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Semin Respir Crit Care Med 2018; 39(01): 064-081
DOI: 10.1055/s-0037-1607981
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Advances and Evolving Concepts in Allergic Asthma

Hui-Ying Tung
1   Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas
,
Evan Li
2   Department of Medicine, Baylor College of Medicine, Houston, Texas
,
Cameron Landers
2   Department of Medicine, Baylor College of Medicine, Houston, Texas
3   Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, Texas
,
An Nguyen
2   Department of Medicine, Baylor College of Medicine, Houston, Texas
,
Farrah Kheradmand
1   Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas
2   Department of Medicine, Baylor College of Medicine, Houston, Texas
4   Biology of Inflammation Center, Baylor College of Medicine, Houston, Texas
5   Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston Texas
,
J. Morgan Knight
1   Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas
,
David B. Corry
1   Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas
2   Department of Medicine, Baylor College of Medicine, Houston, Texas
4   Biology of Inflammation Center, Baylor College of Medicine, Houston, Texas
5   Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston Texas
› Author Affiliations
Further Information

Publication History

Publication Date:
10 February 2018 (online)

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Abstract

Allergic asthma is a heterogeneous disorder that defies a unanimously acceptable definition, but is generally recognized through its highly characteristic clinical expression of dyspnea and cough accompanied by clinical data that document reversible or exaggerated airway constriction and obstruction. The generally rising prevalence of asthma in highly industrialized societies despite significant therapeutic advances suggests that the fundamental cause(s) of asthma remain poorly understood. Detailed analyses of both the indoor (built) and outdoor environments continue to support the concept that not only inhaled particulates, especially carbon-based particulate pollution, pollens, and fungal elements, but also many noxious gases and chemicals, especially biologically derived byproducts such as proteinases, are essential to asthma pathogenesis. Phthalates, another common class of chemical pollutant found in the built environment, are emerging as potentially important mediators or attenuators of asthma. Other biological products such as endotoxin have also been confirmed to be protective in both the indoor and outdoor contexts. Proasthmatic factors are believed to activate, and in some instances initiate, pathologic inflammatory cascades through complex interactions with pattern recognition receptors (PRRs) expressed on many cell types, but especially airway epithelial cells. PRRs initiate the release of proallergic cytokines such as interleukin (IL)-33, IL-25, and others that coordinate activation of innate lymphoid cells type 2 (ILC2), T helper type 2 cells, and immunoglobulin E–secreting B cells that together promote additional inflammation and the major airway remodeling events (airway hyperresponsiveness, mucus hypersecretion) that promote airway obstruction. Proteinases, with airway fungi and viruses being potentially important sources, are emerging as critically important initiators of these inflammatory cascades in part through their effects on clotting factors such as fibrinogen. Recent clinical trials have demonstrated that targeting inflammatory pathways orchestrated through IL-4, IL-5, IL-13, and the prostaglandin receptor CRTH2 is potentially highly effective in adult asthma.

Keywords

asthma - phthalate - proteinase - fungi - virus - TH2 cell - ILC2 - fibrinogen - CRTH2 - endotoxin - TLR4 - IL-4 - IL-5 - IL-13 - pattern recognition receptor
 

  • References

  • 1 Corry DB, Kheradmand F, Luong A, Pandit L. Immunological mechanisms of airway diseases and pathways to therapy. In: Rich RR. , ed. Clinical Immunology: Principles and Practice, 4th ed. Amsterdam, Netherlands: Elsevier Health Sciences; 2013: 491-505
    Google Scholar
  • 2 Akinbami LJ, Moorman JE, Bailey C. , et al. Trends in asthma prevalence, health care use, and mortality in the United States, 2001-2010. NCHS Data Brief 2012; 94: 1-8
    PubMedGoogle Scholar
  • 3 Liu AH. Revisiting the hygiene hypothesis for allergy and asthma. J Allergy Clin Immunol 2015; 136 (04) 860-865
    CrossrefPubMedGoogle Scholar
  • 4 Daley D. The evolution of the hygiene hypothesis: the role of early-life exposures to viruses and microbes and their relationship to asthma and allergic diseases. Curr Opin Allergy Clin Immunol 2014; 14 (05) 390-396
    CrossrefPubMedGoogle Scholar
  • 5 Brooks C, Pearce N, Douwes J. The hygiene hypothesis in allergy and asthma: an update. Curr Opin Allergy Clin Immunol 2013; 13 (01) 70-77
    CrossrefPubMedGoogle Scholar
  • 6 Weber J, Illi S, Nowak D. , et al. Asthma and the hygiene hypothesis. Does cleanliness matter?. Am J Respir Crit Care Med 2015; 191 (05) 522-529
    CrossrefPubMedGoogle Scholar
  • 7 Haahtela T, Holgate S, Pawankar R. , et al; WAO Special Committee on Climate Change and Biodiversity. The biodiversity hypothesis and allergic disease: world allergy organization position statement. World Allergy Organ J 2013; 6 (01) 3
    CrossrefPubMedGoogle Scholar
  • 8 Abrahamsson TR, Jakobsson HE, Andersson AF, Björkstén B, Engstrand L, Jenmalm MC. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin Exp Allergy 2014; 44 (06) 842-850
    CrossrefPubMedGoogle Scholar
  • 9 Russell SL, Gold MJ, Hartmann M. , et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep 2012; 13 (05) 440-447
    CrossrefPubMedGoogle Scholar
  • 10 Olszak T, An D, Zeissig S. , et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 2012; 336 (6080): 489-493
    CrossrefPubMedGoogle Scholar
  • 11 Noverr MC, Falkowski NR, McDonald RA, McKenzie AN, Huffnagle GB. Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13. Infect Immun 2005; 73 (01) 30-38
    CrossrefPubMedGoogle Scholar
  • 12 Kim Y-G, Udayanga KGS, Totsuka N, Weinberg JB, Núñez G, Shibuya A. Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE2 . Cell Host Microbe 2014; 15 (01) 95-102
    CrossrefPubMedGoogle Scholar
  • 13 Hill DA, Siracusa MC, Abt MC. , et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med 2012; 18 (04) 538-546
    CrossrefPubMedGoogle Scholar
  • 14 Herbst T, Sichelstiel A, Schär C. , et al. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am J Respir Crit Care Med 2011; 184 (02) 198-205
    CrossrefPubMedGoogle Scholar
  • 15 Sharpe RA, Bearman N, Thornton CR, Husk K, Osborne NJ. Indoor fungal diversity and asthma: a meta-analysis and systematic review of risk factors. J Allergy Clin Immunol 2015; 135 (01) 110-122
    CrossrefPubMedGoogle Scholar
  • 16 McSharry C, Vesper S, Wymer L. , et al. Decreased FEV1 % in asthmatic adults in Scottish homes with high Environmental Relative Moldiness Index values. Clin Exp Allergy 2015; 45 (05) 902-907
    CrossrefPubMedGoogle Scholar
  • 17 Blatter J, Forno E, Brehm J. , et al. Fungal exposure, atopy, and asthma exacerbations in Puerto Rican children. Ann Am Thorac Soc 2014; 11 (06) 925-932
    CrossrefPubMedGoogle Scholar
  • 18 Lodge CJ, Lowe AJ, Gurrin LC. , et al. House dust mite sensitization in toddlers predicts current wheeze at age 12 years. J Allergy Clin Immunol 2011; 128 (04) 782-788.e9
    CrossrefPubMedGoogle Scholar
  • 19 Andiappan AK, Puan KJ, Lee B. , et al. Allergic airway diseases in a tropical urban environment are driven by dominant mono-specific sensitization against house dust mites. Allergy 2014; 69 (04) 501-509
    CrossrefPubMedGoogle Scholar
  • 20 Kanchongkittiphon W, Mendell MJ, Gaffin JM, Wang G, Phipatanakul W. Indoor environmental exposures and exacerbation of asthma: an update to the 2000 review by the Institute of Medicine. Environ Health Perspect 2015; 123 (01) 6-20
    CrossrefPubMedGoogle Scholar
  • 21 Sheehan WJ, Permaul P, Petty CR. , et al. Association between allergen exposure in inner-city schools and asthma morbidity among students. JAMA Pediatr 2017; 171 (01) 31-38
    CrossrefPubMedGoogle Scholar
  • 22 Cai GH, Hashim JH, Hashim Z. , et al. Fungal DNA, allergens, mycotoxins and associations with asthmatic symptoms among pupils in schools from Johor Bahru, Malaysia. Pediatr Allergy Immunol 2011; 22 (03) 290-297
    CrossrefPubMedGoogle Scholar
  • 23 Baur X, Bakehe P. Allergens causing occupational asthma: an evidence-based evaluation of the literature. Int Arch Occup Environ Health 2014; 87 (04) 339-363
    CrossrefPubMedGoogle Scholar
  • 24 Kheradmand F, Kiss A, Xu J, Lee SH, Kolattukudy PE, Corry DB. A protease-activated pathway underlying Th cell type 2 activation and allergic lung disease. J Immunol 2002; 169 (10) 5904-5911
    CrossrefPubMedGoogle Scholar
  • 25 Clark NA, Demers PA, Karr CJ. , et al. Effect of early life exposure to air pollution on development of childhood asthma. Environ Health Perspect 2010; 118 (02) 284-290
    CrossrefPubMedGoogle Scholar
  • 26 Bowatte G, Lodge C, Lowe AJ. , et al. The influence of childhood traffic-related air pollution exposure on asthma, allergy and sensitization: a systematic review and a meta-analysis of birth cohort studies. Allergy 2015; 70 (03) 245-256
    CrossrefPubMedGoogle Scholar
  • 27 Gleason JA, Bielory L, Fagliano JA. Associations between ozone, PM2.5, and four pollen types on emergency department pediatric asthma events during the warm season in New Jersey: a case-crossover study. Environ Res 2014; 132: 421-429
    CrossrefPubMedGoogle Scholar
  • 28 Gunawan H, Takai T, Ikeda S, Okumura K, Ogawa H. Protease activity of allergenic pollen of cedar, cypress, juniper, birch and ragweed. Allergol Int 2008; 57 (01) 83-91
    CrossrefPubMedGoogle Scholar
  • 29 Gadermaier G, Hauser M, Ferreira F. Allergens of weed pollen: an overview on recombinant and natural molecules. Methods 2014; 66 (01) 55-66
    CrossrefPubMedGoogle Scholar
  • 30 Vinhas R, Cortes L, Cardoso I. , et al. Pollen proteases compromise the airway epithelial barrier through degradation of transmembrane adhesion proteins and lung bioactive peptides. Allergy 2011; 66 (08) 1088-1098
    CrossrefPubMedGoogle Scholar
  • 31 Balenga NA, Klichinsky M, Xie Z. , et al. A fungal protease allergen provokes airway hyper-responsiveness in asthma. Nat Commun 2015; 6: 6763
    CrossrefPubMedGoogle Scholar
  • 32 Millien VO, Lu W, Shaw J. , et al. Cleavage of fibrinogen by proteinases elicits allergic responses through toll-like receptor 4. Science 2013; 341 (6147): 792-796
    CrossrefPubMedGoogle Scholar
  • 33 Kauffman HF, Tamm M, Timmerman JAB, Borger P. House dust mite major allergens Der p 1 and Der p 5 activate human airway-derived epithelial cells by protease-dependent and protease-independent mechanisms. Clin Mol Allergy 2006; 4: 5
    CrossrefPubMedGoogle Scholar
  • 34 Thomas WR, Hales BJ, Smith W-A. House dust mite allergens in asthma and allergy. Trends Mol Med 2010; 16 (07) 321-328
    CrossrefPubMedGoogle Scholar
  • 35 Kelada SN, Wilson MS, Tavarez U. , et al. Strain-dependent genomic factors affect allergen-induced airway hyperresponsiveness in mice. Am J Respir Cell Mol Biol 2011; 45 (04) 817-824
    CrossrefPubMedGoogle Scholar
  • 36 Huntington JA, Stein PE. Structure and properties of ovalbumin. J Chromatogr B Biomed Sci Appl 2001; 756 (1-2): 189-198
    CrossrefPubMedGoogle Scholar
  • 37 van Gent D, Sharp P, Morgan K, Kalsheker N. Serpins: structure, function and molecular evolution. Int J Biochem Cell Biol 2003; 35 (11) 1536-1547
    CrossrefPubMedGoogle Scholar
  • 38 Stein MM, Hrusch CL, Gozdz J. , et al. Innate immunity and asthma risk in Amish and Hutterite farm children. N Engl J Med 2016; 375 (05) 411-421
    CrossrefPubMedGoogle Scholar
  • 39 Feng M, Yang Z, Pan L. , et al. Associations of early life exposures and environmental factors with asthma among children in rural and urban areas of Guangdong, China. Chest 2016; 149 (04) 1030-1041
    CrossrefPubMedGoogle Scholar
  • 40 Michel S, Busato F, Genuneit J. , et al; PASTURE study group. Farm exposure and time trends in early childhood may influence DNA methylation in genes related to asthma and allergy. Allergy 2013; 68 (03) 355-364
    CrossrefPubMedGoogle Scholar
  • 41 Schuijs MJ, Willart MA, Vergote K. , et al. Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells. Science 2015; 349 (6252): 1106-1110
    CrossrefPubMedGoogle Scholar
  • 42 Ather JL, Hodgkins SR, Janssen-Heininger YM, Poynter ME. Airway epithelial NF-κB activation promotes allergic sensitization to an innocuous inhaled antigen. Am J Respir Cell Mol Biol 2011; 44 (05) 631-638
    CrossrefPubMedGoogle Scholar
  • 43 Ather JL, Foley KL, Suratt BT, Boyson JE, Poynter ME. Airway epithelial NF-κB activation promotes the ability to overcome inhalational antigen tolerance. Clin Exp Allergy 2015; 45 (07) 1245-1258
    CrossrefPubMedGoogle Scholar
  • 44 Tully JE, Hoffman SM, Lahue KG. , et al. Epithelial NF-κB orchestrates house dust mite-induced airway inflammation, hyperresponsiveness, and fibrotic remodeling. J Immunol 2013; 191 (12) 5811-5821
    CrossrefPubMedGoogle Scholar
  • 45 Xie T, Luo G, Zhang Y. , et al. Rho-kinase inhibitor fasudil reduces allergic airway inflammation and mucus hypersecretion by regulating STAT6 and NFκB. Clin Exp Allergy 2015; 45 (12) 1812-1822
    CrossrefPubMedGoogle Scholar
  • 46 Polosukhin VV, Polosukhin IV, Hoskins A. , et al. Glutathione S-transferase M1 modulates allergen-induced NF-κB activation in asthmatic airway epithelium. Allergy 2014; 69 (12) 1666-1672
    CrossrefPubMedGoogle Scholar
  • 47 Zucco F, Batto AF, Bises G. , et al. An inter-laboratory study to evaluate the effects of medium composition on the differentiation and barrier function of Caco-2 cell lines. Altern Lab Anim 2005; 33 (06) 603-618
    PubMedGoogle Scholar
  • 48 Srinivasan B, Kolli AR, Esch MB, Abaci HE, Shuler ML, Hickman JJ. TEER measurement techniques for in vitro barrier model systems. J Lab Autom 2015; 20 (02) 107-126
    CrossrefPubMedGoogle Scholar
  • 49 Post S, Nawijn MC, Jonker MR. , et al. House dust mite-induced calcium signaling instigates epithelial barrier dysfunction and CCL20 production. Allergy 2013; 68 (09) 1117-1125
    PubMedGoogle Scholar
  • 50 Blume C, Swindle EJ, Dennison P. , et al. Barrier responses of human bronchial epithelial cells to grass pollen exposure. Eur Respir J 2013; 42 (01) 87-97
    CrossrefPubMedGoogle Scholar
  • 51 Xiao C, Puddicombe SM, Field S. , et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol 2011; 128 (03) 549-56.e1 , 12
    CrossrefPubMedGoogle Scholar
  • 52 Parker JC, Thavagnanam S, Skibinski G. , et al. Chronic IL9 and IL-13 exposure leads to an altered differentiation of ciliated cells in a well-differentiated paediatric bronchial epithelial cell model. PLoS One 2013; 8 (05) e61023
    CrossrefPubMedGoogle Scholar
  • 53 Hackett TL, de Bruin HG, Shaheen F. , et al. Caveolin-1 controls airway epithelial barrier function. Implications for asthma. Am J Respir Cell Mol Biol 2013; 49 (04) 662-671
    CrossrefPubMedGoogle Scholar
  • 54 Sweerus K, Lachowicz-Scroggins M, Gordon E. , et al. Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma. J Allergy Clin Immunol 2017; 139 (01) 72-81.e1
    CrossrefPubMedGoogle Scholar
  • 55 Wawrzyniak P, Wawrzyniak M, Wanke K. , et al. Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients. J Allergy Clin Immunol 2017; 139 (01) 93-103
    CrossrefPubMedGoogle Scholar
  • 56 Zhang R, Dong H, Zhao H, Zhou L, Zou F, Cai S. 1,25-Dihydroxyvitamin D3 targeting VEGF pathway alleviates house dust mite (HDM)-induced airway epithelial barrier dysfunction. Cell Immunol 2017; 312: 15-24
    CrossrefPubMedGoogle Scholar
  • 57 Sussan TE, Gajghate S, Chatterjee S. , et al. Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function. Am J Physiol Lung Cell Mol Physiol 2015; 309 (01) L27-L36
    CrossrefPubMedGoogle Scholar
  • 58 Lambrecht BN, Hammad H. The airway epithelium in asthma. Nat Med 2012; 18 (05) 684-692
    CrossrefPubMedGoogle Scholar
  • 59 Barrett NA, Austen KF. Innate cells and T helper 2 cell immunity in airway inflammation. Immunity 2009; 31 (03) 425-437
    CrossrefPubMedGoogle Scholar
  • 60 Weindl G, Wagener J, Schaller M. Epithelial cells and innate antifungal defense. J Dent Res 2010; 89 (07) 666-675
    CrossrefPubMedGoogle Scholar
  • 61 Svirshchevskaya E, Zubkov D, Mouyna I, Berkova N. Innate immunity and the role of epithelial barrier during Aspergillus fumigatus infection. Curr Immunol Rev 2012; 8 (03) 254-261
    CrossrefPubMedGoogle Scholar
  • 62 Li S, Xie X, Song Y. , et al. Association of TLR4 (896A/G and 1196C/T) gene polymorphisms with asthma risk: a meta-analysis. Med Sci Monit 2015; 21: 3591-3599
    CrossrefPubMedGoogle Scholar
  • 63 Yao Y, Ren X, He L. , et al. TLR4 +896A>G (Asp299Gly) polymorphism is not associated with asthma: a update meta-analysis. Int J Clin Exp Med 2014; 7 (12) 5358-5361
    PubMedGoogle Scholar
  • 64 Sinha S, Singh J, Jindal SK, Birbian N, Singla N. Role of TLR4 C>1196T (Thr399Ile) and TLR4 A>896G (Asp299Gly) polymorphisms in a North Indian population with asthma: a case-control study. Int J Immunogenet 2014; 41 (06) 463-471
    CrossrefPubMedGoogle Scholar
  • 65 Zhang L, Xu AG, Zhao W. , et al. A toll-like receptor 4 (TLR4) variant is associated with asthma severity. Int J Clin Exp Med 2015; 8 (05) 7849-7854
    PubMedGoogle Scholar
  • 66 Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med 2002; 196 (12) 1645-1651
    CrossrefPubMedGoogle Scholar
  • 67 Hammad H, Chieppa M, Perros F, Willart MA, Germain RN, Lambrecht BN. House dust mite allergen induces asthma via toll-like receptor 4 triggering of airway structural cells. Nat Med 2009; 15 (04) 410-416
    CrossrefPubMedGoogle Scholar
  • 68 Hongjia L, Qingling G, Meiying L. , et al. House dust mite regulate the lung inflammation of asthmatic mice through TLR4 pathway in airway epithelial cells. Cell Biochem Funct 2010; 28 (07) 597-603
    CrossrefPubMedGoogle Scholar
  • 69 Matsushita H, Ohta S, Shiraishi H. , et al. Endotoxin tolerance attenuates airway allergic inflammation in model mice by suppression of the T-cell stimulatory effect of dendritic cells. Int Immunol 2010; 22 (09) 739-747
    CrossrefPubMedGoogle Scholar
  • 70 Trompette A, Divanovic S, Visintin A. , et al. Allergenicity resulting from functional mimicry of a toll-like receptor complex protein. Nature 2009; 457 (7229): 585-588
    CrossrefPubMedGoogle Scholar
  • 71 Choi HJ, Park SY, Cho JH. , et al. The TLR4-associated phospholipase D1 activation is crucial for Der f 2-induced IL-13 production. Allergy 2015; 70 (12) 1569-1579
    CrossrefPubMedGoogle Scholar
  • 72 McAlees JW, Whitehead GS, Harley IT. , et al. Distinct Tlr4-expressing cell compartments control neutrophilic and eosinophilic airway inflammation. Mucosal Immunol 2015; 8 (04) 863-873
    CrossrefPubMedGoogle Scholar
  • 73 Kim DH, Choi E, Lee JS. , et al. House dust mite allergen regulates constitutive apoptosis of normal and asthmatic neutrophils via toll-like receptor 4. PLoS One 2015; 10 (05) e0125983
    CrossrefPubMedGoogle Scholar
  • 74 Shalaby KH, Jo T, Nakada E. , et al. ICOS-expressing CD4 T cells induced via TLR4 in the nasal mucosa are capable of inhibiting experimental allergic asthma. J Immunol 2012; 189 (06) 2793-2804
    CrossrefPubMedGoogle Scholar
  • 75 Pace E, Di Sano C, Ferraro M. , et al. Budesonide increases TLR4 and TLR2 expression in Treg lymphocytes of allergic asthmatics. Pulm Pharmacol Ther 2015; 32: 93-100
    CrossrefPubMedGoogle Scholar
  • 76 Liu CF, Drocourt D, Puzo G, Wang JY, Riviere M. Innate immune response of alveolar macrophage to house dust mite allergen is mediated through TLR2/-4 co-activation. PLoS One 2013; 8 (10) e75983
    CrossrefPubMedGoogle Scholar
  • 77 Nawijn MC, Motta AC, Gras R, Shirinbak S, Maazi H, van Oosterhout AJ. TLR-2 activation induces regulatory T cells and long-term suppression of asthma manifestations in mice. PLoS One 2013; 8 (02) e55307
    CrossrefPubMedGoogle Scholar
  • 78 Arizmendi NG, Abel M, Mihara K. , et al. Mucosal allergic sensitization to cockroach allergens is dependent on proteinase activity and proteinase-activated receptor-2 activation. J Immunol 2011; 186 (05) 3164-3172
    CrossrefPubMedGoogle Scholar
  • 79 Asaduzzaman M, Nadeem A, Arizmendi N. , et al. Functional inhibition of PAR2 alleviates allergen-induced airway hyperresponsiveness and inflammation. Clin Exp Allergy 2015; 45 (12) 1844-1855
    CrossrefPubMedGoogle Scholar
  • 80 de Boer JD, Van't Veer C, Stroo I. , et al. Protease-activated receptor-2 deficient mice have reduced house dust mite-evoked allergic lung inflammation. Innate Immun 2014; 20 (06) 618-625
    CrossrefPubMedGoogle Scholar
  • 81 Nichols HL, Saffeddine M, Theriot BS. , et al. β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway. Proc Natl Acad Sci U S A 2012; 109 (41) 16660-16665
    CrossrefPubMedGoogle Scholar
  • 82 Sherwood CL, Daines MO, Price TJ, Vagner J, Boitano S. A highly potent agonist to protease-activated receptor-2 reveals apical activation of the airway epithelium resulting in Ca2+-regulated ion conductance. Am J Physiol Cell Physiol 2014; 307 (08) C718-C726
    CrossrefPubMedGoogle Scholar
  • 83 Lambrecht BN, Hammad H. Allergens and the airway epithelium response: gateway to allergic sensitization. J Allergy Clin Immunol 2014; 134 (03) 499-507
    CrossrefPubMedGoogle Scholar
  • 84 Barlow JL, Flynn RJ, Ballantyne SJ, McKenzie AN. Reciprocal expression of IL-25 and IL-17A is important for allergic airways hyperreactivity. Clin Exp Allergy 2011; 41 (10) 1447-1455
    CrossrefPubMedGoogle Scholar
  • 85 Wang C, Liu Q, Chen F, Xu W, Zhang C, Xiao W. IL-25 promotes Th2 immunity responses in asthmatic mice via nuocytes activation. PLoS One 2016; 11 (09) e0162393
    CrossrefPubMedGoogle Scholar
  • 86 Huang P, Li Y, Lv Z. , et al. Comprehensive attenuation of IL-25-induced airway hyperresponsiveness, inflammation and remodelling by the PI3K inhibitor LY294002. Respirology 2017; 22 (01) 78-85
    PubMedGoogle Scholar
  • 87 Tashiro H, Takahashi K, Hayashi S. , et al. Interleukin-33 from monocytes recruited to the lung contributes to house dust mite-induced airway inflammation in a mouse model. PLoS One 2016; 11 (06) e0157571
    CrossrefPubMedGoogle Scholar
  • 88 Wills-Karp M, Rani R, Dienger K. , et al. Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J Exp Med 2012; 209 (03) 607-622
    CrossrefPubMedGoogle Scholar
  • 89 Yamazumi Y, Sasaki O, Imamura M. , et al. The RNA binding protein Mex-3B is required for IL-33 induction in the development of allergic airway inflammation. Cell Reports 2016; 16 (09) 2456-2471
    CrossrefPubMedGoogle Scholar
  • 90 Park IH, Park JH, Shin JM, Lee HM. Tumor necrosis factor-α regulates interleukin-33 expression through extracellular signal-regulated kinase, p38, and nuclear factor-κB pathways in airway epithelial cells. Int Forum Allergy Rhinol 2016; 6 (09) 973-980
    CrossrefPubMedGoogle Scholar
  • 91 Zoltowska AM, Lei Y, Fuchs B, Rask C, Adner M, Nilsson GP. The interleukin-33 receptor ST2 is important for the development of peripheral airway hyperresponsiveness and inflammation in a house dust mite mouse model of asthma. Clin Exp Allergy 2016; 46 (03) 479-490
    CrossrefPubMedGoogle Scholar
  • 92 Kaur D, Gomez E, Doe C. , et al. IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: airway smooth muscle crosstalk. Allergy 2015; 70 (05) 556-567
    CrossrefPubMedGoogle Scholar
  • 93 Kondo Y, Yoshimoto T, Yasuda K. , et al. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int Immunol 2008; 20 (06) 791-800
    CrossrefPubMedGoogle Scholar
  • 94 Tanabe T, Shimokawaji T, Kanoh S, Rubin BK. IL-33 stimulates CXCL8/IL-8 secretion in goblet cells but not normally differentiated airway cells. Clin Exp Allergy 2014; 44 (04) 540-552
    CrossrefPubMedGoogle Scholar
  • 95 Smith SG, Gugilla A, Mukherjee M. , et al. Thymic stromal lymphopoietin and IL-33 modulate migration of hematopoietic progenitor cells in patients with allergic asthma. J Allergy Clin Immunol 2015; 135 (06) 1594-1602
    CrossrefPubMedGoogle Scholar
  • 96 Endo Y, Hirahara K, Iinuma T. , et al. The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway. Immunity 2015; 42 (02) 294-308
    CrossrefPubMedGoogle Scholar
  • 97 Murakami-Satsutani N, Ito T, Nakanishi T. , et al. IL-33 promotes the induction and maintenance of Th2 immune responses by enhancing the function of OX40 ligand. Allergol Int 2014; 63 (03) 443-455
    CrossrefPubMedGoogle Scholar
  • 98 Ho LH, Ohno T, Oboki K. , et al. IL-33 induces IL-13 production by mouse mast cells independently of IgE-FcepsilonRI signals. J Leukoc Biol 2007; 82 (06) 1481-1490
    CrossrefPubMedGoogle Scholar
  • 99 Hsu CL, Neilsen CV, Bryce PJ. IL-33 is produced by mast cells and regulates IgE-dependent inflammation. PLoS One 2010; 5 (08) e11944
    CrossrefPubMedGoogle Scholar
  • 100 Joulia R, L'Faqihi FE, Valitutti S, Espinosa E. IL-33 fine tunes mast cell degranulation and chemokine production at the single-cell level. J Allergy Clin Immunol 2016; S0091-6749(16)31353-7
    PubMedGoogle Scholar
  • 101 Ito T, Egusa C, Maeda T. , et al. IL-33 promotes MHC class II expression in murine mast cells. Immun Inflamm Dis 2015; 3 (03) 196-208
    CrossrefPubMedGoogle Scholar
  • 102 Morita H, Arae K, Unno H. , et al. An interleukin-33-mast cell-interleukin-2 axis suppresses papain-induced allergic inflammation by promoting regulatory T cell numbers. Immunity 2015; 43 (01) 175-186
    CrossrefPubMedGoogle Scholar
  • 103 Siede J, Fröhlich A, Datsi A. , et al. IL-33 receptor-expressing regulatory T cells are highly activated, Th2 biased and suppress CD4 T cell proliferation through IL-10 and TGFβ release. PLoS One 2016; 11 (08) e0161507
    CrossrefPubMedGoogle Scholar
  • 104 Vasanthakumar A, Moro K, Xin A. , et al. The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat Immunol 2015; 16 (03) 276-285
    CrossrefPubMedGoogle Scholar
  • 105 Schiering C, Krausgruber T, Chomka A. , et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 2014; 513 (7519): 564-568
    CrossrefPubMedGoogle Scholar
  • 106 Hoshino K, Kashiwamura S, Kuribayashi K. , et al. The absence of interleukin 1 receptor-related T1/ST2 does not affect T helper cell type 2 development and its effector function. J Exp Med 1999; 190 (10) 1541-1548
    CrossrefPubMedGoogle Scholar
  • 107 Carriere V, Roussel L, Ortega N. , et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci U S A 2007; 104 (01) 282-287
    CrossrefPubMedGoogle Scholar
  • 108 Vannella KM, Ramalingam TR, Borthwick LA. , et al. Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis. Sci Transl Med 2016; 8 (337) 337ra65
    CrossrefPubMedGoogle Scholar
  • 109 Moro K, Yamada T, Tanabe M. , et al. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature 2010; 463 (7280): 540-544
    CrossrefPubMedGoogle Scholar
  • 110 Neill DR, Wong SH, Bellosi A. , et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 2010; 464 (7293): 1367-1370
    CrossrefPubMedGoogle Scholar
  • 111 Price AE, Liang HE, Sullivan BM. , et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A 2010; 107 (25) 11489-11494
    CrossrefPubMedGoogle Scholar
  • 112 Hoyler T, Klose CS, Souabni A. , et al. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 2012; 37 (04) 634-648
    CrossrefPubMedGoogle Scholar
  • 113 Wong SH, Walker JA, Jolin HE. , et al. Transcription factor RORα is critical for nuocyte development. Nat Immunol 2012; 13 (03) 229-236
    CrossrefPubMedGoogle Scholar
  • 114 Liang HE, Reinhardt RL, Bando JK, Sullivan BM, Ho IC, Locksley RM. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat Immunol 2011; 13 (01) 58-66
    CrossrefPubMedGoogle Scholar
  • 115 Oliphant CJ, Hwang YY, Walker JA. , et al. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4(+) T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 2014; 41 (02) 283-295
    CrossrefPubMedGoogle Scholar
  • 116 Drake LY, Iijima K, Kita H. Group 2 innate lymphoid cells and CD4+ T cells cooperate to mediate type 2 immune response in mice. Allergy 2014; 69 (10) 1300-1307
    CrossrefPubMedGoogle Scholar
  • 117 Halim TY, Steer CA, Mathä L. , et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 2014; 40 (03) 425-435
    CrossrefPubMedGoogle Scholar
  • 118 Gold MJ, Antignano F, Halim TY. , et al. Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures. J Allergy Clin Immunol 2014; 133 (04) 1142-1148
    CrossrefPubMedGoogle Scholar
  • 119 Li BW, de Bruijn MJ, Tindemans I. , et al. T cells are necessary for ILC2 activation in house dust mite-induced allergic airway inflammation in mice. Eur J Immunol 2016; 46 (06) 1392-1403
    CrossrefPubMedGoogle Scholar
  • 120 Halim TY, Hwang YY, Scanlon ST. , et al. Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses. Nat Immunol 2016; 17 (01) 57-64
    CrossrefPubMedGoogle Scholar
  • 121 Mohapatra A, Van Dyken SJ, Schneider C, Nussbaum JC, Liang HE, Locksley RM. Group 2 innate lymphoid cells utilize the IRF4-IL-9 module to coordinate epithelial cell maintenance of lung homeostasis. Mucosal Immunol 2016; 9 (01) 275-286
    CrossrefPubMedGoogle Scholar
  • 122 Walker JA, Oliphant CJ, Englezakis A. , et al. Bcl11b is essential for group 2 innate lymphoid cell development. J Exp Med 2015; 212 (06) 875-882
    CrossrefPubMedGoogle Scholar
  • 123 Yu Y, Wang C, Clare S. , et al. The transcription factor Bcl11b is specifically expressed in group 2 innate lymphoid cells and is essential for their development. J Exp Med 2015; 212 (06) 865-874
    CrossrefPubMedGoogle Scholar
  • 124 Califano D, Cho JJ, Uddin MN. , et al. Transcription factor Bcl11b controls identity and function of mature type 2 innate lymphoid cells. Immunity 2015; 43 (02) 354-368
    CrossrefPubMedGoogle Scholar
  • 125 Bal SM, Bernink JH, Nagasawa M. , et al. IL-1β, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs. Nat Immunol 2016; 17 (06) 636-645
    CrossrefPubMedGoogle Scholar
  • 126 Lim AI, Menegatti S, Bustamante J. , et al. IL-12 drives functional plasticity of human group 2 innate lymphoid cells. J Exp Med 2016; 213 (04) 569-583
    CrossrefPubMedGoogle Scholar
  • 127 Ohne Y, Silver JS, Thompson-Snipes L. , et al. IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity. Nat Immunol 2016; 17 (06) 646-655
    CrossrefPubMedGoogle Scholar
  • 128 Kamachi F, Isshiki T, Harada N, Akiba H, Miyake S. ICOS promotes group 2 innate lymphoid cell activation in lungs. Biochem Biophys Res Commun 2015; 463 (04) 739-745
    CrossrefPubMedGoogle Scholar
  • 129 Maazi H, Patel N, Sankaranarayanan I. , et al. ICOS:ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity. Immunity 2015; 42 (03) 538-551
    CrossrefPubMedGoogle Scholar
  • 130 Paclik D, Stehle C, Lahmann A, Hutloff A, Romagnani C. ICOS regulates the pool of group 2 innate lymphoid cells under homeostatic and inflammatory conditions in mice. Eur J Immunol 2015; 45 (10) 2766-2772
    CrossrefPubMedGoogle Scholar
  • 131 Mchedlidze T, Kindermann M, Neves AT, Voehringer D, Neurath MF, Wirtz S. IL-27 suppresses type 2 immune responses in vivo via direct effects on group 2 innate lymphoid cells. Mucosal Immunol 2016; 9 (06) 1384-1394
    CrossrefPubMedGoogle Scholar
  • 132 Moro K, Kabata H, Tanabe M. , et al. Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses. Nat Immunol 2016; 17 (01) 76-86
    CrossrefPubMedGoogle Scholar
  • 133 Brightling CE, Chanez P, Leigh R. , et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 2015; 3 (09) 692-701
    CrossrefPubMedGoogle Scholar
  • 134 Piper E, Brightling C, Niven R. , et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J 2013; 41 (02) 330-338
    CrossrefPubMedGoogle Scholar
  • 135 Bagnasco D, Ferrando M, Varricchi G, Passalacqua G, Canonica GW. A critical evaluation of anti-IL-13 and anti-IL-4 strategies in severe asthma. Int Arch Allergy Immunol 2016; 170 (02) 122-131
    CrossrefPubMedGoogle Scholar
  • 136 Hanania NA, Noonan M, Corren J. , et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax 2015; 70 (08) 748-756
    CrossrefPubMedGoogle Scholar
  • 137 Noonan M, Korenblat P, Mosesova S. , et al. Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. J Allergy Clin Immunol 2013; 132 (03) 567-574 .e12
    CrossrefPubMedGoogle Scholar
  • 138 Corry DB, Kheradmand F. Biology and therapeutic potential of the interleukin-4/interleukin-13 signaling pathway in asthma. Am J Respir Med 2002; 1 (03) 185-193
    CrossrefPubMedGoogle Scholar
  • 139 Wenzel S, Castro M, Corren J. , et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016; 388 (10039): 31-44
    CrossrefPubMedGoogle Scholar
  • 140 Wenzel S, Ford L, Pearlman D. , et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013; 368 (26) 2455-2466
    CrossrefPubMedGoogle Scholar
  • 141 Ortega HG, Liu MC, Pavord ID. , et al; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371 (13) 1198-1207
    CrossrefPubMedGoogle Scholar
  • 142 Ortega HG, Yancey SW, Mayer B. , et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med 2016; 4 (07) 549-556
    CrossrefPubMedGoogle Scholar
  • 143 Pavord ID, Korn S, Howarth P. , et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380 (9842): 651-659
    CrossrefPubMedGoogle Scholar
  • 144 Bjermer L, Lemiere C, Maspero J, Weiss S, Zangrilli J, Germinaro M. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest 2016; 150 (04) 789-798
    CrossrefPubMedGoogle Scholar
  • 145 Castro M, Mathur S, Hargreave F. , et al; Res-5-0010 Study Group. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 2011; 184 (10) 1125-1132
    CrossrefPubMedGoogle Scholar
  • 146 Castro M, Zangrilli J, Wechsler ME. , et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med 2015; 3 (05) 355-366
    CrossrefPubMedGoogle Scholar
  • 147 Tan HT, Sugita K, Akdis CA. Novel biologicals for the treatment of allergic diseases and asthma. Curr Allergy Asthma Rep 2016; 16 (10) 70
    CrossrefPubMedGoogle Scholar
  • 148 Ghazi A, Trikha A, Calhoun WJ. Benralizumab--a humanized mAb to IL-5Rα with enhanced antibody-dependent cell-mediated cytotoxicity--a novel approach for the treatment of asthma. Expert Opin Biol Ther 2012; 12 (01) 113-118
    CrossrefPubMedGoogle Scholar
  • 149 Bleecker ER, FitzGerald JM, Chanez P. , et al; SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016; 388 (10056): 2115-2127
    CrossrefPubMedGoogle Scholar
  • 150 FitzGerald JM, Bleecker ER, Nair P. , et al; CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2016; 388 (10056): 2128-2141
    CrossrefPubMedGoogle Scholar
  • 151 Castro M, Wenzel SE, Bleecker ER. , et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med 2014; 2 (11) 879-890
    CrossrefPubMedGoogle Scholar
  • 152 Townley RG, Agrawal S. CRTH2 antagonists in the treatment of allergic responses involving TH2 cells, basophils, and eosinophils. Ann Allergy Asthma Immunol 2012; 109 (06) 365-374
    CrossrefPubMedGoogle Scholar
  • 153 Hall IP, Fowler AV, Gupta A. , et al. Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment. Pulm Pharmacol Ther 2015; 32: 37-44
    CrossrefPubMedGoogle Scholar
  • 154 Kuna P, Bjermer L, Tornling G. Two phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma. Drug Des Devel Ther 2016; 10: 2759-2770
    CrossrefPubMedGoogle Scholar
  • 155 Pettipher R, Hunter MG, Perkins CM. , et al. Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459. Allergy 2014; 69 (09) 1223-1232
    CrossrefPubMedGoogle Scholar
  • 156 Sly PD, Kusel M, Holt PG. Do early-life viral infections cause asthma?. J Allergy Clin Immunol 2010; 125 (06) 1202-1205
    CrossrefPubMedGoogle Scholar
  • 157 Holt PG, Sly PD. Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment. Nat Med 2012; 18 (05) 726-735
    CrossrefPubMedGoogle Scholar
  • 158 Gern JE. Virus/allergen interaction in asthma exacerbation. Ann Am Thorac Soc 2015; 12 (Suppl. 02) S137-S143
    PubMedGoogle Scholar
  • 159 Lan F, Zhang N, Gevaert E, Zhang L, Bachert C. Viruses and bacteria in Th2-biased allergic airway disease. Allergy 2016; 71 (10) 1381-1392
    CrossrefPubMedGoogle Scholar
  • 160 Singh M, Lee SH, Porter P. , et al. Human rhinovirus proteinase 2A induces TH1 and TH2 immunity in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 2010; 125 (06) 1369-1378.e2
    CrossrefPubMedGoogle Scholar
  • 161 Pulimood TB, Corden JM, Bryden C, Sharples L, Nasser SM. Epidemic asthma and the role of the fungal mold Alternaria alternata . J Allergy Clin Immunol 2007; 120 (03) 610-617
    CrossrefPubMedGoogle Scholar
  • 162 Dales RE, Cakmak S, Judek S. , et al. The role of fungal spores in thunderstorm asthma. Chest 2003; 123 (03) 745-750
    CrossrefPubMedGoogle Scholar
  • 163 Tham R, Vicendese D, Dharmage SC. , et al. Associations between outdoor fungal spores and childhood and adolescent asthma hospitalizations. J Allergy Clin Immunol 2017; 139 (04) 1140-1147.e4
    CrossrefPubMedGoogle Scholar
  • 164 Sheehan WJ, Phipatanakul W. Indoor allergen exposure and asthma outcomes. Curr Opin Pediatr 2016; 28 (06) 772-777
    CrossrefPubMedGoogle Scholar
  • 165 Porter P, Susarla SC, Polikepahad S. , et al. Link between allergic asthma and airway mucosal infection suggested by proteinase-secreting household fungi. Mucosal Immunol 2009; 2 (06) 504-517
    CrossrefPubMedGoogle Scholar
  • 166 Porter PC, Lim DJ, Maskatia ZK. , et al. Airway surface mycosis in chronic TH2-associated airway disease. J Allergy Clin Immunol 2014; 134 (02) 325-331
    CrossrefPubMedGoogle Scholar
  • 167 Porter P, Polikepahad S, Qian Y. , et al. Respiratory tract allergic disease and atopy: experimental evidence for a fungal infectious etiology. Med Mycol 2011; 49 (Suppl. 01) S158-S163
    CrossrefPubMedGoogle Scholar
  • 168 Porter PC, Roberts L, Fields A. , et al. Necessary and sufficient role for T helper cells to prevent fungal dissemination in allergic lung disease. Infect Immun 2011; 79 (11) 4459-4471
    CrossrefPubMedGoogle Scholar
  • 169 Chishimba L, Niven RM, Cooley J, Denning DW. Voriconazole and posaconazole improve asthma severity in allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization. J Asthma 2012; 49 (04) 423-433
    CrossrefPubMedGoogle Scholar
  • 170 Denning DW, O'Driscoll BR, Powell G. , et al. Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization: the Fungal Asthma Sensitization Trial (FAST) study. Am J Respir Crit Care Med 2009; 179 (01) 11-18
    CrossrefPubMedGoogle Scholar
  • 171 Agbetile J, Bourne M, Fairs A. , et al. Effectiveness of voriconazole in the treatment of Aspergillus fumigatus-associated asthma (EVITA3 study). J Allergy Clin Immunol 2014; 134 (01) 33-39
    CrossrefPubMedGoogle Scholar
  • 172 Kuna P, Kaczmarek J, Kupczyk M. Efficacy and safety of immunotherapy for allergies to Alternaria alternata in children. J Allergy Clin Immunol 2011; 127 (02) 502-508.e1 , 6
    CrossrefPubMedGoogle Scholar
  • 173 Esch RE. Manufacturing and standardizing fungal allergen products. J Allergy Clin Immunol 2004; 113 (02) 210-215
    CrossrefPubMedGoogle Scholar
  • 174 North ML, Takaro TK, Diamond ML, Ellis AK. Effects of phthalates on the development and expression of allergic disease and asthma. Ann Allergy Asthma Immunol 2014; 112 (06) 496-502
    CrossrefPubMedGoogle Scholar
  • 175 Bornehag CG, Sundell J, Weschler CJ. , et al. The association between asthma and allergic symptoms in children and phthalates in house dust: a nested case-control study. Environ Health Perspect 2004; 112 (14) 1393-1397
    CrossrefPubMedGoogle Scholar
  • 176 Jaakkola JJ, Ieromnimon A, Jaakkola MS. Interior surface materials and asthma in adults: a population-based incident case-control study. Am J Epidemiol 2006; 164 (08) 742-749
    CrossrefPubMedGoogle Scholar
  • 177 Bekö G, Callesen M, Weschler CJ. , et al. Phthalate exposure through different pathways and allergic sensitization in preschool children with asthma, allergic rhinoconjunctivitis and atopic dermatitis. Environ Res 2015; 137: 432-439
    CrossrefPubMedGoogle Scholar
  • 178 Butala JH, David RM, Gans G. , et al. Phthalate treatment does not influence levels of IgE or Th2 cytokines in B6C3F1 mice. Toxicology 2004; 201 (1-3): 77-85
    CrossrefPubMedGoogle Scholar
  • 179 Lee MH, Park J, Chung SW, Kang BY, Kim SH, Kim TS. Enhancement of interleukin-4 production in activated CD4+ T cells by diphthalate plasticizers via increased NF-AT binding activity. Int Arch Allergy Immunol 2004; 134 (03) 213-222
    CrossrefPubMedGoogle Scholar
  • 180 Larsen ST, Hansen JS, Hansen EW, Clausen PA, Nielsen GD. Airway inflammation and adjuvant effect after repeated airborne exposures to di-(2-ethylhexyl)phthalate and ovalbumin in BALB/c mice. Toxicology 2007; 235 (1-2): 119-129
    CrossrefPubMedGoogle Scholar
  • 181 Dearman RJ, Beresford L, Bailey L, Caddick HT, Betts CJ, Kimber I. Di-(2-ethylhexyl) phthalate is without adjuvant effect in mice on ovalbumin. Toxicology 2008; 244 (2-3): 231-241
    CrossrefPubMedGoogle Scholar
  • 182 Whyatt RM, Perzanowski MS, Just AC. , et al. Asthma in inner-city children at 5-11 years of age and prenatal exposure to phthalates: the Columbia Center for Children's Environmental Health Cohort. Environ Health Perspect 2014; 122 (10) 1141-1146
    CrossrefPubMedGoogle Scholar
  • 183 Gascon M, Casas M, Morales E. , et al. Prenatal exposure to bisphenol A and phthalates and childhood respiratory tract infections and allergy. J Allergy Clin Immunol 2015; 135 (02) 370-378
    CrossrefPubMedGoogle Scholar
  • 184 Ku HY, Su PH, Wen HJ. , et al; TMICS Group. Prenatal and postnatal exposure to phthalate esters and asthma: a 9-year follow-up study of a Taiwanese birth cohort. PLoS One 2015; 10 (04) e0123309
    CrossrefPubMedGoogle Scholar
  • 185 Shin IS, Lee MY, Cho ES, Choi EY, Son HY, Lee KY. Effects of maternal exposure to di(2-ethylhexyl)phthalate (DEHP) during pregnancy on susceptibility to neonatal asthma. Toxicol Appl Pharmacol 2014; 274 (03) 402-407
    CrossrefPubMedGoogle Scholar
  • 186 Chen L, Chen J, Xie CM, Zhao Y, Wang X, Zhang YH. Maternal disononyl phthalate exposure activates allergic airway inflammation via stimulating the phosphoinositide 3-kinase/Akt pathway in rat pups. Biomed Environ Sci 2015; 28 (03) 190-198
    PubMedGoogle Scholar
  • 187 Ober C, Yao TC. The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev 2011; 242 (01) 10-30
    CrossrefPubMedGoogle Scholar
  • 188 Singh S, Li SS. Epigenetic effects of environmental chemicals bisphenol A and phthalates. Int J Mol Sci 2012; 13 (08) 10143-10153
    CrossrefPubMedGoogle Scholar
  • 189 Soto-Ramírez N, Arshad SH, Holloway JW. , et al. The interaction of genetic variants and DNA methylation of the interleukin-4 receptor gene increase the risk of asthma at age 18 years. Clin Epigenetics 2013; 5 (01) 1
    CrossrefPubMedGoogle Scholar
  • 190 Huen K, Calafat AM, Bradman A, Yousefi P, Eskenazi B, Holland N. Maternal phthalate exposure during pregnancy is associated with DNA methylation of LINE-1 and Alu repetitive elements in Mexican-American children. Environ Res 2016; 148: 55-62
    CrossrefPubMedGoogle Scholar
  • 191 Ho SM. Environmental epigenetics of asthma: an update. J Allergy Clin Immunol 2010; 126 (03) 453-465
    CrossrefPubMedGoogle Scholar
  • 192 Wang IJ, Karmaus WJ, Chen SL, Holloway JW, Ewart S. Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation. Clin Epigenetics 2015; 7: 27
    CrossrefPubMedGoogle Scholar
  • 193 Campioli E, Martinez-Arguelles DB, Papadopoulos V. In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate promotes local adipose and systemic inflammation in adult male offspring. Nutr Diabetes 2014; 4: e115
    CrossrefPubMedGoogle Scholar
  • 194 Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK. Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS One 2013; 8 (01) e55387
    CrossrefPubMedGoogle Scholar