693
Views
26
CrossRef citations to date
0
Altmetric
Review

What’s new in asthma pathophysiology and immunopathology?

, , &
Pages 605-629 | Published online: 09 Jan 2014

References

  • GeurtsvanKessel CH, Lambrecht BN. Division of labor between dendritic cell subsets of the lung. Mucosal Immunol.1(6), 442–450 (2008).
  • Hammad H, Lambrecht BN. Recent progress in the biology of airway dendritic cells and implications for understanding the regulation of asthmatic inflammation. J. Allergy Clin. Immunol.118(2), 331–336 (2006).
  • Pouliot P, Willart MA, Hammad H, Lambrecht BN. Studying the function of dendritic cells in mouse models of asthma. Methods Mol. Biol.595, 331–349 (2010).
  • Kushwah R, Wu J, Oliver JR et al. Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3+ Treg. Eur. J. Immunol.40(4), 1022–1035 (2010).
  • Hammad H, Lambrecht BN. Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat. Rev. Immunol.8(3), 193–204 (2008).
  • Barrett NA, Maekawa A, Rahman OM, Austen KF, Kanaoka Y. Dectin-2 recognition of house dust mite triggers cysteinyl leukotriene generation by dendritic cells. J. Immunol.182(2), 1119–1128 (2009).
  • Ito T, Yang M, Wang YH et al. Plasmacytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costimulator ligand. J. Exp. Med.204(1), 105–115 (2007).
  • Kitamura K, Takeda K, Koya T et al. Critical role of the Fc receptor γ-chain on APCs in the development of allergen-induced airway hyperresponsiveness and inflammation. J. Immunol.178(1), 480–488 (2007).
  • Riese RJ, Chapman HA. Cathepsins and compartmentalization in antigen presentation. Curr. Opin. Immunol.12(1), 107–113 (2000).
  • Liu YJ. Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation. J. Allergy Clin. Immunol.120(2), 238–244; quiz 245–236 (2007).
  • Luthi AU, Cullen SP, McNeela EA et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity31(1), 84–98 (2009).
  • Pease JE, Williams TJ. Chemokines and their receptors in allergic disease. J. Allergy Clin. Immunol.118(2), 305–318; quiz 319–320 (2006).
  • Hintzen G, Ohl L, del Rio ML et al. 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(10), 7346–7354 (2006).
  • Jakubzick C, Tacke F, Llodra J, van Rooijen N, Randolph GJ. Modulation of dendritic cell trafficking to and from the airways. J. Immunol.176(6), 3578–3584 (2006).
  • Cleret A, Quesnel-Hellmann A, Vallon-Eberhard A et al. Lung dendritic cells rapidly mediate anthrax spore entry through the pulmonary route. J. Immunol.178(12), 7994–8001 (2007).
  • van Rijt LS, Vos N, Willart M et al. Essential role of dendritic cell CD80/CD86 costimulation in the induction, but not reactivation, of TH2 effector responses in a mouse model of asthma. J. Allergy Clin. Immunol.114(1), 166–173 (2004).
  • Smit JJ, Rudd BD, Lukacs NW. Plasmacytoid dendritic cells inhibit pulmonary immunopathology and promote clearance of respiratory syncytial virus. J. Exp. Med.203(5), 1153–1159 (2006).
  • Lambrecht BN, Hammad H. Biology of lung dendritic cells at the origin of asthma. Immunity31(3), 412–424 (2009).
  • Grohmann U, Volpi C, Fallarino F et al. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat. Med.13(5), 579–586 (2007).
  • Gehring U, Strikwold M, Schram-Bijkerk D et al. Asthma and allergic symptoms in relation to house dust endotoxin: Phase Two of the International Study on Asthma and Allergies in Childhood (ISAAC II). Clin. Exp. Allergy38(12), 1911–1920 (2008).
  • Annunziato F, Romagnani S. Heterogeneity of human effector CD4+ T cells. Arthritis Res. Ther.11(6), 257 (2009).
  • Romagnani S. Regulation of the T cell response. Clin. Exp. Allergy36(11), 1357–1366 (2006).
  • Ponsonby AL, Dwyer T, van der Mei I et al. Asthma onset prior to multiple sclerosis and the contribution of sibling exposure in early life. Clin. Exp. Immunol.146(3), 463–470 (2006).
  • Karsh J, Angel JB, Young CD et al. Association of the frequency of respiratory illness in early childhood with a change in the distribution of blood lymphocyte subpopulations. Allergy Asthma Clin. Immunol.1(4), 135–141 (2005).
  • Orihara K, Nakae S, Pawankar R, Saito H. Role or regulatory and proinflammatory T-cell populations in allergic diseases. WAO J.1(1), 9–14 (2008).
  • Nguyen KD, Fohner A, Booker JD, Dong C, Krensky AM, Nadeau KC. XCL1 enhances regulatory activities of CD4+ CD25high CD127low/- T cells in human allergic asthma. J. Immunol.181(8), 5386–5395 (2008).
  • Nguyen KD, Vanichsarn C, Fohner A, Nadeau KC. Selective deregulation in chemokine signaling pathways of CD4+CD25hiCD127lo/-regulatory T cells in human allergic asthma. J. Allergy Clin. Immunol.123(4), 933–939.e10 (2009).
  • Sakaguchi S, Ono M, Setoguchi R et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol. Rev.212, 8–27 (2006).
  • Collison LW, Workman CJ, Kuo TT et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature450(7169), 566–569 (2007).
  • Bardel E, Larousserie F, Charlot-Rabiega P, Coulomb-L’Hermine A, Devergne O. Human CD4+ CD25+ Foxp3+ regulatory T cells do not constitutively express IL-35. J. Immunol.181(10), 6898–6905 (2008).
  • Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille JJ, Curotto de Lafaille MA. Oral tolerance in the absence of naturally occurring Tregs. J. Clin. Invest.115(7), 1923–1933 (2005).
  • Akdis CA, Akdis M. Mechanisms and treatment of allergic disease in the big picture of regulatory T cells. J. Allergy Clin. Immunol.123(4), 735–746; quiz 747–738 (2009).
  • Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-β: the role of T regulatory cells. Immunology117(4), 433–442 (2006).
  • Ray A, Khare A, Krishnamoorthy N, Qi Z, Ray P. Regulatory T cells in many flavors control asthma. Mucosal Immunol.3(3), 216–229 (2010).
  • Jutel M, Akdis CA. T-cell regulatory mechanisms in specific immunotherapy. Chem. Immunol. Allergy94, 158–177 (2008).
  • Li L, Wang H, Wang B. Anergic cells generated by blocking CD28 and CD40 costimulatory pathways in vitro ameliorate collagen induced arthritis. Cell Immunol.254(1), 39–45 (2008).
  • Gri G, Piconese S, Frossi B et al. CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40–OX40L interaction. Immunity29(5), 771–781 (2008).
  • Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Invest.117(5), 1147–1154 (2007).
  • Bacchetta R, Gambineri E, Roncarolo MG. Role of regulatory T cells and FOXP3 in human diseases. J. Allergy Clin. Immunol.120(2), 227–235; quiz 236–227 (2007).
  • Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFb in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity24(2), 179–189 (2006).
  • Bettelli E, Carrier Y, Gao W et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature441(7090), 235–238 (2006).
  • Ivanov II, McKenzie BS, Zhou L et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell126(6), 1121–1133 (2006).
  • Oboki K, Ohno T, Saito H, Nakae S. Th17 and allergy. Allergol. Int.57(2), 121–134 (2008).
  • Henness S, Johnson CK, Ge Q, Armour CL, Hughes JM, Ammit AJ. IL-17A augments TNF-α-induced IL-6 expression in airway smooth muscle by enhancing mRNA stability. J. Allergy Clin. Immunol.114(4), 958–964 (2004).
  • Chakir J, Shannon J, Molet S et al. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-β, IL-11, IL-17, and type I and type III collagen expression. J. Allergy Clin. Immunol.111(6), 1293–1298 (2003).
  • Fujiwara M, Hirose K, Kagami S et al. T-bet inhibits both TH2 cell-mediated eosinophil recruitment and TH17 cell-mediated neutrophil recruitment into the airways. J. Allergy Clin. Immunol.119(3), 662–670 (2007).
  • Horvat JC, Starkey MR, Kim RY et al. Chlamydial respiratory infection during allergen sensitization drives neutrophilic allergic airways disease. J. Immunol.184(8), 4159–4169 (2010).
  • He R, Oyoshi MK, Jin H, Geha RS. Epicutaneous antigen exposure induces a Th17 response that drives airway inflammation after inhalation challenge. Proc. Natl Acad. Sci. USA104(40), 15817–15822 (2007).
  • Wei H, Zhang J, Xiao W, Feng J, Sun R, Tian Z. Involvement of human natural killer cells in asthma pathogenesis: natural killer 2 cells in type 2 cytokine predominance. J. Allergy Clin. Immunol.115(4), 841–847 (2005).
  • Ozdemir O. Type 2 natural killer cells in asthma? J. Allergy Clin. Immunol.116(5), 1165–1166; author reply 1166–1167 (2005).
  • Korsgren M, Persson CG, Sundler F et al. Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice. J. Exp. Med.189(3), 553–562 (1999).
  • Scharton TM, Scott P. Natural killer cells are a source of interferon g that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J. Exp. Med.178(2), 567–577 (1993).
  • Hussell T, Openshaw PJ. IL-12-activated NK cells reduce lung eosinophilia to the attachment protein of respiratory syncytial virus but do not enhance the severity of illness in CD8 T cell-immunodeficient conditions. J. Immunol.165(12), 7109–7115 (2000).
  • Matsubara S, Takeda K, Kodama T et al. IL-2 and IL-18 attenuation of airway hyperresponsiveness requires STAT4, IFN-γ, and natural killer cells. Am. J. Respir. Cell Mol. Biol.36(3), 324–332 (2007).
  • Pichavant M, Goya S, Meyer EH et al. Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17. J. Exp. Med.205(2), 385–393 (2008).
  • Kim EY, Battaile JT, Patel AC et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat. Med.14(6), 633–640 (2008).
  • Stock P, Lombardi V, Kohlrautz V, Akbari O. Induction of airway hyperreactivity by IL-25 is dependent on a subset of invariant NKT cells expressing IL-17RB. J. Immunol.182(8), 5116–5122 (2009).
  • Meyer EH, Goya S, Akbari O et al. Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells. Proc. Natl Acad. Sci. USA103(8), 2782–2787 (2006).
  • Coquet JM, Chakravarti S, Kyparissoudis K et al. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population. Proc. Natl Acad. Sci. USA105(32), 11287–11292 (2008).
  • Mutalithas K, Croudace J, Guillen C et al. Bronchoalveolar lavage invariant natural killer T cells are not increased in asthma. J. Allergy Clin. Immunol.119(5), 1274–1276 (2007).
  • Thomas SY, Lilly CM, Luster AD. Invariant natural killer T cells in bronchial asthma. N. Engl. J. Med.354(24), 2613–2616; author reply 2613–2616 (2006).
  • Bratke K, Julius P, Virchow JC. Invariant natural killer T cells in obstructive pulmonary diseases. N. Engl. J. Med.357(2), 194; author reply 194–195 (2007).
  • Matangkasombut P, Marigowda G, Ervine A et al. Natural killer T cells in the lungs of patients with asthma. J. Allergy Clin. Immunol.123(5), 1181–1185 (2009).
  • Reynolds C, Barkans J, Clark P et al. Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma. J. Allergy Clin. Immunol.124(4), 860–862; author reply 862 (2009).
  • Adamko DJ, Odemuyiwa SO, Vethanayagam D, Moqbel R. The rise of the phoenix: the expanding role of the eosinophil in health and disease. Allergy60(1), 13–22 (2005).
  • Adamko D, Lacy P, Moqbel R. Eosinophil function in allergic inflammation: from bone marrow to tissue response. Curr. Allergy Asthma Rep.4(2), 149–158 (2004).
  • Kay AB. The role of eosinophils in the pathogenesis of asthma. Trends Mol. Med.11(4), 148–152 (2005).
  • Lemiere C, Ernst P, Olivenstein R et al. Airway inflammation assessed by invasive and noninvasive means in severe asthma: eosinophilic and noneosinophilic phenotypes. J. Allergy Clin. Immunol.118(5), 1033–1039 (2006).
  • Djukanovic R, Homeyard S, Gratziou C et al. The effect of treatment with oral corticosteroids on asthma symptoms and airway inflammation. Am. J. Respir. Crit. Care Med.155(3), 826–832 (1997).
  • Hogan SP, Rosenberg HF, Moqbel R et al. Eosinophils: biological properties and role in health and disease. Clin. Exp. Allergy38(5), 709–750 (2008).
  • Robinson DS, North J, Zeibecoglou K et al. Eosinophil development and bone marrow and tissue eosinophils in atopic asthma. Int. Arch. Allergy Immunol.118(2–4), 98–100 (1999).
  • Sehmi R, Dorman S, Baatjes A et al. 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. Immunology109(4), 536–546 (2003).
  • Lacy P, Abdel-Latif D, Steward M, Musat-Marcu S, Man SF, Moqbel R. Divergence of mechanisms regulating respiratory burst in blood and sputum eosinophils and neutrophils from atopic subjects. J. Immunol.170(5), 2670–2679 (2003).
  • Moqbel R, Lacy P. Molecular mechanisms in eosinophil activation. Chem. Immunol.78, 189–198 (2000).
  • Schwingshackl A, Duszyk M, Brown N, Moqbel R. Human eosinophils release matrix metalloproteinase-9 on stimulation with TNF-α. J. Allergy Clin. Immunol.104(5), 983–989 (1999).
  • Nair P, Pizzichini MM, Kjarsgaard M et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med.360(10), 985–993 (2009).
  • Haldar P, Brightling CE, Hargadon B et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med.360(10), 973–984 (2009).
  • Lee JJ, Dimina D, Macias MP et al. Defining a link with asthma in mice congenitally deficient in eosinophils. Science305(5691), 1773–1776 (2004).
  • Hamid Q, Tulic M. Immunobiology of asthma. Annu. Rev. Physiol.71, 489–507 (2009).
  • Nissim Ben Efraim AH, Levi-Schaffer F. Tissue remodeling and angiogenesis in asthma: the role of the eosinophil. Ther. Adv. Respir. Dis.2(3), 163–171 (2008).
  • Fattouh R, Jordana M. TGF-β, eosinophils and IL-13 in allergic airway remodeling: a critical appraisal with therapeutic considerations. Inflamm. Allergy Drug Targets7(4), 224–236 (2008).
  • Holgate ST. Pathogenesis of asthma. Clin. Exp. Allergy38(6), 872–897 (2008).
  • Broide DH. Immunologic and inflammatory mechanisms that drive asthma progression to remodeling. J. Allergy Clin. Immunol.121(3), 560–570; quiz 571–562 (2008).
  • Humbles AA, Lloyd CM, McMillan SJ et al. A critical role for eosinophils in allergic airways remodeling. Science305(5691), 1776–1779 (2004).
  • Celestin J, Rotschke O, Falk K et al. IL-3 induces B7.2 (CD86) expression and costimulatory activity in human eosinophils. J. Immunol.167(11), 6097–6104 (2001).
  • MacKenzie JR, Mattes J, Dent LA, Foster PS. Eosinophils promote allergic disease of the lung by regulating CD4+ Th2 lymphocyte function. J. Immunol.167(6), 3146–3155 (2001).
  • Shi HZ, Humbles A, Gerard C, Jin Z, Weller PF. Lymph node trafficking and antigen presentation by endobronchial eosinophils. J. Clin. Invest.105(7), 945–953 (2000).
  • Matthews AN, Friend DS, Zimmermann N et al. Eotaxin is required for the baseline level of tissue eosinophils. Proc. Natl Acad. Sci. USA95(11), 6273–6278 (1998).
  • Contreiras EC, Lenzi HL, Meirelles MN et al. The equine thymus microenvironment: a morphological and immunohistochemical analysis. Dev. Comp. Immunol.28(3), 251–264 (2004).
  • Throsby M, Herbelin A, Pleau JM, Dardenne M. CD11c+ eosinophils in the murine thymus: developmental regulation and recruitment upon MHC class I-restricted thymocyte deletion. J. Immunol.165(4), 1965–1975 (2000).
  • Tulic MK, Sly PD, Andrews D et al. Thymic indoleamine 2,3-dioxygenase-positive eosinophils in young children: potential role in maturation of the naive immune system. Am. J. Pathol.175(5), 2043–2052 (2009).
  • Lacy P, Moqbel R. Eosinophil cytokines. Chem. Immunol.76, 134–155 (2000).
  • Fallarino F, Grohmann U, Vacca C et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ.9(10), 1069–1077 (2002).
  • Woerly G, Roger N, Loiseau S, Dombrowicz D, Capron A, Capron M. Expression of CD28 and CD86 by human eosinophils and role in the secretion of type 1 cytokines (interleukin 2 and interferon γ): inhibition by immunoglobulin a complexes. J. Exp. Med.190(4), 487–495 (1999).
  • Odemuyiwa SO, Ghahary A, Li Y et al. Cutting edge: human eosinophils regulate T cell subset selection through indoleamine 2,3-dioxygenase. J. Immunol.173(10), 5909–5913 (2004).
  • Jacobsen EA, Ochkur SI, Pero RS et al. Allergic pulmonary inflammation in mice is dependent on eosinophil-induced recruitment of effector T cells. J. Exp. Med.205(3), 699–710 (2008).
  • Lee JJ, Jacobsen EA, McGarry MP, Schleimer RP, Lee NA. Eosinophils in health and disease: the LIAR hypothesis. Clin. Exp. Allergy40(4), 563–575 (2010).
  • Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax57(7), 643–648 (2002).
  • Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N. Engl. J. Med.320(5), 271–277 (1989).
  • Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma : evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest119(5), 1329–1336 (2001).
  • Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD, Martin RJ. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am. J. Respir. Crit. Care Med.156(3 Pt 1), 737–743 (1997).
  • Louis R, Lau LC, Bron AO, Roldaan AC, Radermecker M, Djukanovic R. The relationship between airways inflammation and asthma severity. Am. J. Respir. Crit. Care Med.161(1), 9–16 (2000).
  • Woodruff PG, Khashayar R, Lazarus SC et al. Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma. J. Allergy Clin. Immunol.108(5), 753–758 (2001).
  • Tsokos M, Paulsen F. Expression of pulmonary lactoferrin in sudden-onset and slow-onset asthma with fatal outcome. Virchows Arch.441(5), 494–499 (2002).
  • Lamblin C, Gosset P, Tillie-Leblond I et al. Bronchial neutrophilia in patients with noninfectious status asthmaticus. Am. J. Respir. Crit. Care Med.157(2), 394–402 (1998).
  • Leung DY, Spahn JD, Szefler SJ. Steroid-unresponsive asthma. Semin. Respir. Crit. Care Med.23(4), 387–398 (2002).
  • Wallen N, Kita H, Weiler D, Gleich GJ. Glucocorticoids inhibit cytokine-mediated eosinophil survival. J. Immunol.147(10), 3490–3495 (1991).
  • Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax57(10), 875–879 (2002).
  • Fukakusa M, Bergeron C, Tulic MK et al. Oral corticosteroids decrease eosinophil and CC chemokine expression but increase neutrophil, IL-8, and IFN-γ-inducible protein 10 expression in asthmatic airway mucosa. J. Allergy Clin. Immunol.115(2), 280–286 (2005).
  • Cox G. Glucocorticoid treatment inhibits apoptosis in human neutrophils. Separation of survival and activation outcomes. J. Immunol.154(9), 4719–4725 (1995).
  • Schleimer RP, Freeland HS, Peters SP, Brown KE, Derse CP. An assessment of the effects of glucocorticoids on degranulation, chemotaxis, binding to vascular endothelium and formation of leukotriene B4 by purified human neutrophils. J. Pharmacol. Exp. Ther.250(2), 598–605 (1989).
  • Louis R, Djukanovic R. Is the neutrophil a worthy target in severe asthma and chronic obstructive pulmonary disease? Clin. Exp. Allergy36(5), 563–567 (2006).
  • Foley SC, Hamid Q. Images in allergy and immunology: neutrophils in asthma. J. Allergy Clin. Immunol.119(5), 1282–1286 (2007).
  • Kamath AV, Pavord ID, Ruparelia PR, Chilvers ER. Is the neutrophil the key effector cell in severe asthma? Thorax60(7), 529–530 (2005).
  • Matsunaga K, Yanagisawa S, Ichikawa T et al. Airway cytokine expression measured by means of protein array in exhaled breath condensate: correlation with physiologic properties in asthmatic patients. J. Allergy Clin. Immunol.118(1), 84–90 (2006).
  • Bullens DM, Truyen E, Coteur L et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir. Res.7, 135 (2006).
  • Molet S, Hamid Q, Davoine F et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J. Allergy Clin. Immunol.108(3), 430–438 (2001).
  • Wong CK, Ho CY, Ko FW et al. Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-γ, IL-4, IL-10 and IL-13) in patients with allergic asthma. Clin. Exp. Immunol.125(2), 177–183 (2001).
  • Al-Ramli W, Prefontaine D, Chouiali F et al. T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J. Allergy Clin. Immunol.123(5), 1185–1187 (2009).
  • Barczyk A, Pierzchala W, Sozanska E. Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine. Respir. Med.97(6), 726–733 (2003).
  • Pene J, Chevalier S, Preisser L et al. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J. Immunol.180(11), 7423–7430 (2008).
  • Kikuchi I, Kikuchi S, Kobayashi T et al. Eosinophil trans-basement membrane migration induced by interleukin-8 and neutrophils. Am. J. Respir. Cell Mol. Biol.34(6), 760–765 (2006).
  • Metz M, Grimbaldeston MA, Nakae S, Piliponsky AM, Tsai M, Galli SJ. Mast cells in the promotion and limitation of chronic inflammation. Immunol. Rev.217, 304–328 (2007).
  • Galli SJ, Grimbaldeston M, Tsai M. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat. Rev. Immunol.8(6), 478–486 (2008).
  • Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nat. Immunol.9(11), 1215–1223 (2008).
  • Shahana S, Bjornsson E, Ludviksdottir D et al. Ultrastructure of bronchial biopsies from patients with allergic and non-allergic asthma. Respir. Med.99(4), 429–443 (2005).
  • Bradding P, Walls AF, Holgate ST. The role of the mast cell in the pathophysiology of asthma. J. Allergy Clin. Immunol.117(6), 1277–1284 (2006).
  • Bradding P, Okayama Y, Howarth PH, Church MK, Holgate ST. Heterogeneity of human mast cells based on cytokine content. J. Immunol.155(1), 297–307 (1995).
  • Wilson SJ, Shute JK, Holgate ST, Howarth PH, Bradding P. Localization of interleukin (IL) -4 but not IL-5 to human mast cell secretory granules by immunoelectron microscopy. Clin. Exp. Allergy30(4), 493–500 (2000).
  • Okumura S, Sagara H, Fukuda T, Saito H, Okayama Y. FcεRI-mediated amphiregulin production by human mast cells increases mucin gene expression in epithelial cells. J. Allergy Clin. Immunol.115(2), 272–279 (2005).
  • Okayama Y, Okumura S, Sagara H et al. FcεRI-mediated thymic stromal lymphopoietin production by interleukin-4-primed human mast cells. Eur. Respir. J.34(2), 425–435 (2009).
  • Iikura M, Suto H, Kajiwara N et al. IL-33 can promote survival, adhesion and cytokine production in human mast cells. Lab. Invest.87(10), 971–978 (2007).
  • Piconese S, Gri G, Tripodo C et al. Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation. Blood114(13), 2639–2648 (2009).
  • Hueber AJ, Asquith DL, Miller AM et al. Mast cells express IL-17A in rheumatoid arthritis synovium. J. Immunol.184(7), 3336–3340 (2010).
  • Okayama Y, Ra C, Saito H. Role of mast cells in airway remodeling. Curr. Opin. Immunol.19(6), 687–693 (2007).
  • Kajiwara N, Sasaki T, Bradding P et al. Activation of human mast cells through the platelet-activating factor receptor. J. Allergy Clin. Immunol.125(5), 1137–1145.e6 (2010).
  • Galli SJ, Tsai M. Mast cells in allergy and infection: versatile effector and regulatory cells in innate and adaptive immunity. Eur. J. Immunol.40(7), 1843–1851 (2010).
  • Lu LF, Lind EF, Gondek DC et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature442(7106), 997–1002 (2006).
  • Hakim-Rad K, Metz M, Maurer M. Mast cells: makers and breakers of allergic inflammation. Curr. Opin. Allergy Clin. Immunol.9(5), 427–430 (2009).
  • Mukai K, Obata K, Tsujimura Y, Karasuyama H. New insights into the roles for basophils in acute and chronic allergy. Allergol. Int.58(1), 11–19 (2009).
  • Schroeder JT. Basophils beyond effector cells of allergic inflammation. Adv. Immunol.101, 123–161 (2009).
  • Hida S, Yamasaki S, Sakamoto Y et al. Fc receptor γ-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils. Nat. Immunol.10(2), 214–222 (2009).
  • Schroeder JT, Chichester KL, Bieneman AP. Human basophils secrete IL-3: evidence of autocrine priming for phenotypic and functional responses in allergic disease. J. Immunol.182(4), 2432–2438 (2009).
  • Sokol CL, Medzhitov R. Role of basophils in the initiation of Th2 responses. Curr. Opin. Immunol.22(1), 73–77 (2010).
  • Tsujimura Y, Obata K, Mukai K et al. Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis. Immunity28(4), 581–589 (2008).
  • Obata K, Mukai K, Tsujimura Y et al. Basophils are essential initiators of a novel type of chronic allergic inflammation. Blood110(3), 913–920 (2007).
  • Gibbs BF. Human basophils as effectors and immunomodulators of allergic inflammation and innate immunity. Clin. Exp. Med.5(2), 43–49 (2005).
  • Mukai K, Matsuoka K, Taya C et al. Basophils play a critical role in the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. Immunity23(2), 191–202 (2005).
  • Guilbert TW, Morgan WJ, Zeiger RS et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N. Engl. J. Med.354(19), 1985–1997 (2006).
  • Bosse Y, Rola-Pleszczynski M. Controversy surrounding the increased expression of TGF β 1 in asthma. Respir. Res.8, 66 (2007).
  • Sumi Y, Hamid Q. Airway remodeling in asthma. Allergol. Int.56(4), 341–348 (2007).
  • Postma DS, Timens W. Remodeling in asthma and chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc.3(5), 434–439 (2006).
  • Xie S, Sukkar MB, Issa R, Khorasani NM, Chung KF. Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-β. Am. J. Physiol. Lung Cell Mol. Physiol.293(1), L245–L253 (2007).
  • Wegmann M, Goggel R, Sel S et al. Effects of a low-molecular-weight CCR-3 antagonist on chronic experimental asthma. Am. J. Respir. Cell Mol. Biol.36(1), 61–67 (2007).
  • Puxeddu I, Bader R, Piliponsky AM, Reich R, Levi-Schaffer F, Berkman N. The CC chemokine eotaxin/CCL11 has a selective profibrogenic effect on human lung fibroblasts. J. Allergy Clin. Immunol.117(1), 103–110 (2006).
  • Bhandari V, Choo-Wing R, Chapoval SP et al. Essential role of nitric oxide in VEGF-induced, asthma-like angiogenic, inflammatory, mucus, and physiologic responses in the lung. Proc. Natl Acad. Sci. USA103(29), 11021–11026 (2006).
  • Enomoto Y, Orihara K, Takamasu T et al. Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack. J. Allergy Clin. Immunol.124(5), 913–920.e1–7 (2009).
  • Prefontaine D, Hamid Q. Airway epithelial cells in asthma. J. Allergy Clin. Immunol.120(6), 1475–1478 (2007).
  • Holgate ST. Epithelium dysfunction in asthma. J. Allergy Clin. Immunol.120(6), 1233–1244; quiz 1245–1236 (2007).
  • Hutchison S, Choo-Kang BS, Bundick RV et al. Tumour necrosis factor-α blockade suppresses murine allergic airways inflammation. Clin. Exp. Immunol.151(1), 114–122 (2008).
  • Holgate ST. The airway epithelium is central to the pathogenesis of asthma. Allergol. Int.57(1), 1–10 (2008).
  • Heijink IH, van Oosterhout A, Kapus A. EGFR signaling contributes to house dust mite-induced epithelial barrier dysfunction. Eur. Respir. J. DOI: 10.1183/09031936.00125809 (2010) (Epub ahead of print).
  • Zietkowski Z, Skiepko R, Tomasiak MM, Bodzenta-Lukaszyk A. Endothelin-1 in exhaled breath condensate of allergic asthma patients with exercise-induced bronchoconstriction. Respir. Res.8(1), 76 (2007).
  • Kato A, Schleimer RP. Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity. Curr. Opin. Immunol.19(6), 711–720 (2007).
  • Allakhverdi Z, Comeau MR, Jessup HK et al. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J. Exp. Med.204(2), 253–258 (2007).
  • Kato A, Favoreto S Jr, Avila PC, Schleimer RP. TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells. J. Immunol.179(2), 1080–1087 (2007).
  • Futamura K, Orihara K, Hashimoto N et al. β(2)-adrenoceptor agonists enhance cytokine-induced release of thymic stromal lymphopoietin by lung tissue cells. Int. Arch. Allergy Immunol.152(4), 353–361 (2010).
  • Gregory LG, Mathie SA, Walker SA, Pegorier S, Jones CP, Lloyd CM. Overexpression of SMAD2 drives hdm mediated airway remodeling and AHR via activin and IL-25. Am. J. Respir. Crit. Care Med.182(2), 143–154 (2010).
  • Prefontaine D, Nadigel J, Chouiali F et al. Increased IL-33 expression by epithelial cells in bronchial asthma. J. Allergy Clin. Immunol.125(3), 752–754 (2010).
  • Yoshihara S, Yamada Y, Abe T, Linden A, Arisaka O. Association of epithelial damage and signs of neutrophil mobilization in the airways during acute exacerbations of paediatric asthma. Clin. Exp. Immunol.144(2), 212–216 (2006).
  • Cohen L, E X, Tarsi J et al. Epithelial cell proliferation contributes to airway remodeling in severe asthma. Am. J. Respir. Crit. Care Med.176(2), 138–145 (2007).
  • Hamilton LM, Puddicombe SM, Dearman RJ et al. Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium. Eur. Respir. J.25(6), 978–985 (2005).
  • Davies DE. The role of the epithelium in airway remodeling in asthma. Proc. Am. Thorac. Soc.6(8), 678–682 (2009).
  • Dougherty RH, Fahy JV. Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype. Clin. Exp. Allergy39(2), 193–202 (2009).
  • Curran DR, Cohn L. Advances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease. Am. J. Respir. Cell Mol. Biol.42(3), 268–275 (2010).
  • Rose MC, Voynow JA. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol. Rev.86(1), 245–278 (2006).
  • Busse W, Kraft M. Cysteinyl leukotrienes in allergic inflammation: strategic target for therapy. Chest127(4), 1312–1326 (2005).
  • Ishinaga H, Takeuchi K, Kishioka C, Suzuki S, Basbaum C, Majima Y. Pranlukast inhibits NF-κB activation and MUC2 gene expression in cultured human epithelial cells. Pharmacology73(2), 89–96 (2005).
  • Hodge S, Holmes M, Banerjee B et al. Posttransplant bronchiolitis obliterans syndrome is associated with bronchial epithelial to mesenchymal transition. Am. J. Transplant.9(4), 727–733 (2009).
  • Hackett TL, Warner SM, Stefanowicz D et al. Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-β1. Am. J. Respir. Crit. Care Med.180(2), 122–133 (2009).
  • Stevens PT, Kicic A, Sutanto EN, Knight DA, Stick SM. Dysregulated repair in asthmatic paediatric airway epithelial cells: the role of plasminogen activator inhibitor-1. Clin. Exp. Allergy38(12), 1901–1910 (2008).
  • Kicic A, Hallstrand TS, Sutanto EN et al. Decreased fibronectin production significantly contributes to dysregulated repair of asthmatic epithelium. Am. J. Respir. Crit. Care Med.181(9), 889–898 (2010).
  • Matsumoto H, Niimi A, Takemura M et al. Relationship of airway wall thickening to an imbalance between matrix metalloproteinase-9 and its inhibitor in asthma. Thorax60(4), 277–281 (2005).
  • Lazaar AL, Panettieri RA Jr. Airway smooth muscle: a modulator of airway remodeling in asthma. J. Allergy Clin. Immunol.116(3), 488–495; quiz 496 (2005).
  • Lee CG, Kang HR, Homer RJ, Chupp G, Elias JA. Transgenic modeling of transforming growth factor-β(1): role of apoptosis in fibrosis and alveolar remodeling. Proc. Am. Thorac. Soc.3(5), 418–423 (2006).
  • Jude JA, Wylam ME, Walseth TF, Kannan MS. Calcium signaling in airway smooth muscle. Proc. Am. Thorac. Soc.5(1), 15–22 (2008).
  • Begueret H, Berger P, Vernejoux JM, Dubuisson L, Marthan R, Tunon-de-Lara JM. Inflammation of bronchial smooth muscle in allergic asthma. Thorax62(1), 8–15 (2007).
  • Amin K, Janson C, Boman G, Venge P. The extracellular deposition of mast cell products is increased in hypertrophic airways smooth muscles in allergic asthma but not in nonallergic asthma. Allergy60(10), 1241–1247 (2005).
  • Prefontaine D, Lajoie-Kadoch S, Foley S et al. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J. Immunol.183(8), 5094–5103 (2009).
  • Haitchi HM, Powell RM, Shaw TJ et al. ADAM33 expression in asthmatic airways and human embryonic lungs. Am. J. Respir. Crit. Care Med.171(9), 958–965 (2005).
  • Dekkers BG, Maarsingh H, Meurs H, Gosens R. Airway structural components drive airway smooth muscle remodeling in asthma. Proc. Am. Thorac. Soc.6(8), 683–692 (2009).
  • Bentley JK, Hershenson MB. Airway smooth muscle growth in asthma: proliferation, hypertrophy, and migration. Proc. Am. Thorac. Soc.5(1), 89–96 (2008).
  • Henderson WR Jr, Chiang GK, Tien YT, Chi EY. Reversal of allergen-induced airway remodeling by CysLT1 receptor blockade. Am. J. Respir. Crit. Care Med.173(7), 718–728 (2006).
  • Ceresa CC, Knox AJ, Johnson SR. Use of a three-dimensional cell culture model to study airway smooth muscle-mast cell interactions in airway remodeling. Am. J. Physiol. Lung Cell Mol. Physiol.296(6), L1059–L1066 (2009).
  • Panettieri RA, Yadvish PA, Kelly AM, Rubinstein NA, Kotlikoff MI. Histamine stimulates proliferation of airway smooth muscle and induces c-fos expression. Am. J. Physiol.259(6 Pt 1), L365–L371 (1990).
  • Neveu WA, Allard JL, Raymond DM et al. Elevation of IL-6 in the allergic asthmatic airway is independent of inflammation but associates with loss of central airway function. Respir. Res.11, 28 (2010).
  • Bosse Y, Rola-Pleszczynski M. FGF2 in asthmatic airway-smooth-muscle-cell hyperplasia. Trends Mol. Med.14(1), 3–11 (2008).
  • Saunders R, Sutcliffe A, Kaur D et al. Airway smooth muscle chemokine receptor expression and function in asthma. Clin. Exp. Allergy39(11), 1684–1692 (2009).
  • Bentley JK, Deng H, Linn MJ et al. Airway smooth muscle hyperplasia and hypertrophy correlate with glycogen synthase kinase-3(b) phosphorylation in a mouse model of asthma. Am. J. Physiol. Lung Cell Mol. Physiol.296(2), L176–L184 (2009).
  • Woodruff PG. Gene expression in asthmatic airway smooth muscle. Proc. Am. Thorac. Soc.5(1), 113–118 (2008).
  • Kranenburg AR, Willems-Widyastuti A, Moori WJ et al. Enhanced bronchial expression of extracellular matrix proteins in chronic obstructive pulmonary disease. Am. J. Clin. Pathol.126(5), 725–735 (2006).
  • Horowitz JC, Thannickal VJ. Epithelial–mesenchymal interactions in pulmonary fibrosis. Semin. Respir. Crit. Care Med.27(6), 600–612 (2006).
  • Xie S, Macedo P, Hew M, Nassenstein C, Lee KY, Chung KF. Expression of transforming growth factor-β (TGF-β) in chronic idiopathic cough. Respir. Res.10, 40 (2009).
  • Howell JE, McAnulty RJ. TGF-β: its role in asthma and therapeutic potential. Curr. Drug Targets7(5), 547–565 (2006).
  • Bottoms SE, Howell JE, Reinhardt AK, Evans IC, McAnulty RJ. TGF-β isoform specific regulation of airway inflammation and remodelling in a murine model of asthma. PLoS One5(3), e9674 (2010).
  • Doerner AM, Zuraw BL. TGF-β1 induced epithelial to mesenchymal transition (EMT) in human bronchial epithelial cells is enhanced by IL-1β but not abrogated by corticosteroids. Respir. Res.10, 100 (2009).
  • Reinhardt AK, Bottoms SE, Laurent GJ, McAnulty RJ. Quantification of collagen and proteoglycan deposition in a murine model of airway remodelling. Respir. Res.6, 30 (2005).
  • Kohan M, Breuer R, Berkman N. Osteopontin induces airway remodeling and lung fibroblast activation in a murine model of asthma. Am. J. Respir. Cell Mol. Biol.41(3), 290–296 (2009).
  • Bergeron C, Al-Ramli W, Hamid Q. Remodeling in asthma. Proc. Am. Thorac. Soc.6(3), 301–305 (2009).
  • James A. Airway remodeling in asthma. Curr. Opin. Pulm. Med.11(1), 1–6 (2005).
  • Kanazawa H, Asai K, Nomura S. Vascular endothelial growth factor as a non-invasive marker of pulmonary vascular remodeling in patients with bronchitis-type of COPD. Respir. Res.8, 22 (2007).
  • Tsuburai T, Tsurikisawa N, Morita S et al. Relationship between exhaled nitric oxide measured by two offline methods and bronchial hyperresponsiveness in Japanese adults with asthma. Allergol. Int.57(3), 223–229 (2008).
  • Pegorier S, Arouche N, Dombret MC, Aubier M, Pretolani M. Augmented epithelial endothelin-1 expression in refractory asthma. J. Allergy Clin. Immunol.120(6), 1301–1307 (2007).
  • Orihara K, Matsuda A. Pathophysiological roles of microvascular alterations in pulmonary inflammatory diseases: possible implications of tumor necrosis factor-α and CXC chemokines. Int. J. Chron. Obstruct. Pulmon. Dis.3(4), 619–627 (2008).
  • Papaioannou AI, Kostikas K, Kollia P, Gourgoulianis KI. Clinical implications for vascular endothelial growth factor in the lung: friend or foe? Respir. Res.7, 128 (2006).
  • Zani BG, Kojima K, Vacanti CA, Edelman ER. Tissue-engineered endothelial and epithelial implants differentially and synergistically regulate airway repair. Proc. Natl Acad. Sci. USA105(19), 7046–7051 (2008).
  • Tuder RM, Yun JH. Vascular endothelial growth factor of the lung: friend or foe. Curr. Opin. Pharmacol.8(3), 255–260 (2008).
  • Babu AN, Murakawa T, Thurman JM et al. Microvascular destruction identifies murine allografts that cannot be rescued from airway fibrosis. J. Clin. Invest.117(12), 3774–3785 (2007).
  • Puxeddu I, Berkman N, Nissim Ben Efraim AH et al. The role of eosinophil major basic protein in angiogenesis. Allergy64(3), 368–374 (2009).
  • Trevethick MA, Mantell SJ, Stuart EF, Barnard A, Wright KN, Yeadon M. Treating lung inflammation with agonists of the adenosine A2A receptor: promises, problems and potential solutions. Br. J. Pharmacol.155(4), 463–474 (2008).
  • Feltis BN, Wignarajah D, Reid DW, Ward C, Harding R, Walters EH. Effects of inhaled fluticasone on angiogenesis and vascular endothelial growth factor in asthma. Thorax62(4), 314–319 (2007).
  • Burdick MD, Murray LA, Keane MP et al. CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling. Am. J. Respir. Crit. Care Med.171(3), 261–268 (2005).
  • Matsuda A, Fukuda S, Matsumoto K, Saito H. Th1/Th2 cytokines reciprocally regulate in vitro pulmonary angiogenesis via CXC chemokine synthesis. Am. J. Respir. Cell Mol. Biol.38(2), 168–175 (2008).
  • Matsuda A, Orihara K, Fukuda S, Fujinaga H, Matsumoto K, Saito H. Corticosteroid enhances TNF-α-mediated leukocyte adhesion to pulmonary microvascular endothelial cells. Allergy63(12), 1610–1616 (2008).
  • Wang Y, Liu H, McKenzie G et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat. Med.16(3), 279–285 (2010).
  • Odemuyiwa SO, Ebeling C, Duta V et al. Tryptophan catabolites regulate mucosal sensitization to ovalbumin in respiratory airways. Allergy64(3), 488–492 (2009).
  • He R, Geha RS. Thymic stromal lymphopoietin. Ann. NY Acad. Sci.1183, 13–24 (2010).
  • Ziegler SF, Artis D. Sensing the outside world: TSLP regulates barrier immunity. Nat. Immunol.11(4), 289–293 (2010).
  • Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat. Rev. Immunol.9(8), 556–567 (2009).
  • Iwakura Y, Nakae S, Saijo S, Ishigame H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol. Rev.226, 57–79 (2008).
  • Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol.25, 821–852 (2007).
  • Wright JF, Bennett F, Li B et al. The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J. Immunol.181(4), 2799–2805 (2008).
  • Yang XO, Chang SH, Park H et al. Regulation of inflammatory responses by IL-17F. J. Exp. Med.205(5), 1063–1075 (2008).
  • Kuestner RE, Taft DW, Haran A et al. Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. J. Immunol.179(8), 5462–5473 (2007).
  • Liang SC, Long AJ, Bennett F et al. A IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment. J. Immunol.179(11), 7791–7799 (2007).
  • Wright JF, Guo Y, Quazi A et al. Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells. J. Biol. Chem.282(18), 13447–13455 (2007).
  • Al-Shami A, Spolski R, Kelly J, Keane-Myers A, Leonard WJ. A role for TSLP in the development of inflammation in an asthma model. J. Exp. Med.202(6), 829–839 (2005).
  • Ito T, Wang YH, Duramad O et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J. Exp. Med.202(9), 1213–1223 (2005).
  • Zhang K, Shan L, Rahman MS, Unruh H, Halayko AJ, Gounni AS. Constitutive and inducible thymic stromal lymphopoietin expression in human airway smooth muscle cells: role in chronic obstructive pulmonary disease. Am. J. Physiol. Lung Cell Mol. Physiol.293(2), L375–L382 (2007).
  • Ozawa T, Koyama K, Ando T et al. Thymic stromal lymphopoietin secretion of synovial fibroblasts is positively and negatively regulated by Toll-like receptors/nuclear factor-κB pathway and interferon-γ/dexamethasone. Mod. Rheumatol.17(6), 459–463 (2007).
  • Ying S, O’Connor B, Ratoff J et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J. Immunol.174(12), 8183–8190 (2005).
  • Zhou B, Comeau MR, De Smedt T et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat. Immunol.6(10), 1047–1053 (2005).
  • Schmitz J, Owyang A, Oldham E et al.IL-33 aninterleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity23(5), 479–490 (2005).
  • Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat. Rev. Immunol.10(2), 103–110 (2010).
  • Allakhverdi Z, Smith DE, Comeau MR, Delespesse G. Cutting edge: The ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J. Immunol.179(4), 2051–2054 (2007).
  • Ho LH, Ohno T, Oboki K et al. IL-33 induces IL-13 production by mouse mast cells independently of IgE-FcεRI signals. J. Leukoc. Biol.82(6), 1481–1490 (2007).
  • Suzukawa M, Koketsu R, Iikura M et al. Interleukin-33 enhances adhesion, CD11b expression and survival in human eosinophils. Lab. Invest.88(11), 1245–1253 (2008).
  • Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J. Allergy Clin. Immunol.121(6), 1484–1490 (2008).
  • Suzukawa M, Iikura M, Koketsu R et al. An IL-1 cytokine member, IL-33, induces human basophil activation via its ST2 receptor. J. Immunol.181(9), 5981–5989 (2008).
  • Tajima S, Bando M, Ohno S et al.ST2 gene induced by type 2 helper T cell (Th2) and proinflammatory cytokine stimuli may modulate lung injury and fibrosis. Exp. Lung Res.33(2), 81–97 (2007).
  • Allakhverdi Z, Comeau MR, Smith DE et al. CD34+ hemopoietic progenitor cells are potent effectors of allergic inflammation. J. Allergy Clin. Immunol.123(2), 472–478 (2009).
  • Rank MA, Kobayashi T, Kozaki H, Bartemes KR, Squillace DL, Kita H. IL-33-activated dendritic cells induce an atypical TH2-type response. J. Allergy Clin. Immunol.123(5), 1047–1054 (2009).
  • Gudbjartsson DF, Bjornsdottir US, Halapi E et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat. Genet.41(3), 342–347 (2009).
  • Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol.27, 519–550 (2009).
  • Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat. Rev. Immunol.10(2), 89–102 (2010).
  • Soroosh P, Doherty TA. Th9 and allergic disease. Immunology127(4), 450–458 (2009).
  • Uyttenhove C, Brombacher F, Van Snick J. TGF-β interactions with IL-1 family members trigger IL-4-independent IL-9 production by mouse CD4+ T cells. Eur. J. Immunol. DOI: 10.1002/eji.200940281 (2010) (Epub ahead of print).
  • Klagas I, Goulet S, Karakiulakis G et al. Decreased hyaluronan in airway smooth muscle cells from patients with asthma and COPD. Eur. Respir. J.34(3), 616–628 (2009).
  • Bousquet J, Chanez P, Lacoste JY et al. Indirect evidence of bronchial inflammation assessed by titration of inflammatory mediators in BAL fluid of patients with asthma. J. Allergy Clin. Immunol.88(4), 649–660 (1991).
  • Slats AM, Janssen K, van Schadewijk A et al. Expression of smooth muscle and extracellular matrix proteins in relation to airway function in asthma. J. Allergy Clin. Immunol.121(5), 1196–1202 (2008).
  • Ober C, Chupp GL. The chitinase and chitinase-like proteins: a review of genetic and functional studies in asthma and immune-mediated diseases. Curr. Opin. Allergy Clin. Immunol.9(5), 401–408 (2009).
  • Elias JA, Homer RJ, Hamid Q, Lee CG. Chitinases and chitinase-like proteins in T(H)2 inflammation and asthma. J. Allergy Clin. Immunol.116(3), 497–500 (2005).
  • Chupp GL, Lee CG, Jarjour N et al. A chitinase-like protein in the lung and circulation of patients with severe asthma. N. Engl. J. Med.357(20), 2016–2027 (2007).
  • Maizels RM. Infections and allergy – helminths, hygiene and host immune regulation. Curr. Opin. Immunol.17(6), 656–661 (2005).
  • Sutherland TE, Maizels RM, Allen JE. Chitinases and chitinase-like proteins: potential therapeutic targets for the treatment of T-helper type 2 allergies. Clin. Exp. Allergy39(7), 943–955 (2009).
  • Hartl D, He CH, Koller B et al. Acidic mammalian chitinase regulates epithelial cell apoptosis via a chitinolytic-independent mechanism. J. Immunol.182(8), 5098–5106 (2009).
  • Lee CG, Elias JA. Role of breast regression protein-39/YKL-40 in asthma and allergic responses. Allergy Asthma Immunol. Res.2(1), 20–27 (2010).
  • Matsumoto T, Inoue H, Sato Y et al. Demethylallosamidin, a chitinase inhibitor, suppresses airway inflammation and hyperresponsiveness. Biochem. Biophys. Res. Commun.390(1), 103–108 (2009).
  • Reese TA, Liang HE, Tager AM et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature447(7140), 92–96 (2007).
  • Da Silva CA, Hartl D, Liu W, Lee CG, Elias JA. TLR-2 and IL-17A in chitin-induced macrophage activation and acute inflammation. J. Immunol.181(6), 4279–4286 (2008).
  • Bateman ED, Hurd SS, Barnes PJ et al. Global strategy for asthma management and prevention: GINA executive summary. Eur. Respir. J.31(1), 143–178 (2008).
  • Berry M, Morgan A, Shaw DE et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax62(12), 1043–1049 (2007).
  • Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax65(5), 384–390 (2010).
  • Hargreave FE, Nair P. The definition and diagnosis of asthma. Clin. Exp. Allergy39(11), 1652–1658 (2009).
  • Hargreave FE. Quantitative sputum cell counts as a marker of airway inflammation in clinical practice. Curr. Opin. Allergy Clin. Immunol.7(1), 102–106 (2007).
  • Garcia-Marcos L, Brand PL. The utility of sputum eosinophils and exhaled nitric oxide for monitoring asthma control with special attention to childhood asthma. Allergol. Immunopathol. (Madr).38(1), 41–46 (2010).
  • Chung KF, Caramori G, Adcock IM. Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future. Eur. J. Clin. Pharmacol.65(9), 853–871 (2009).
  • Irwin RS, Richardson ND. Side effects with inhaled corticosteroids: the physician’s perception. Chest130(1 Suppl.), 41S–53S (2006).
  • Barnes PJ. New therapies for asthma. Trends Mol. Med.12(11), 515–520 (2006).
  • Matera MG, Curradi G, Cazzola M. Long-acting β(2) agonists in asthma and allergic rhinitis. Expert Opin. Pharmacother.9(9), 1531–1539 (2008).
  • Lipworth BJ. Benefits of long-acting β2-agonists. J. Allergy Clin. Immunol.120(3), 725; author reply 726 (2007).
  • Rodrigo GJ. Meta analysis: increased risk of asthma death with salmeterol monotherapy compared with placebo, but not with salmeterol plus inhaled corticosteroids compared with inhaled corticosteroids alone. Evid. Based Med.15(2), 37–38 (2010).
  • Beasley R, Wijesinghe M, Weatherall M. Potential risks of using LABAs with ICS therapy. Am. J. Respir. Crit. Care Med.180(6), 581; author reply 581–582 (2009).
  • Huynh PN, Scott LG, Kwong KY. Long-term maintenance of pediatric asthma: focus on budesonide/formoterol inhalation aerosol. Ther. Clin. Risk Manag.6, 65–75 (2010).
  • Toscano WA, Oehlke KP. Systems biology: new approaches to old environmental health problems. Int. J. Environ. Res. Public Health2(1), 4–9 (2005).
  • Carraro S, Rezzi S, Reniero F et al. Metabolomics applied to exhaled breath condensate in childhood asthma. Am. J. Respir. Crit. Care Med.175(10), 986–990 (2007).
  • Louhelainen N, Myllarniemi M, Rahman I, Kinnula VL. Airway biomarkers of the oxidant burden in asthma and chronic obstructive pulmonary disease: current and future perspectives. Int. J. Chron. Obstruct. Pulmon. Dis.3(4), 585–603 (2008).
  • Saude EJ, Obiefuna IP, Somorjai RL et al. Metabolomic biomarkers in a model of asthma exacerbation: urine nuclear magnetic resonance. Am. J. Respir. Crit. Care Med.179(1), 25–34 (2009).
  • Holloway JW, Yang IA, Holgate ST. Genetics of allergic disease. J. Allergy Clin. Immunol.125(2 Suppl. 2), S81–S94 (2010).
  • Kasper CE. Genomics and proteomics methodologies for vulnerable populations research. Annu. Rev. Nurs. Res.25, 191–217 (2007).
  • Houtman R, van den Worm E. Asthma, the ugly duckling of lung disease proteomics? J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci.815(1–2), 285–294 (2005).
  • Sepper R, Prikk K. Proteomics: is it an approach to understand the progression of chronic lung disorders? J. Proteome Res.3(2), 277–281 (2004).
  • Halapi E, Hakonarson H. Recent development in genomic and proteomic research for asthma. Curr. Opin. Pulm. Med.10(1), 22–30 (2004).
  • Sampson AP, Pizzichini E, Bisgaard H. Effects of cysteinyl leukotrienes and leukotriene receptor antagonists on markers of inflammation. J. Allergy Clin. Immunol.111(1 Suppl.), S49–S59; discussion S59–S61 (2003).
  • del Giudice MM, Pezzulo A, Capristo C et al. Leukotriene modifiers in the treatment of asthma in children. Ther. Adv. Respir. Dis.3(5), 245–251 (2009).
  • de Benedictis FM, del Giudice MM, Forenza N, Decimo F, de Benedictis D, Capristo A. Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children. Eur. Respir. J.28(2), 291–295 (2006).
  • Malmstrom K, Rodriguez-Gomez G, Guerra J et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. Montelukast/Beclomethasone Study Group. Ann. Intern. Med.130(6), 487–495 (1999).
  • Bacharier LB, Boner A, Carlsen KH et al. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy63(1), 5–34 (2008).
  • Park JS, Jang AS, Park SW et al. Protection of leukotriene receptor antagonist against aspirin-induced bronchospasm in asthmatics. Allergy Asthma Immunol. Res.2(1), 48–54 (2010).
  • Abadoglu O, Mungan D, Aksu O, Erekul S, Misirligil Z. The effect of montelukast on eosinophil apoptosis: induced sputum findings of patients with mild persistent asthma. Allergol. Immunopathol. (Madr.)33(2), 105–111 (2005).
  • FitzGerald JM, Gibson PG. Asthma exacerbations. 4: prevention. Thorax61(11), 992–999 (2006).
  • O’Byrne PM, Gauvreau GM, Murphy DM. Efficacy of leukotriene receptor antagonists and synthesis inhibitors in asthma. J. Allergy Clin. Immunol.124(3), 397–403 (2009).
  • Ram FS, Cates CJ, Ducharme FM. Long-acting β2-agonists versus anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma. Cochrane Database Syst. Rev.1, CD003137 (2005).
  • Bibby S, Healy B, Steele R, Kumareswaran K, Nelson H, Beasley R. Association between leukotriene receptor antagonist therapy and Churg–Strauss syndrome: an analysis of the FDA AERS database. Thorax65(2), 132–138 (2010).
  • Balzar S, Strand M, Rhodes D, Wenzel SE. IgE expression pattern in lung: relation to systemic IgE and asthma phenotypes. J. Allergy Clin. Immunol.119(4), 855–862 (2007).
  • Muh HC, Tong JC, Tammi MT. AllerHunter: a SVM-pairwise system for assessment of allergenicity and allergic cross-reactivity in proteins. PLoS One4(6), e5861 (2009).
  • Fiset PO, Cameron L, Hamid Q. Local isotype switching to IgE in airway mucosa. J. Allergy Clin. Immunol.116(1), 233–236 (2005).
  • Gould HJ, Takhar P, Harries HE, Durham SR, Corrigan CJ. Germinal-centre reactions in allergic inflammation. Trends Immunol.27(10), 446–452 (2006).
  • Kato A, Xiao H, Chustz RT, Liu MC, Schleimer RP. Local release of B cell-activating factor of the TNF family after segmental allergen challenge of allergic subjects. J. Allergy Clin. Immunol.123(2), 369–375 (2009).
  • Schneider P. The role of APRIL and BAFF in lymphocyte activation. Curr. Opin. Immunol.17(3), 282–289 (2005).
  • Cancro MP, Hao Y, Scholz JL et al. B cells and aging: molecules and mechanisms. Trends Immunol.30(7), 313–318 (2009).
  • Mackay F, Silveira PA, Brink R. B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling. Curr. Opin. Immunol.19(3), 327–336 (2007).
  • Poulsen LK, Hummelshoj L. Triggers of IgE class switching and allergy development. Ann. Med.39(6), 440–456 (2007).
  • Holgate S, Smith N, Massanari M, Jimenez P. Effects of omalizumab on markers of inflammation in patients with allergic asthma. Allergy64(12), 1728–1736 (2009).
  • Toungoussova O, Migliori GB, Foschino Barbaro MP et al. Changes in sputum composition during 15 min of sputum induction in healthy subjects and patients with asthma and chronic obstructive pulmonary disease. Respir. Med.101(7), 1543–1548 (2007).
  • Hajek AR, Lindley AR, Favoreto S Jr, Carter R, Schleimer RP, Kuperman DA. 12/15-Lipoxygenase deficiency protects mice from allergic airways inflammation and increases secretory IgA levels. J. Allergy Clin. Immunol.122(3), 633–639.e3 (2008).
  • Balzar S, Strand M, Nakano T, Wenzel SE. Subtle immunodeficiency in severe asthma: IgA and IgG2 correlate with lung function and symptoms. Int. Arch. Allergy Immunol.140(2), 96–102 (2006).
  • Pilette C, Durham SR, Vaerman JP, Sibille Y. Mucosal immunity in asthma and chronic obstructive pulmonary disease: a role for immunoglobulin A? Proc. Am. Thorac. Soc.1(2), 125–135 (2004).
  • Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy. J. Allergy Clin. Immunol.119(4), 780–791 (2007).
  • Akdis CA, Blaser K, Akdis M. Mechanisms of allergen-specific immunotherapy. Chem. Immunol. Allergy91, 195–203 (2006).
  • Meiler F, Zumkehr J, Klunker S, Ruckert B, Akdis CA, Akdis M. In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J. Exp. Med.205(12), 2887–2898 (2008).
  • Meiler F, Klunker S, Zimmermann M, Akdis CA, Akdis M. Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors. Allergy63(11), 1455–1463 (2008).
  • Akdis M. Immune tolerance in allergy. Curr. Opin. Immunol.21(6), 700–707 (2009).
  • Klunker S, Saggar LR, Seyfert-Margolis V et al. Combination treatment with omalizumab and rush immunotherapy for ragweed-induced allergic rhinitis: inhibition of IgE-facilitated allergen binding. J. Allergy Clin. Immunol.120(3), 688–695 (2007).
  • van der Neut Kolfschoten M, Schuurman J, Losen M et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science317(5844), 1554–1557 (2007).
  • Marcucci F, Duse M, Frati F, Incorvaia C, Marseglia GL, La Rosa M. The future of sublingual immunotherapy. Int. J. Immunopathol. Pharmacol.22(4 Suppl.), 31–33 (2009).
  • Bahceciler NN, Arikan C, Taylor A et al. Impact of sublingual immunotherapy on specific antibody levels in asthmatic children allergic to house dust mites. Int. Arch. Allergy Immunol.136(3), 287–294 (2005).
  • Orange JS, Hossny EM, Weiler CR et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy Asthma and Immunology. J. Allergy Clin. Immunol.117(4 Suppl.), S525–S553 (2006).
  • Lee SJ, Chinen J, Kavanaugh A. Immunomodulator therapy: monoclonal antibodies, fusion proteins, cytokines, and immunoglobulins. J. Allergy Clin. Immunol.125(2 Suppl. 2), S314–S323 (2010).
  • Schwartz HJ, Hostoffer RW, McFadden ER Jr, Berger M. The response to intravenous immunoglobulin replacement therapy in patients with asthma with specific antibody deficiency. Allergy Asthma Proc.27(1), 53–58 (2006).
  • Gruenberg D, Busse W. Biologic therapies for asthma. Curr. Opin. Pulm. Med.16(1), 19–24 (2010).
  • Holgate ST, Holloway J, Wilson S et al. Understanding the pathophysiology of severe asthma to generate new therapeutic opportunities. J. Allergy Clin. Immunol.117(3), 496–506; quiz 507 (2006).
  • MacGlashan D. Loss of receptors and IgE in vivo during treatment with anti-IgE antibody. J. Allergy Clin. Immunol.114(6), 1472–1474 (2004).
  • Noga O, Hanf G, Brachmann I et al. Effect of omalizumab treatment on peripheral eosinophil and T-lymphocyte function in patients with allergic asthma. J. Allergy Clin. Immunol.117(6), 1493–1499 (2006).
  • Miller CW, Krishnaswamy N, Johnston C, Krishnaswamy G. Severe asthma and the omalizumab option. Clin. Mol. Allergy6, 4 (2008).
  • Milgrom H, Berger W, Nayak A et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics108(2), E36 (2001).
  • Ben-Shoshan M. Omalizumab: not only for asthma. Recent Pat. Inflamm. Allergy Drug Discov.2(3), 191–201 (2008).
  • Rambasek TE, Lang DM, Kavuru MS. Omalizumab: where does it fit into current asthma management? Cleve. Clin. J. Med.71(3), 251–261 (2004).
  • Finkelman FD, Hogan SP, Hershey GK, Rothenberg ME, Wills-Karp M. Importance of cytokines in murine allergic airway disease and human asthma. J. Immunol.184(4), 1663–1674 (2010).
  • Walsh GM. Mepolizumab and eosinophil-mediated disease. Curr. Med. Chem.16(36), 4774–4778 (2009).
  • Leckie MJ, ten Brinke A, Khan J et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet356(9248), 2144–2148 (2000).
  • O’Byrne PM, Inman MD, Parameswaran K. The trials and tribulations of IL-5, eosinophils, and allergic asthma. J. Allergy Clin. Immunol.108(4), 503–508 (2001).
  • Flood-Page P, Menzies-Gow A, Phipps S et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J. Clin. Invest.112(7), 1029–1036 (2003).
  • Stein ML, Villanueva JM, Buckmeier BK et al. Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels. J. Allergy Clin. Immunol.121(6), 1473–1483 (2008).
  • Brightling C, Berry M, Amrani Y. Targeting TNF-α: a novel therapeutic approach for asthma. J. Allergy Clin. Immunol.121(1), 5–10; quiz 11–12 (2008).
  • Berry MA, Hargadon B, Shelley M et al. Evidence of a role of tumor necrosis factor α in refractory asthma. N. Engl. J. Med.354(7), 697–708 (2006).
  • Howarth PH, Babu KS, Arshad HS et al. Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax60(12), 1012–1018 (2005).
  • Morjaria JB, Chauhan AJ, Babu KS, Polosa R, Davies DE, Holgate ST. The role of a soluble TNFα receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax63(7), 584–591 (2008).
  • Wenzel SE, Barnes PJ, Bleecker ER et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-α blockade in severe persistent asthma. Am. J. Respir. Crit. Care Med.179(7), 549–558 (2009).
  • Busse WW, Israel E, Nelson HS et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am. J. Respir. Crit. Care Med.178(10), 1002–1008 (2008).
  • Antoniu SA. MEDI-528, an anti-IL-9 humanized antibody for the treatment of asthma. Curr. Opin. Mol. Ther.12(2), 233–239 (2010).
  • Kips JC, Tournoy KG, Pauwels RA. New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5. Eur. Respir. J.17(3), 499–506 (2001).
  • Borish L. IL-4 and IL-13 dual antagonism: a promising approach to the dilemma of generating effective asthma biotherapeutics. Am. J. Respir. Crit. Care Med.181(8), 769–770 (2010).
  • Steinke JW. Anti-interleukin-4 therapy. Immunol Allergy Clin. North Am.24(4), 599–614, vi (2004).
  • Vollmer J, Krieg AM. Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists. Adv. Drug Deliv. Rev.61(3), 195–204 (2009).
  • Casale TB, Stokes JR. Immunomodulators for allergic respiratory disorders. J. Allergy Clin. Immunol.121(2), 288–296; quiz 297–288 (2008).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.