT, Harrington LE, Mangan PR et al (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24: 677–688
Wenzel SE (2006) Asthma: defining of the persistent adult phenotypes. Lancet 368: 804–813
Wenzel SE, Balzar S, Cundall M et al (2003) Subepithelial basement membrane immunoreactivity for matrix metalloproteinase 9: association with asthma severity, neutrophilic inflammation, and wound repair. J Allergy Clin Immunol 111: 1345–1352
Wenzel S, Wilbraham D, Fuller R et al (2007) Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 370: 1422–1431
Weskamp G, Ford JW, Sturgill J et al (2006) ADAM10 is a principal ‘sheddase’ of the low-affinity immunoglobulin E receptor CD23. Nat Immunol 7: 1293–1298
Wicks J, Haitchi HM, Holgate ST (2006) Enhanced upregulation of smooth muscle related transcripts by TGF beta2 in asthmatic (myo) fibroblasts. Thorax 61: 313–319
Williams AP, Krishna MT, Frew AJ (2004) The safety of immunotherapy. Clin Exp Allergy 34: 513–514
Williams TJ, Jose PJ (2000) Role of eotaxin and related CC chemokines in allergy and asthma. Chem Immunol 78: 166–177
Xystrakis E, Kusumakar S, Boswell S et al (2006) Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest 116: 146–155
Yanagihara Y, Kajiwara K, Basaki Y et al (1998) Cultured basophils but not cultured mast cells induce human IgE synthesis in B cells after immunologic stimulation. Clin Exp Immunol 111: 136–143
Yang D, Chen Q, Su SB et al (2008) Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. J Exp Med 205: 79–90
Ying S, Meng Q, Corrigan CJ et al (2006) Lack of filaggrin expression in the human bronchial mucosa. J Allergy Clin Immunol 118: 1386–1388
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Buc, M., Dzurilla, M., Vrlik, M. et al. Immunopathogenesis of bronchial asthma. Arch. Immunol. Ther. Exp. 57, 331–344 (2009). https://doi.org/10.1007/s00005-009-0039-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00005-009-0039-4