Advances and Evolving Concepts in Allergic Asthma

Hui-Ying Tung; Evan Li; Cameron Landers; An Nguyen; Farrah Kheradmand; J. Morgan Knight; David B. Corry

doi:10.1055/s-0037-1607981

Seminars in Respiratory and Critical Care Medicine, Table of Contents

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

Authors

Hui-Ying Tung

¹Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas
Evan Li

²Department of Medicine, Baylor College of Medicine, Houston, Texas
Cameron Landers

²Department of Medicine, Baylor College of Medicine, Houston, Texas

³Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, Texas
An Nguyen

²Department of Medicine, Baylor College of Medicine, Houston, Texas
Farrah Kheradmand

¹Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas

²Department of Medicine, Baylor College of Medicine, Houston, Texas

⁴Biology of Inflammation Center, Baylor College of Medicine, Houston, Texas

⁵Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston Texas
J. Morgan Knight

¹Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas
David B. Corry

¹Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas

²Department of Medicine, Baylor College of Medicine, Houston, Texas

⁴Biology of Inflammation Center, Baylor College of Medicine, Houston, Texas

⁵Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston Texas

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 - T_H2 cell - ILC2 - fibrinogen - CRTH2 - endotoxin - TLR4 - IL-4 - IL-5 - IL-13 - pattern recognition receptor

Full Text

References

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
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
3 Liu AH. Revisiting the hygiene hypothesis for allergy and asthma. J Allergy Clin Immunol 2015; 136 (04) 860-865
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
29 Gadermaier G, Hauser M, Ferreira F. Allergens of weed pollen: an overview on recombinant and natural molecules. Methods 2014; 66 (01) 55-66
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
31 Balenga NA, Klichinsky M, Xie Z. , et al. A fungal protease allergen provokes airway hyper-responsiveness in asthma. Nat Commun 2015; 6: 6763
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
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
34 Thomas WR, Hales BJ, Smith W-A. House dust mite allergens in asthma and allergy. Trends Mol Med 2010; 16 (07) 321-328
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
36 Huntington JA, Stein PE. Structure and properties of ovalbumin. J Chromatogr B Biomed Sci Appl 2001; 756 (1-2): 189-198
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
58 Lambrecht BN, Hammad H. The airway epithelium in asthma. Nat Med 2012; 18 (05) 684-692
59 Barrett NA, Austen KF. Innate cells and T helper 2 cell immunity in airway inflammation. Immunity 2009; 31 (03) 425-437
60 Weindl G, Wagener J, Schaller M. Epithelial cells and innate antifungal defense. J Dent Res 2010; 89 (07) 666-675
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
83 Lambrecht BN, Hammad H. Allergens and the airway epithelium response: gateway to allergic sensitization. J Allergy Clin Immunol 2014; 134 (03) 499-507
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
113 Wong SH, Walker JA, Jolin HE. , et al. Transcription factor RORα is critical for nuocyte development. Nat Immunol 2012; 13 (03) 229-236
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
156 Sly PD, Kusel M, Holt PG. Do early-life viral infections cause asthma?. J Allergy Clin Immunol 2010; 125 (06) 1202-1205
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
158 Gern JE. Virus/allergen interaction in asthma exacerbation. Ann Am Thorac Soc 2015; 12 (Suppl. 02) S137-S143
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
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
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
162 Dales RE, Cakmak S, Judek S. , et al. The role of fungal spores in thunderstorm asthma. Chest 2003; 123 (03) 745-750
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
164 Sheehan WJ, Phipatanakul W. Indoor allergen exposure and asthma outcomes. Curr Opin Pediatr 2016; 28 (06) 772-777
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
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
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
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
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
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
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
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
173 Esch RE. Manufacturing and standardizing fungal allergen products. J Allergy Clin Immunol 2004; 113 (02) 210-215
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
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
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
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
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
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
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
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
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
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
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
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
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
187 Ober C, Yao TC. The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev 2011; 242 (01) 10-30
188 Singh S, Li SS. Epigenetic effects of environmental chemicals bisphenol A and phthalates. Int J Mol Sci 2012; 13 (08) 10143-10153
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
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
191 Ho SM. Environmental epigenetics of asthma: an update. J Allergy Clin Immunol 2010; 126 (03) 453-465
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
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
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