Skip to main content
SpringerLink
Log in

Adaptive Immunity of Airway Inflammation in Asthma

  • Chapter
  • First Online:
Immunopharmacology and Inflammation

  • 1432 Accesses

Abstract

Respiratory immunity is responsible for pathogen elimination and prevention of chronic inflammation through both innate and adaptive mechanisms. Inappropriate activation of these immune systems in the respiratory mucosa results in chronic inflammatory airways disease such as asthma. Adaptive immunity is stimulated for example by allergen exposure that activates T and B lymphocytes leading to IgE production and influx of eosinophilic granulocytes into the airways. Presence of IgE and eosinophilia are diagnostic hallmarks as well as key pathogenic components that have been utilized in the search for improved therapies of allergic asthma for the past several decades. The recent breakthroughs in successful clinical application of biologicals in asthma were driven by improved genetic, biochemical, and immunological screening methods, novel imaging and bioinformatics technology, biomarker discovery and a better understanding of immune regulation of allergic airway inflammation. In this chapter we discuss our current understanding of immune regulation of airway inflammation in asthma, with a special focus on the interactions between the adaptive and innate immune systems and the epithelial mucosal tissue.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bostock J (1819) Case of a periodical affection of the eyes and chest. Med Chir Trans 10:161–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Shulman ST (2016) Clemens von Pirquet: a remarkable life and career. J Pediatric Infect Dis Soc. https://doi.org/10.1093/jpids/piw063

  3. Silverstein A, Clemens M (2000) Freiherr von Pirquet: explaining immune complex disease in 1906. Nat Immunol 1:453–455. https://doi.org/10.1038/82691

    Article  PubMed  CAS  Google Scholar 

  4. Ring J, Gutermuth J (2011) 100 years of hyposensitization: history of allergen-specific immunotherapy (ASIT). Allergy 66:713–724. https://doi.org/10.1111/j.1398-9995.2010.02541.x

    Article  PubMed  CAS  Google Scholar 

  5. Johansson SGO (2016) The discovery of IgE. J Allergy Clin Immunol 137:1671–1673. https://doi.org/10.1016/j.jaci.2016.04.004

    Article  PubMed  CAS  Google Scholar 

  6. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357

    PubMed  CAS  Google Scholar 

  7. Robinson DS et al (1992) Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 326:298–304. https://doi.org/10.1056/NEJM199201303260504

    Article  PubMed  CAS  Google Scholar 

  8. Cousins DJ, McDonald J, Lee TH (2008) Therapeutic approaches for control of transcription factors in allergic disease. J Allergy Clin Immunol 121:803–809; quiz 810–801. doi:https://doi.org/10.1016/j.jaci.2008.02.008

    Article  PubMed  CAS  Google Scholar 

  9. Corrigan CJ et al (1996) Glucocorticoid resistant asthma: T-lymphocyte steroid metabolism and sensitivity to glucocorticoids and immunosuppressive agents. Eur Respir J 9:2077–2086

    Article  CAS  PubMed  Google Scholar 

  10. Corrigan CJ (1996) Glucocorticoid-resistant asthma. T-lymphocyte defects. Am J Respir Crit Care Med 154:S53–S55; discussion S55–S57. doi:https://doi.org/10.1164/ajrccm/154.2_Pt_2.S53

    Article  PubMed  CAS  Google Scholar 

  11. Haczku A et al (1994) The effect of dexamethasone, cyclosporine, and rapamycin on T-lymphocyte proliferation in vitro: comparison of cells from patients with glucocorticoid-sensitive and glucocorticoid-resistant chronic asthma. J Allergy Clin Immunol 93:510–519

    Article  CAS  PubMed  Google Scholar 

  12. Corrigan CJ et al (1991) Glucocorticoid resistance in chronic asthma. Peripheral blood T lymphocyte activation and comparison of the T lymphocyte inhibitory effects of glucocorticoids and cyclosporin A. Am Rev Respir Dis 144:1026–1032. https://doi.org/10.1164/ajrccm/144.5.page

    Article  PubMed  CAS  Google Scholar 

  13. Corrigan CJ et al (1991) Glucocorticoid resistance in chronic asthma. Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro. Am Rev Respir Dis 144:1016–1025. https://doi.org/10.1164/ajrccm/144.5.1016

    Article  PubMed  CAS  Google Scholar 

  14. Radauer C et al (2014) Update of the WHO/IUIS Allergen Nomenclature Database based on analysis of allergen sequences. Allergy 69:413–419

    Article  CAS  PubMed  Google Scholar 

  15. Mueller GA (2017) Contributions and future directions for structural biology in the study of allergens. Int Arch Allergy Immunol 174:57–66. https://doi.org/10.1159/000481078

    Article  PubMed  CAS  Google Scholar 

  16. Breiteneder H, Radauer C (2004) A classification of plant food allergens. J Allergy Clin Immunol 113:821–830; quiz 831, doi:https://doi.org/10.1016/j.jaci.2004.01.779

    Article  PubMed  CAS  Google Scholar 

  17. Radauer C (2017) Navigating through the jungle of allergens: features and applications of allergen databases. Int Arch Allergy Immunol 173:1–11. https://doi.org/10.1159/000471806

    Article  PubMed  CAS  Google Scholar 

  18. Nadel JA (1988) Role of airway epithelial cells in the defense of airways. Prog Clin Biol Res 263:331–339

    PubMed  CAS  Google Scholar 

  19. Holgate ST (2007) Epithelium dysfunction in asthma. J Allergy Clin Immunol 120:1233–1244; quiz 1245–1236. doi:https://doi.org/10.1016/j.jaci.2007.10.025

    Article  PubMed  CAS  Google Scholar 

  20. Hammad H, Lambrecht BN (2015) Barrier epithelial cells and the control of type 2 immunity. Immunity 43:29–40. https://doi.org/10.1016/j.immuni.2015.07.007

    Article  PubMed  CAS  Google Scholar 

  21. Golebski K et al (2013) The multi-faceted role of allergen exposure to the local airway mucosa. Allergy 68:152–160. https://doi.org/10.1111/all.12080

    Article  PubMed  CAS  Google Scholar 

  22. Muller L, Jaspers I (2012) Epithelial cells, the “switchboard” of respiratory immune defense responses: effects of air pollutants. Swiss Med Wkly 142:w13653. https://doi.org/10.4414/smw.2012.13653

    Article  PubMed  PubMed Central  Google Scholar 

  23. Waters CM, Roan E, Navajas D (2012) Mechanobiology in lung epithelial cells: measurements, perturbations, and responses. Compr Physiol 2:1–20. https://doi.org/10.1002/cphy.c100090

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hammad H, Lambrecht BN (2011) Dendritic cells and airway epithelial cells at the interface between innate and adaptive immune responses. Allergy 66:579–587. https://doi.org/10.1111/j.1398-9995.2010.02528.x

    Article  PubMed  CAS  Google Scholar 

  25. Lambrecht BN, Hammad H (2010) The role of dendritic and epithelial cells as master regulators of allergic airway inflammation. Lancet 376:835–843. https://doi.org/10.1016/S0140-6736(10)61226-3

    Article  PubMed  CAS  Google Scholar 

  26. Rock JR, Randell SH, Hogan BL (2010) Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling. Dis Model Mech 3:545–556. https://doi.org/10.1242/dmm.006031

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Bourdin A, Gras D, Vachier I, Chanez P (2009) Upper airway x 1: allergic rhinitis and asthma: united disease through epithelial cells. Thorax 64:999–1004. https://doi.org/10.1136/thx.2008.112862

    Article  PubMed  CAS  Google Scholar 

  28. Crystal RG, Randell SH, Engelhardt JF, Voynow J, Sunday ME (2008) Airway epithelial cells: current concepts and challenges. Proc Am Thorac Soc 5:772–777. https://doi.org/10.1513/pats.200805-041HR

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wang Y, Bai C, Li K, Adler KB, Wang X (2008) Role of airway epithelial cells in development of asthma and allergic rhinitis. Respir Med 102:949–955. https://doi.org/10.1016/j.rmed.2008.01.017

    Article  PubMed  Google Scholar 

  30. Prefontaine D, Hamid Q (2007) Airway epithelial cells in asthma. J Allergy Clin Immunol 120:1475–1478. https://doi.org/10.1016/j.jaci.2007.09.041

    Article  PubMed  Google Scholar 

  31. Chiba T et al (2007) Possible novel receptor for PGD2 on human bronchial epithelial cells. Int Arch Allergy Immunol 143(Suppl 1):23–27. https://doi.org/10.1159/000101400

    Article  PubMed  CAS  Google Scholar 

  32. Upham JW, Stick SM (2006) Interactions between airway epithelial cells and dendritic cells: implications for the regulation of airway inflammation. Curr Drug Targets 7:541–545

    Article  CAS  PubMed  Google Scholar 

  33. Campbell AM (1997) Bronchial epithelial cells in asthma. Allergy 52:483–489

    Article  CAS  PubMed  Google Scholar 

  34. Maazi H, Akbari O (2017) Type two innate lymphoid cells: the Janus cells in health and disease. Immunol Rev 278:192–206. https://doi.org/10.1111/imr.12554

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Kubo M (2017) Innate and adaptive type 2 immunity in lung allergic inflammation. Immunol Rev 278:162–172. https://doi.org/10.1111/imr.12557

    Article  PubMed  CAS  Google Scholar 

  36. Hoffmann F et al (2016) Origin, localization, and immunoregulatory properties of pulmonary phagocytes in allergic asthma. Front Immunol 7:107. https://doi.org/10.3389/fimmu.2016.00107

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Cook PC, MacDonald AS (2016) Dendritic cells in lung immunopathology. Semin Immunopathol 38:449–460. https://doi.org/10.1007/s00281-016-0571-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Hirota JA, Knight DA (2012) Human airway epithelial cell innate immunity: relevance to asthma. Curr Opin Immunol 24:740–746

    Article  CAS  PubMed  Google Scholar 

  39. Deban L, Jaillon S, Garlanda C, Bottazzi B, Mantovani A (2011) Pentraxins in innate immunity: lessons from PTX3. Cell Tissue Res 343:237–249. https://doi.org/10.1007/s00441-010-1018-0

    Article  PubMed  CAS  Google Scholar 

  40. Garred P, Honore C, Ma YJ, Munthe-Fog L, Hummelshoj T (2009) MBL2, FCN1, FCN2 and FCN3-The genes behind the initiation of the lectin pathway of complement. Mol Immunol 46:2737–2744. https://doi.org/10.1016/j.molimm.2009.05.005

    Article  PubMed  CAS  Google Scholar 

  41. Iwasaki A, Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327:291–295. https://doi.org/10.1126/science.1183021

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Schleimer RP, Kato A, Kern R, Kuperman D, Avila PC (2007) Epithelium: at the interface of innate and adaptive immune responses. J Allergy Clin Immunol 120:1279–1284. https://doi.org/10.1016/j.jaci.2007.08.046

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Walport M, Complement J (2001) First of two parts. N Engl J Med 344:1058–1066. https://doi.org/10.1056/NEJM200104053441406

    Article  PubMed  CAS  Google Scholar 

  44. Manfredi AA, Rovere-Querini P, Bottazzi B, Garlanda C, Mantovani A (2008) Pentraxins, humoral innate immunity and tissue injury. Curr Opin Immunol 20:538–544. https://doi.org/10.1016/j.coi.2008.05.004

    Article  PubMed  CAS  Google Scholar 

  45. Gakhar L et al (2010) PLUNC is a novel airway surfactant protein with anti-biofilm activity. PLoS One 5:e9098. https://doi.org/10.1371/journal.pone.0009098

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Kool M et al (2011) An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma. Immunity 34:527–540. doi:S1074-7613(11)00122-1 [pii] https://doi.org/10.1016/j.immuni.2011.03.015

  47. Kouzaki H, Iijima K, Kobayashi T, O’Grady SM, Kita H (2011) The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate Th2-type responses. J Immunol 186:4375–4387. doi:jimmunol.1003020 [pii] https://doi.org/10.4049/jimmunol.1003020

  48. Shaw MH, Reimer T, Kim YG, Nunez G (2008) NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Curr Opin Immunol 20:377–382. https://doi.org/10.1016/j.coi.2008.06.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Modlin RL (2012) Innate immunity: ignored for decades, but not forgotten. J Invest Dermatol 132:882–886. https://doi.org/10.1038/jid.2011.373

    Article  PubMed  CAS  Google Scholar 

  50. Kawai T, Akira S (2007) TLR signaling. Semin Immunol 19:24–32. https://doi.org/10.1016/j.smim.2006.12.004

    Article  PubMed  CAS  Google Scholar 

  51. Lee MS, Kim YJ (2007) Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu Rev Biochem 76:447–480. https://doi.org/10.1146/annurev.biochem.76.060605.122847

    Article  PubMed  CAS  Google Scholar 

  52. Cambi A, Figdor CG (2005) Levels of complexity in pathogen recognition by C-type lectins. Curr Opin Immunol 17:345–351. https://doi.org/10.1016/j.coi.2005.05.011

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Lan RS, Stewart GA, Henry PJ (2002) Role of protease-activated receptors in airway function: a target for therapeutic intervention? Pharmacol Ther 95:239–257

    Article  CAS  PubMed  Google Scholar 

  54. Vinhas R et al (2011) Pollen proteases compromise the airway epithelial barrier through degradation of transmembrane adhesion proteins and lung bioactive peptides. Allergy 66:1088–1098. https://doi.org/10.1111/j.1398-9995.2011.02598.x

    Article  PubMed  CAS  Google Scholar 

  55. Page K, Hughes VS, Bennett GW, Wong HR (2006) German cockroach proteases regulate matrix metalloproteinase-9 in human bronchial epithelial cells. Allergy 61:988–995. https://doi.org/10.1111/j.1398-9995.2006.01103.x

    Article  PubMed  CAS  Google Scholar 

  56. Tai HY et al (2006) Pen ch 13 allergen induces secretion of mediators and degradation of occludin protein of human lung epithelial cells. Allergy 61:382–388. https://doi.org/10.1111/j.1398-9995.2005.00958.x

    Article  PubMed  CAS  Google Scholar 

  57. Yike I (2011) Fungal proteases and their pathophysiological effects. Mycopathologia 171:299–323. https://doi.org/10.1007/s11046-010-9386-2

    Article  PubMed  CAS  Google Scholar 

  58. Mathews JA et al (2011) A potential new target for asthma therapy: a disintegrin and metalloprotease 10 (ADAM10) involvement in murine experimental asthma. Allergy 66:1193–1200. https://doi.org/10.1111/j.1398-9995.2011.02614.x

    Article  PubMed  CAS  Google Scholar 

  59. Wan H et al (1999) Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest 104:123–133. https://doi.org/10.1172/JCI5844

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Carr MJ, Schechter NM, Undem BJ (2000) Trypsin-induced, neurokinin-mediated contraction of guinea pig bronchus. Am J Respir Crit Care Med 162:1662–1667. https://doi.org/10.1164/ajrccm.162.5.9912099

    Article  PubMed  CAS  Google Scholar 

  61. de Boer JD, Majoor CJ, van ‘t Veer C, Bel EH, van der Poll T (2012) Asthma and coagulation. Blood 119:3236–3244. https://doi.org/10.1182/blood-2011-11-391532

    Article  PubMed  CAS  Google Scholar 

  62. Endo, Y., Matsushita, M. & Fujita, T. Role of ficolin in innate immunity and its molecular basis. Immunobiology 212, 371-379, doi:https://doi.org/10.1016/j.imbio.2006.11.014 (2007)

  63. Holmskov U, Thiel S, Jensenius JC (2003) Collections and ficolins: humoral lectins of the innate immune defense. Annu Rev Immunol 21:547–578. https://doi.org/10.1146/annurev.immunol.21.120601.140954

    Article  PubMed  CAS  Google Scholar 

  64. Holmskov UL (2000) Collectins and collectin receptors in innate immunity. APMIS Suppl 100:1–59

    PubMed  CAS  Google Scholar 

  65. Shpacovitch V, Feld M, Hollenberg MD, Luger TA, Steinhoff M (2008) Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity. J Leukoc Biol 83:1309–1322. https://doi.org/10.1189/jlb.0108001

    Article  PubMed  CAS  Google Scholar 

  66. Sudha VT, Arora N, Gaur SN, Pasha S, Singh BP (2008) Identification of a serine protease as a major allergen (Per a 10) of Periplaneta americana. Allergy 63:768–776. https://doi.org/10.1111/j.1398-9995.2007.01602.x

    Article  PubMed  CAS  Google Scholar 

  67. Togbe D et al (2013) Thymic stromal lymphopoietin enhances Th2/Th22 and reduces IL-17A in protease-allergen-induced airways inflammation. ISRN Allergy 2013:971036. https://doi.org/10.1155/2013/971036

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Page K (2012) Role of cockroach proteases in allergic disease. Curr Allergy Asthma Rep 12:448–455. https://doi.org/10.1007/s11882-012-0276-1

    Article  PubMed  CAS  Google Scholar 

  69. Matsuwaki Y, Wada K, Moriyama H, Kita H (2011) Human eosinophil innate response to Alternaria fungus through protease-activated receptor-2. Int Arch Allergy Immunol 155(Suppl 1):123–128. https://doi.org/10.1159/000327498

    Article  PubMed  CAS  Google Scholar 

  70. Ebeling C et al (2005) Proteinase-activated receptor 2 activation in the airways enhances antigen-mediated airway inflammation and airway hyperresponsiveness through different pathways. J Allergy Clin Immunol 115:623–630. doi:S0091674904031203 [pii] https://doi.org/10.1016/j.jaci.2004.11.042

  71. Reed CE, Kita H (2004) The role of protease activation of inflammation in allergic respiratory diseases. J Allergy Clin Immunol 114:997–1008.; quiz 1009. https://doi.org/10.1016/j.jaci.2004.07.060

    Article  PubMed  CAS  Google Scholar 

  72. D’Agostino B et al (2007) Activation of protease-activated receptor-2 reduces airways inflammation in experimental allergic asthma. Clin Exp Allergy 37:1436–1443. https://doi.org/10.1111/j.1365-2222.2007.02793.x

    Article  PubMed  CAS  Google Scholar 

  73. Hammad H et al (2010) Inflammatory dendritic cells--not basophils--are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J Exp Med 207:2097–2111. doi:jem.20101563 [pii] https://doi.org/10.1084/jem.20101563

  74. Wang Q et al (2009) Role of double-stranded RNA pattern recognition receptors in rhinovirus-induced airway epithelial cell responses. J Immunol 183:6989–6997. doi:jimmunol.0901386 [pii] https://doi.org/10.4049/jimmunol.0901386

  75. Trompette A et al (2009) Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature 457:585–588. doi:nature07548 [pii] https://doi.org/10.1038/nature07548

  76. Rigaux P et al (2009) Immunomodulatory properties of Lactobacillus plantarum and its use as a recombinant vaccine against mite allergy. Allergy 64:406–414. https://doi.org/10.1111/j.1398-9995.2008.01825.x

    Article  PubMed  CAS  Google Scholar 

  77. Hammad H et al (2009) House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med 15:410–416, doi:nm.1946 [pii] https://doi.org/10.1038/nm.1946

  78. Lam D, Ng N, Lee S, Batzer G, Horner AA (2008) Airway house dust extract exposures modify allergen-induced airway hypersensitivity responses by TLR4-dependent and independent pathways. J Immunol 181:2925–2932. doi:181/4/2925 [pii]

    Google Scholar 

  79. Kato A, Favoreto S Jr, Avila PC, Schleimer RP (2007) TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells. J Immunol 179:1080–1087

    Article  CAS  PubMed  Google Scholar 

  80. Sha Q, Truong-Tran AQ, Plitt JR, Beck LA, Schleimer RP (2004) Activation of airway epithelial cells by toll-like receptor agonists. Am J Respir Cell Mol Biol 31:358–364. https://doi.org/10.1165/rcmb.2003-0388OC

    Article  PubMed  CAS  Google Scholar 

  81. Liu, AH (2002) Endotoxin exposure in allergy and asthma: reconciling a paradox. J Allergy Clin Immunol 109:379–392. doi:S0091674902085688 [pii]

    Google Scholar 

  82. Lambrecht BN, Hammad H (2012) The airway epithelium in asthma. Nat Med 18:684–692. doi:nm.2737 [pii] https://doi.org/10.1038/nm.2737

  83. Ryu JH et al (2013) Distinct TLR-mediated pathways regulate house dust mite-induced allergic disease in the upper and lower airways. J Allergy Clin Immunol 131:549–561. https://doi.org/10.1016/j.jaci.2012.07.050

    Article  PubMed  CAS  Google Scholar 

  84. Holtzman MJ et al (2009) Immune pathways for translating viral infection into chronic airway disease. Adv Immunol 102:245–276. doi:S0065-2776(09)01205-X [pii] https://doi.org/10.1016/S0065-2776(09)01205-X

  85. Gavala ML, Bertics PJ, Gern JE (2011) Rhinoviruses, allergic inflammation, and asthma. Immunol Rev 242:69–90. https://doi.org/10.1111/j.1600-065X.2011.01031.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. See H, Wark P (2008) Innate immune response to viral infection of the lungs. Paediatr Respir Rev 9:243–250

    Article  PubMed  PubMed Central  Google Scholar 

  87. Hsu AC, See HV, Hansbro PM, Wark PA (2012) Innate immunity to influenza in chronic airways diseases. Respirology 17:1166–1175. https://doi.org/10.1111/j.1440-1843.2012.02200.x

    Article  PubMed  Google Scholar 

  88. Chang YJ et al (2011) Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol 12:631–638, doi:ni.2045 [pii] https://doi.org/10.1038/ni.2045

  89. Mastrangelo P, Hegele RG (2013) RSV fusion: time for a new model. Virus 5:873–885. https://doi.org/10.3390/v5030873

    Article  CAS  Google Scholar 

  90. Terajima M et al (1997) Rhinovirus infection of primary cultures of human tracheal epithelium: role of ICAM-1 and IL-1beta. Am J Phys 273:L749–L759

    CAS  Google Scholar 

  91. Bianco A, Spiteri MA (1998) A biological model to explain the association between human rhinovirus respiratory infections and bronchial asthma. Monaldi Arch Chest Dis 53:83–87

    PubMed  CAS  Google Scholar 

  92. Papi A et al (2013) Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor kappaB and c-Jun N-terminal kinase activation. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2013.05.028

  93. Sykes A et al (2013) TLR3, TLR4 and TLRs7-9 induced interferons are not impaired in airway and blood cells in well controlled asthma. PLoS One 8:e65921. https://doi.org/10.1371/journal.pone.0065921

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Slater L et al (2010) Co-ordinated role of TLR3, RIG-I and MDA5 in the innate response to rhinovirus in bronchial epithelium. PLoS Pathog 6:e1001178. https://doi.org/10.1371/journal.ppat.1001178

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Contoli M et al (2006) Role of deficient type III interferon-lambda production in asthma exacerbations. Nat Med 12:1023–1026. https://doi.org/10.1038/nm1462

    Article  PubMed  CAS  Google Scholar 

  96. Monticelli LA et al (2011) Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol 12:1045–1054. https://doi.org/10.1031/ni.2131

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Bartemes KR, Kita H (2012) Dynamic role of epithelium-derived cytokines in asthma. Clin Immunol 143:222–235. doi:S1521-6616(12)00085-X [pii] https://doi.org/10.1016/j.clim.2012.03.001

  98. Fort MM et al (2001) IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15:985–995. doi:S1074–7613(01)00243–6 [pii]

    Google Scholar 

  99. Schmitz J et al (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23:479–490. doi:S1074-7613(05)00311-0 [pii] https://doi.org/10.1016/j.immuni.2005.09.015

  100. Zhou B et al (2005) Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol 6:1047–1053. doi:ni1247 [pii] https://doi.org/10.1038/ni1247

  101. Oboki K et al (2010) IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc Natl Acad Sci U S A 107:18581–18586. https://doi.org/10.1073/pnas.1003059107

    Article  PubMed  PubMed Central  Google Scholar 

  102. Perros F, Hoogsteden HC, Coyle AJ, Lambrecht BN, Hammad H (2009) Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation. Allergy 64:995–1002. doi:ALL2095 [pii] https://doi.org/10.1111/j.1398-9995.2009.02095.x

  103. Schutyser E, Struyf S, Van Damme J (2003) The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev 14:409–426

    Article  CAS  PubMed  Google Scholar 

  104. Onishi RM, Gaffen SL (2010) Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease. Immunology 129:311–321. https://doi.org/10.1111/j.1365-2567.2009.03240.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Park H et al (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141. doi:ni1261 [pii] https://doi.org/10.1038/ni1261

  106. Alcorn JF, Crowe CR, Kolls JK (2010) TH17 cells in asthma and COPD. Annu Rev Physiol 72:495–516. https://doi.org/10.1146/annurev-physiol-021909-135926

    Article  PubMed  CAS  Google Scholar 

  107. Lajoie S et al (2010) Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol 11:928–935. doi:ni.1926 [pii] https://doi.org/10.1038/ni.1926

  108. Schnyder-Candrian S et al (2006) Interleukin-17 is a negative regulator of established allergic asthma. J Exp Med 203:2715–2725. doi:jem.20061401 [pii] https://doi.org/10.1084/jem.20061401

  109. Gudbjartsson DF et al (2009) Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 41:342–347. https://doi.org/10.1038/ng.323

    Article  PubMed  CAS  Google Scholar 

  110. Moffatt MF et al (2010) A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 363:1211–1221. https://doi.org/10.1056/NEJMoa0906312

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Hunninghake GM et al (2010) TSLP polymorphisms are associated with asthma in a sex-specific fashion. Allergy 65:1566–1575. https://doi.org/10.1111/j.1398-9995.2010.02415.x

    Article  PubMed  Google Scholar 

  112. Ober C, Yao TC (2011) The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev 242:10–30. https://doi.org/10.1111/j.1600-065X.2011.01029.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Karmaus W, Ziyab AH, Everson T, Holloway JW (2013) Epigenetic mechanisms and models in the origins of asthma. Curr Opin Allergy Clin Immunol 13:63–69. https://doi.org/10.1097/ACI.0b013e32835ad0e7

    Article  PubMed  PubMed Central  Google Scholar 

  114. Sofer T et al (2013) Exposure to airborne particulate matter is associated with methylation pattern in the asthma pathway. Epigenomics 5:147–154. https://doi.org/10.2217/epi.13.16

    Article  PubMed  CAS  Google Scholar 

  115. Chen W et al (2013) ADCYAP1R1 and asthma in Puerto Rican children. Am J Respir Crit Care Med 187:584–588. https://doi.org/10.1164/rccm.201210-1789OC

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Reinius LE et al (2013) DNA methylation in the Neuropeptide S Receptor 1 (NPSR1) promoter in relation to asthma and environmental factors. PLoS One 8:e53877. https://doi.org/10.1371/journal.pone.0053877

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Hammad H, Lambrecht BN (2008) Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat Rev Immunol 8:193–204. https://doi.org/10.1038/nri2275

    Article  PubMed  CAS  Google Scholar 

  118. Reibman J, Hsu Y, Chen LC, Bleck B, Gordon T (2003) Airway epithelial cells release MIP-3alpha/CCL20 in response to cytokines and ambient particulate matter. Am J Respir Cell Mol Biol 28:648–654. https://doi.org/10.1165/rcmb.2002-0095OC

    Article  PubMed  CAS  Google Scholar 

  119. Haczku A (2012) The dendritic cell niche in chronic obstructive pulmonary disease. Respir Res 13:80. https://doi.org/10.1186/1465-9921-13-80

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Lukacs NW, Prosser DM, Wiekowski M, Lira SA, Cook DN (2001) Requirement for the chemokine receptor CCR6 in allergic pulmonary inflammation. J Exp Med 194:551–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Phadke AP, Akangire G, Park SJ, Lira SA, Mehrad B (2007) The role of CC chemokine receptor 6 in host defense in a model of invasive pulmonary aspergillosis. Am J Respir Crit Care Med 175:1165–1172. https://doi.org/10.1164/rccm.200602-256OC

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Soumelis V et al (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3:673–680. https://doi.org/10.1038/ni805

    Article  PubMed  CAS  Google Scholar 

  123. Ito T et al (2005) TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med 202:1213–1223. https://doi.org/10.1084/jem.20051135

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Wang YH et al (2006) Maintenance and polarization of human TH2 central memory T cells by thymic stromal lymphopoietin-activated dendritic cells. Immunity 24:827–838. https://doi.org/10.1016/j.immuni.2006.03.019

    Article  PubMed  CAS  Google Scholar 

  125. Omori M, Ziegler S (2007) Induction of IL-4 expression in CD4(+) T cells by thymic stromal lymphopoietin. J Immunol 178:1396–1404

    Article  CAS  PubMed  Google Scholar 

  126. Wang YH et al (2007) IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J Exp Med 204:1837–1847. https://doi.org/10.1084/jem.20070406

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Moreira AP, Hogaboam CM (2011) Macrophages in allergic asthma: fine-tuning their pro- and anti-inflammatory actions for disease resolution. J Interf Cytokine Res 31:485–491. https://doi.org/10.1089/jir.2011.0027

    Article  CAS  Google Scholar 

  128. Boorsma CE, Draijer C, Melgert BN (2013) Macrophage heterogeneity in respiratory diseases. Mediat Inflamm 2013:769214. https://doi.org/10.1155/2013/769214

    Article  Google Scholar 

  129. Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461

    Article  CAS  PubMed  Google Scholar 

  130. Chistiakov DA et al (2015) Macrophage phenotypic plasticity in atherosclerosis: the associated features and the peculiarities of the expression of inflammatory genes. Int J Cardiol 184:436–445. https://doi.org/10.1016/j.ijcard.2015.03.055

    Article  PubMed  Google Scholar 

  131. Jiang Z, Zhu L (2016) Update on the role of alternatively activated macrophages in asthma. J Asthma Allergy 9:101–107. https://doi.org/10.2147/JAA.S104508

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Muraille E, Leo O, Moser M (2014) Th1/Th2 paradigm extended: macrophage polarization as an unappreciated pathogen-driven escape mechanism? Front Immunol 5:603. https://doi.org/10.3389/fimmu.2014.00603

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Draijer C, Robbe P, Boorsma CE, Hylkema MN, Melgert BN (2013) Characterization of macrophage phenotypes in three murine models of house-dust-mite-induced asthma. Mediat Inflamm 2013:10. https://doi.org/10.1155/2013/632049

    Article  CAS  Google Scholar 

  134. Joshi AD et al (2010) Interleukin-33 contributes to both M1 and M2 chemokine marker expression in human macrophages. BMC Immunol 11:52. https://doi.org/10.1186/1471-2172-11-52

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Kurowska-Stolarska M et al (2009) IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J Immunol 183:6469–6477. https://doi.org/10.4049/jimmunol.0901575

    Article  PubMed  CAS  Google Scholar 

  136. Martinez FO et al (2013) Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences. Blood 121:e57–e69. https://doi.org/10.1182/blood-2012-06-436212

    Article  PubMed  CAS  Google Scholar 

  137. Kim EY et al (2008) Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med 14:633–640. https://doi.org/10.1038/nm1770

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Girodet PO et al (2016) Alternative macrophage activation is increased in asthma. Am J Respir Cell Mol Biol 55:467–475. https://doi.org/10.1165/rcmb.2015-0295OC

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Artis D, Spits H (2015) The biology of innate lymphoid cells. Nature 517:293–301. https://doi.org/10.1038/nature14189

    Article  PubMed  CAS  Google Scholar 

  140. Saenz SA, Noti M, Artis D (2010) Innate immune cell populations function as initiators and effectors in Th2 cytokine responses. Trends Immunol 31:407–413. doi:S1471-4906(10)00125-0 [pii] https://doi.org/10.1016/j.it.2010.09.001

  141. Neill DR et al (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464:1367–1370. doi:nature08900 [pii] https://doi.org/10.1038/nature08900

  142. Moro K et al (2010) Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature 463:540–544. doi:nature08636 [pii] https://doi.org/10.1038/nature08636

  143. Barlow JL et al (2012) Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J Allergy Clin Immunol 129:191–198 e191–e194. doi:S0091-6749(11)01565-X [pii] https://doi.org/10.1016/j.jaci.2011.09.041

  144. Yasuda K et al (2012) Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc Natl Acad Sci U S A 109:3451–3456. doi:1201042109 [pii] https://doi.org/10.1073/pnas.1201042109

  145. Klein Wolterink RG et al (2012) Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur J Immunol 42:1106–1116. https://doi.org/10.1002/eji.201142018

    Article  PubMed  CAS  Google Scholar 

  146. Yang Q et al (2013) T cell factor 1 is required for group 2 innate lymphoid cell generation. Immunity 38:694–704. https://doi.org/10.1016/j.immuni.2012.12.003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Mjosberg JM et al (2011) Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol 12:1055–1062. https://doi.org/10.1038/ni.2104

    Article  PubMed  CAS  Google Scholar 

  148. Smith SG et al (2016) Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol 137:75–86.e78. https://doi.org/10.1016/j.jaci.2015.05.037

    Article  PubMed  CAS  Google Scholar 

  149. Yang Q et al (2016) Group 2 innate lymphoid cells mediate ozone-induced airway inflammation and hyperresponsiveness in mice. J Allergy Clin Immunol 137:571–578. https://doi.org/10.1016/j.jaci.2015.06.037

    Article  PubMed  CAS  Google Scholar 

  150. Monticelli LA et al (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17:656. https://doi.org/10.1038/ni.3421. https://www.nature.com/articles/ni.3421 – supplementary-information

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Halim TY, Krauss RH, Sun AC, Takei F (2012) Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36:451–463. https://doi.org/10.1016/j.immuni.2011.12.020

    Article  PubMed  CAS  Google Scholar 

  152. Shen X et al (2018) Group-2 innate lymphoid cells promote airway hyperresponsiveness through production of VEGFA. J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2018.01.005

  153. Possa SS, Leick EA, Prado CM, Martins MA, Tibério IFLC (2013) Eosinophilic inflammation in allergic asthma. Front Pharmacol 4:46. https://doi.org/10.3389/fphar.2013.00046

    Article  PubMed  PubMed Central  Google Scholar 

  154. Saito T et al (1997) Respiratory syncytial virus induces selective production of the chemokine RANTES by upper airway epithelial cells. J Infect Dis 175:497–504

    Article  CAS  PubMed  Google Scholar 

  155. Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H (2008) A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol 121:1484–1490. doi:S0091-6749(08)00719-7 [pii] https://doi.org/10.1016/j.jaci.2008.04.005

  156. Wong CK, Cheung PF, Ip WK, Lam CW (2005) Interleukin-25-induced chemokines and interleukin-6 release from eosinophils is mediated by p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and nuclear factor-kappaB. Am J Respir Cell Mol Biol 33:186–194. doi:2005-0034OC [pii] https://doi.org/10.1165/rcmb.2005-0034OC

  157. Pegorier S, Wagner LA, Gleich GJ, Pretolani M (2006) Eosinophil-derived cationic proteins activate the synthesis of remodeling factors by airway epithelial cells. J Immunol 177:4861–4869. doi:177/7/4861 [pii]

    Google Scholar 

  158. Laan M et al (1999) Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J Immunol 162:2347–2352

    PubMed  CAS  Google Scholar 

  159. Cromwell O et al (1992) Expression and generation of interleukin-8, IL-6 and granulocyte-macrophage colony-stimulating factor by bronchial epithelial cells and enhancement by IL-1 beta and tumour necrosis factor-alpha. Immunology 77:330–337

    PubMed  PubMed Central  CAS  Google Scholar 

  160. Osterlund C, Gronlund H, Gafvelin G, Bucht A (2010) Non-proteolytic aeroallergens from mites, cat and dog exert adjuvant-like activation of bronchial epithelial cells. Int Arch Allergy Immunol 155:111–118. doi:000318743 [pii] https://doi.org/10.1159/000318743

  161. McAllister F et al (2005) Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis. J Immunol 175:404–412

    Article  CAS  PubMed  Google Scholar 

  162. Churchill L, Friedman B, Schleimer RP, Proud D (1992) Production of granulocyte-macrophage colony-stimulating factor by cultured human tracheal epithelial cells. Immunology 75:189–195

    PubMed  PubMed Central  CAS  Google Scholar 

  163. Kim KC et al (1987) Human neutrophil elastase releases cell surface mucins from primary cultures of hamster tracheal epithelial cells. Proc Natl Acad Sci U S A 84:9304–9308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. van Wetering S et al (2000) Regulation of secretory leukocyte proteinase inhibitor (SLPI) production by human bronchial epithelial cells: increase of cell-associated SLPI by neutrophil elastase. J Investig Med 48:359–366

    PubMed  Google Scholar 

  165. Lefrancais E et al (2012) IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc Natl Acad Sci U S A 109:1673–1678. https://doi.org/10.1073/pnas.1115884109

    Article  PubMed  PubMed Central  Google Scholar 

  166. Alves-Filho JC et al (2010) Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat Med 16:708–712. https://doi.org/10.1038/nm.2156

    Article  PubMed  CAS  Google Scholar 

  167. Hueber AJ et al (2011) IL-33 induces skin inflammation with mast cell and neutrophil activation. Eur J Immunol 41:2229–2237. https://doi.org/10.1002/eji.201041360

    Article  PubMed  CAS  Google Scholar 

  168. Wenzel SE et al (1997) Bronchoscopic evaluation of severe asthma. Am J Respir Crit Care Med 156:737–743. https://doi.org/10.1164/ajrccm.156.3.9610046

    Article  PubMed  CAS  Google Scholar 

  169. Fahy JV, Kim KW, Liu J, Boushey HA (1995) Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol 95:843–852

    Article  CAS  PubMed  Google Scholar 

  170. Holgate ST (2011) The sentinel role of the airway epithelium in asthma pathogenesis. Immunol Rev 242:205–219. https://doi.org/10.1111/j.1600-065X.2011.01030.x

    Article  PubMed  CAS  Google Scholar 

  171. Allakhverdi Z et al (2007) Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med 204:253–258. https://doi.org/10.1084/jem.20062211

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Allakhverdi, Z., Smith, D. E., Comeau, M. R. & Delespesse, G. (2007) Cutting edge: The ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J Immunol 179, 2051–2054, doi:179/4/2051 [pii]

    Google Scholar 

  173. Iikura M et al (2007) IL-33 can promote survival, adhesion and cytokine production in human mast cells. Lab Investig 87:971–978. doi:3700663 [pii] https://doi.org/10.1038/labinvest.3700663

  174. Kohda F, Koga T, Uchi H, Urabe K, Furue M (2002) Histamine-induced IL-6 and IL-8 production are differentially modulated by IFN-gamma and IL-4 in human keratinocytes. J Dermatol Sci 28:34–41

    Article  CAS  PubMed  Google Scholar 

  175. Siracusa MC, Kim BS, Spergel JM, Artis D (2013) Basophils and allergic inflammation. J Allergy Clin Immunol 132:789–788. https://doi.org/10.1016/j.jaci.2013.07.046

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Pecaric-Petkovic T, Didichenko SA, Kaempfer S, Spiegl N, Dahinden CA (2009) Human basophils and eosinophils are the direct target leukocytes of the novel IL-1 family member IL-33. Blood 113:1526–1534. doi:blood-2008-05-157818 [pii] https://doi.org/10.1182/blood-2008-05-157818

  177. Schneider E et al (2009) IL-33 activates unprimed murine basophils directly in vitro and induces their in vivo expansion indirectly by promoting hematopoietic growth factor production. J Immunol 183:3591–3597. doi:jimmunol.0900328 [pii] https://doi.org/10.4049/jimmunol.0900328

  178. Siracusa MC et al (2011) TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477:229–233. doi:nature10329 [pii] https://doi.org/10.1038/nature10329

  179. Noti M et al (2013) Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis. Nat Med 19:1005–1013. https://doi.org/10.1038/nm.3281

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Kepley CL, McFeeley PJ, Oliver JM, Lipscomb MF (2001) Immunohistochemical detection of human basophils in postmortem cases of fatal asthma. Am J Respir Crit Care Med 164:1053–1058. https://doi.org/10.1164/ajrccm.164.6.2102025

    Article  PubMed  CAS  Google Scholar 

  181. Terashima A et al (2008) A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity. J Exp Med 205:2727–2733. doi:jem.20080698 [pii] https://doi.org/10.1084/jem.20080698

  182. Tupin E, Kinjo Y, Kronenberg M (2007) The unique role of natural killer T cells in the response to microorganisms. Nat Rev Microbiol 5:405–417. doi:nrmicro1657 [pii] https://doi.org/10.1038/nrmicro1657

  183. Wingender G et al (2011) Invariant NKT cells are required for airway inflammation induced by environmental antigens. J Exp Med 208:1151–1162. https://doi.org/10.1084/jem.20102229

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Nie H et al (2015) Invariant NKT cells act as an adjuvant to enhance Th2 inflammatory response in an OVA-induced mouse model of asthma. PLoS One 10:e0119901. https://doi.org/10.1371/journal.pone.0119901

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Matangkasombut P et al (2008) Direct activation of natural killer T cells induces airway hyperreactivity in nonhuman primates. J Allergy Clin Immunol 121:1287–1289. https://doi.org/10.1016/j.jaci.2008.02.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Akbari O et al (2006) CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N Engl J Med 354:1117–1129. https://doi.org/10.1056/NEJMoa053614

    Article  PubMed  CAS  Google Scholar 

  187. Vijayanand P et al (2007) Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N Engl J Med 356:1410–1422. https://doi.org/10.1056/NEJMoa064691

    Article  PubMed  CAS  Google Scholar 

  188. Recaldin T, Fear DJ (2016) Transcription factors regulating B cell fate in the germinal centre. Clin Exp Immunol 183:65–75. https://doi.org/10.1111/cei.12702

    Article  PubMed  CAS  Google Scholar 

  189. Peled JU et al (2008) The biochemistry of somatic hypermutation. Annu Rev Immunol 26:481–511. https://doi.org/10.1146/annurev.immunol.26.021607.090236

    Article  PubMed  CAS  Google Scholar 

  190. van de Veen W et al (2016) Role of regulatory B cells in immune tolerance to allergens and beyond. J Allergy Clin Immunol 138:654–665. https://doi.org/10.1016/j.jaci.2016.07.006

    Article  PubMed  CAS  Google Scholar 

  191. Allakhverdi Z et al (2009) CD34+ hemopoietic progenitor cells are potent effectors of allergic inflammation. J Allergy Clin Immunol 123:472–478. doi:S0091-6749(08)01875-7 [pii] https://doi.org/10.1016/j.jaci.2008.10.022

  192. Adcock IM, Caramori G, Chung KF (2008) New targets for drug development in asthma. Lancet 372:1073–1087. https://doi.org/10.1016/S0140-6736(08)61449-X

    Article  PubMed  CAS  Google Scholar 

  193. Chung KF (2011) p38 mitogen-activated protein kinase pathways in asthma and COPD. Chest 139:1470–1479. https://doi.org/10.1378/chest.10-1914

    Article  PubMed  CAS  Google Scholar 

  194. Van Raemdonck K, Van den Steen PE, Liekens S, Van Damme J, Struyf S (2015) CXCR3 ligands in disease and therapy. Cytokine Growth Factor Rev 26:311–327. https://doi.org/10.1016/j.cytogfr.2014.11.009

    Article  PubMed  CAS  Google Scholar 

  195. Proud D, Leigh R (2011) Epithelial cells and airway diseases. Immunol Rev 242:186–204. https://doi.org/10.1111/j.1600-065X.2011.01033.x

    Article  PubMed  CAS  Google Scholar 

  196. Spurrell JC, Wiehler S, Zaheer RS, Sanders SP, Proud D (2005) Human airway epithelial cells produce IP-10 (CXCL10) in vitro and in vivo upon rhinovirus infection. Am J Physiol Lung Cell Mol Physiol 289:L85–L95. https://doi.org/10.1152/ajplung.00397.2004

    Article  PubMed  CAS  Google Scholar 

  197. Terada N et al (2001) Expression of C-C chemokine TARC in human nasal mucosa and its regulation by cytokines. Clin Exp Allergy 31:1923–1931

    Article  CAS  PubMed  Google Scholar 

  198. Heijink IH et al (2007) Der p, IL-4, and TGF-beta cooperatively induce EGFR-dependent TARC expression in airway epithelium. Am J Respir Cell Mol Biol 36:351–359. https://doi.org/10.1165/rcmb.2006-0160OC

    Article  PubMed  CAS  Google Scholar 

  199. Panina-Bordignon P et al (2001) The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics. J Clin Invest 107:1357–1364. https://doi.org/10.1172/JCI12655

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Montes-Vizuet R et al (2006) CC chemokine ligand 1 is released into the airways of atopic asthmatics. Eur Respir J 28:59–67. https://doi.org/10.1183/09031936.06.00134304

    Article  PubMed  CAS  Google Scholar 

  201. O'Shea JJ, Paul WE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327:1098–1102. https://doi.org/10.1126/science.1178334

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Taha R, Hamid Q, Cameron L, Olivenstein R (2003) T helper type 2 cytokine receptors and associated transcription factors GATA-3, c-MAF, and signal transducer and activator of transcription factor-6 in induced sputum of atopic asthmatic patients. Chest 123:2074–2082

    Article  CAS  PubMed  Google Scholar 

  203. Malik S et al (2017) Transcription factor Foxo1 is essential for IL-9 induction in T helper cells. Nat Commun 8:815. https://doi.org/10.1038/s41467-017-00674-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Chang HS et al (2017) Neutrophilic inflammation in asthma: mechanisms and therapeutic considerations. Expert Rev Respir Med 11:29–40. https://doi.org/10.1080/17476348.2017.1268919

    Article  PubMed  CAS  Google Scholar 

  205. Valeri M, Raffatellu M (2016) Cytokines IL-17 and IL-22 in the host response to infection. Pathog Dis 74. https://doi.org/10.1093/femspd/ftw111

  206. Boyman O et al (2015) EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders. Allergy 70:727–754. https://doi.org/10.1111/all.12616

    Article  CAS  PubMed  Google Scholar 

  207. Chung KF (2016) Asthma phenotyping: a necessity for improved therapeutic precision and new targeted therapies. J Intern Med 279:192–204. https://doi.org/10.1111/joim.12382

    Article  PubMed  CAS  Google Scholar 

  208. Flayer CH, Haczku A (2017) The Th2 gene cluster unraveled: role of RHS6. Allergy 72:679–681. https://doi.org/10.1111/all.13130

    Article  PubMed  CAS  Google Scholar 

  209. Ansel KM, Djuretic I, Tanasa B, Rao A (2006) Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol 24:607–656. https://doi.org/10.1146/annurev.immunol.23.021704.115821

    Article  PubMed  CAS  Google Scholar 

  210. Dekker J, Marti-Renom MA, Mirny LA (2013) Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat Rev Genet 14:390–403. https://doi.org/10.1038/nrg3454

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  211. Chatila TA, Li N, Garcia-Lloret M, Kim HJ, Nel AE (2008) T-cell effector pathways in allergic diseases: transcriptional mechanisms and therapeutic targets. J Allergy Clin Immunol 121:812–823.; quiz 824-815. https://doi.org/10.1016/j.jaci.2008.02.025

    Article  PubMed  CAS  Google Scholar 

  212. Wang C, Collins M, Kuchroo VK (2015) Effector T cell differentiation: are master regulators of effector T cells still the masters? Curr Opin Immunol 37:6–10. https://doi.org/10.1016/j.coi.2015.08.001

    Article  PubMed  CAS  Google Scholar 

  213. Lee GR, Kim ST, Spilianakis CG, Fields PE, Flavell RA (2006) T helper cell differentiation: regulation by cis elements and epigenetics. Immunity 24:369–379. https://doi.org/10.1016/j.immuni.2006.03.007

    Article  PubMed  CAS  Google Scholar 

  214. Mercer TR, Mattick JS (2013) Understanding the regulatory and transcriptional complexity of the genome through structure. Genome Res 23:1081–1088. https://doi.org/10.1101/gr.156612.113

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Hwang SS, Jang SW, Lee KO, Kim HS, Lee GR (2016) RHS6 coordinately regulates the Th2 cytokine genes by recruiting GATA3, SATB1, and IRF4. Allergy. https://doi.org/10.1111/all.13078

  216. Mohrs M et al (2001) Deletion of a coordinate regulator of type 2 cytokine expression in mice. Nat Immunol 2:842–847. https://doi.org/10.1038/ni0901-842

    Article  PubMed  CAS  Google Scholar 

  217. Lee GR, Fields PE, Griffin TJ, Flavell RA (2003) Regulation of the Th2 cytokine locus by a locus control region. Immunity 19:145–153

    Article  CAS  PubMed  Google Scholar 

  218. Lee GR, Fields PE, Flavell RA (2001) Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level. Immunity 14:447–459

    Article  CAS  PubMed  Google Scholar 

  219. Fields PE, Lee GR, Kim ST, Bartsevich VV, Flavell RA (2004) Th2-specific chromatin remodeling and enhancer activity in the Th2 cytokine locus control region. Immunity 21:865–876. https://doi.org/10.1016/j.immuni.2004.10.015

    Article  PubMed  CAS  Google Scholar 

  220. Koh BH et al (2010) Th2 LCR is essential for regulation of Th2 cytokine genes and for pathogenesis of allergic asthma. Proc Natl Acad Sci U S A 107:10614–10619. https://doi.org/10.1073/pnas.1005383107

    Article  PubMed  PubMed Central  Google Scholar 

  221. Williams A et al (2013) Hypersensitive site 6 of the Th2 locus control region is essential for Th2 cytokine expression. Proc Natl Acad Sci U S A 110:6955–6960. https://doi.org/10.1073/pnas.1304720110

    Article  PubMed  PubMed Central  Google Scholar 

  222. Zeng WP (2013) ‘All things considered’: transcriptional regulation of T helper type 2 cell differentiation from precursor to effector activation. Immunology 140:31–38. https://doi.org/10.1111/imm.12121

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  223. Kim K, Kim N, Lee GR (2016) Transcription factors Oct-1 and GATA-3 cooperatively regulate Th2 cytokine gene expression via the RHS5 within the Th2 locus control region. PLoS One 11:e0148576. https://doi.org/10.1371/journal.pone.0148576

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Hwang SS, Jang SW, Lee GR (2017) RHS6-mediated chromosomal looping and nuclear substructure binding is required for Th2 cytokine gene expression. Biochim Biophys Acta 1860:383–391. https://doi.org/10.1016/j.bbagrm.2017.01.008

    Article  CAS  Google Scholar 

  225. Hwang SS, Jang SW, Lee KO, Kim HS, Lee GR (2017) RHS6 coordinately regulates the Th2 cytokine genes by recruiting GATA3, SATB1, and IRF4. Allergy 72:772–782. https://doi.org/10.1111/all.13078

    Article  PubMed  CAS  Google Scholar 

  226. Zhu J (2010) Transcriptional regulation of Th2 cell differentiation. Immunol Cell Biol 88:244–249. https://doi.org/10.1038/icb.2009.114

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  227. Burute M, Gottimukkala K, Galande S (2012) Chromatin organizer SATB1 is an important determinant of T-cell differentiation. Immunol Cell Biol 90:852–859

    Article  CAS  PubMed  Google Scholar 

  228. Accordini S et al (2016) An interleukin 13 polymorphism is associated with symptom severity in adult subjects with ever asthma. PLoS One 11:e0151292. https://doi.org/10.1371/journal.pone.0151292

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  229. Schieck M et al (2014) A polymorphism in the TH 2 locus control region is associated with changes in DNA methylation and gene expression. Allergy 69:1171–1180. https://doi.org/10.1111/all.12450

    Article  PubMed  CAS  Google Scholar 

  230. Sharma V et al (2014) Fine-mapping of IgE-associated loci 1q23, 5q31, and 12q13 using 1000 Genomes Project data. Allergy 69:1077–1084. https://doi.org/10.1111/all.12431

    Article  PubMed  CAS  Google Scholar 

  231. Slifka MK, Amanna I (2014) How advances in immunology provide insight into improving vaccine efficacy. Vaccine 32:2948–2957. https://doi.org/10.1016/j.vaccine.2014.03.078

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  232. Killingbeck SS, Ge MQ, Haczku A (2017) Patching it together: epicutaneous vaccination with heat-labile Escherichia coli toxin against birch pollen allergy. Allergy 72:5–8. https://doi.org/10.1111/all.13064

    Article  PubMed  CAS  Google Scholar 

  233. Levitz SM (2016) Aspergillus vaccines: Hardly worth studying or worthy of hard study? Med Mycol. https://doi.org/10.1093/mmy/myw081

  234. Calderon MA et al (2013) Allergen immunotherapy: a new semantic framework from the European Academy of Allergy and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL consensus report. Allergy 68:825–828

    Article  CAS  PubMed  Google Scholar 

  235. Akdis M, Akdis CA (2014) Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens. J Allergy Clin Immunol 133:621–631. https://doi.org/10.1016/j.jaci.2013.12.1088

    Article  PubMed  CAS  Google Scholar 

  236. Larche M, Akdis CA, Valenta R (2006) Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol 6:761–771. https://doi.org/10.1038/nri1934

    Article  PubMed  CAS  Google Scholar 

  237. Curtis HH (1902) The Immunization Treatment of Hay Fever. JAMA XXXIX(20):1267–1268. doi:10.1001/jama.1902.02480460045013

    Article  Google Scholar 

  238. Bachmann MF, Kundig TM (2016) Allergen specific immunotherapy: is it vaccination against toxins after all? Allergy. https://doi.org/10.1111/all.12890

  239. Tam HH et al (2016) Specific allergen immunotherapy for the treatment of atopic eczema: a Cochrane systematic review. Allergy 71:1345–1356. https://doi.org/10.1111/all.12932

    Article  CAS  PubMed  Google Scholar 

  240. Jutel M, Kosowska A, Smolinska S (2016) Allergen immunotherapy: past, present, and future. Allergy, Asthma Immunol Res 8:191–197. https://doi.org/10.4168/aair.2016.8.3.191

    Article  CAS  Google Scholar 

  241. Assa'ad A (2009) Eosinophilic gastrointestinal disorders. Allergy Asthma Proc 30:17–22. https://doi.org/10.2500/aap.2009.30.3189

    Article  PubMed  Google Scholar 

  242. Nelson HS (2016) Allergen immunotherapy now and in the future. Allergy Asthma Proc 37:268–272. https://doi.org/10.2500/aap.2016.37.3966

    Article  PubMed  CAS  Google Scholar 

  243. Burks AW et al (2013) Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report. J Allergy Clin Immunol 131:1288–1296. e1283. https://doi.org/10.1016/j.jaci.2013.01.049

    Article  PubMed  Google Scholar 

  244. Canonica GW et al (2016) Therapeutic interventions in severe asthma. World Allergy Organ J 9:40. https://doi.org/10.1186/s40413-016-0130-3

    Article  PubMed  PubMed Central  Google Scholar 

  245. Akdis M et al (2016) Interleukins (from IL-1 to IL-38), interferons, transforming growth factor beta, and TNF-alpha: receptors, functions, and roles in diseases. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2016.06.033

  246. van der Neut Kolfschoten M et al (2007) Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 317:1554–1557. https://doi.org/10.1126/science.1144603

    Article  PubMed  CAS  Google Scholar 

  247. Ozdemir C, Kucuksezer UC, Akdis M, Akdis CA (2016) Mechanisms of aeroallergen immunotherapy: subcutaneous immunotherapy and sublingual immunotherapy. Immunol Allergy Clin N Am 36:71–86. https://doi.org/10.1016/j.iac.2015.08.003

    Article  Google Scholar 

  248. Rosser EC, Mauri C (2015) Regulatory B cells: origin, phenotype, and function. Immunity 42:607–612. https://doi.org/10.1016/j.immuni.2015.04.005

    Article  PubMed  CAS  Google Scholar 

  249. Behrens RH et al (2014) Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers' diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala. Lancet Infect Dis 14:197–204. https://doi.org/10.1016/S1473-3099(13)70297-4

    Article  PubMed  CAS  Google Scholar 

  250. Ma Y (2016) Recent advances in nontoxic Escherichia coli heat-labile toxin and its derivative adjuvants. Expert Rev Vaccines:1–11. https://doi.org/10.1080/14760584.2016.1182868

  251. da Hora VP, Conceicao FR, Dellagostin OA, Doolan DL (2011) Non-toxic derivatives of LT as potent adjuvants. Vaccine 29:1538–1544. https://doi.org/10.1016/j.vaccine.2010.11.091

    Article  PubMed  CAS  Google Scholar 

  252. Liang S, Hajishengallis G (2010) Heat-labile enterotoxins as adjuvants or anti-inflammatory agents. Immunol Investig 39:449–467

    Article  CAS  Google Scholar 

  253. El-Kassas S et al (2015) Cell clustering and delay/arrest in T-cell division implicate a novel mechanism of immune modulation by E. coli heat-labile enterotoxin B-subunits. Cell Immunol 295:150–162. https://doi.org/10.1016/j.cellimm.2015.02.014

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  254. Cabauatan CR et al (2017) Heat-labile Escherichia coli toxin enhances the induction of allergen-specific IgG antibodies in epicutaneous patch vaccination. Allergy 72:164–168. https://doi.org/10.1111/all.13036

    Article  PubMed  CAS  Google Scholar 

  255. Valenta R, Campana R, Focke-Tejkl M, Niederberger V (2016) Vaccine development for allergen-specific immunotherapy based on recombinant allergens and synthetic allergen peptides: lessons from the past and novel mechanisms of action for the future. J Allergy Clin Immunol 137:351–357. https://doi.org/10.1016/j.jaci.2015.12.1299

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  256. Palucka K, Banchereau J, Mellman I (2010) Designing vaccines based on biology of human dendritic cell subsets. Immunity 33:464–478. https://doi.org/10.1016/j.immuni.2010.10.007

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  257. Zaleska A et al (2014) Immune regulation by intralymphatic immunotherapy with modular allergen translocation MAT vaccine. Allergy 69:1162–1170. https://doi.org/10.1111/all.12461

    Article  PubMed  CAS  Google Scholar 

  258. Lin CY et al (2015) Biodegradable polymeric microsphere-based vaccines and their applications in infectious diseases. Hum Vaccin Immunother 11:650–656. https://doi.org/10.1080/21645515.2015.1009345

    Article  PubMed  PubMed Central  Google Scholar 

  259. Cabauatan CR et al (2016) Heat-labile Escherichia coli toxin enhances the induction of allergen-specific IgG antibodies in epicutaneous patch vaccination. Allergy. https://doi.org/10.1111/all.13036

  260. Lin CH, Cheng SL (2016) A review of omalizumab for the management of severe asthma. Drug Des Devel Ther 10:2369–2378. https://doi.org/10.2147/DDDT.S112208

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  261. Chang TW et al (2015) The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol 135:337–342. https://doi.org/10.1016/j.jaci.2014.04.036

    Article  PubMed  CAS  Google Scholar 

  262. Chang TW, Shiung YY (2006) Anti-IgE as a mast cell-stabilizing therapeutic agent. J Allergy Clin Immunol 117:1203–1212.; quiz 1213. https://doi.org/10.1016/j.jaci.2006.04.005

    Article  PubMed  CAS  Google Scholar 

  263. Ortega HG et al (2014) Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 371:1198–1207. https://doi.org/10.1056/NEJMoa1403290

    Article  PubMed  CAS  Google Scholar 

  264. Bel EH et al (2014) Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 371:1189–1197. https://doi.org/10.1056/NEJMoa1403291

    Article  PubMed  CAS  Google Scholar 

  265. Tan LD, Bratt JM, Godor D, Louie S, Kenyon NJ (2016) Benralizumab: a unique IL-5 inhibitor for severe asthma. J Asthma Allergy 9:71–81. https://doi.org/10.2147/JAA.S78049

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  266. Varricchi G, Bagnasco D, Borriello F, Heffler E, Canonica GW (2016) Interleukin-5 pathway inhibition in the treatment of eosinophilic respiratory disorders: evidence and unmet needs. Curr Opin Allergy Clin Immunol 16:186–200. https://doi.org/10.1097/ACI.0000000000000251

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  267. Wang FP, Liu T, Lan Z, Li SY, Mao H (2016) Efficacy and safety of anti-interleukin-5 therapy in patients with asthma: a systematic review and meta-analysis. PLoS One 11:e0166833. https://doi.org/10.1371/journal.pone.0166833

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  268. Antoniu SA (2017) Benralizumab as a potential treatment of asthma. Expert Opin Biol Ther:1–6. https://doi.org/10.1080/14712598.2017.1319471

  269. Cabon Y et al (2017) Comparison of anti-interleukin-5 therapies in patients with severe asthma: global and indirect meta-analyses of randomized placebo-controlled trials. Clin Exp Allergy 47:129–138. https://doi.org/10.1111/cea.12853

    Article  PubMed  CAS  Google Scholar 

  270. Ferguson GT et al (2017) Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. https://doi.org/10.1016/S2213-2600(17)30190-X

  271. Nair P et al (2017) Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med. https://doi.org/10.1056/NEJMoa1703501

  272. Nair P et al (2009) Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 360:985–993. https://doi.org/10.1056/NEJMoa0805435

    Article  PubMed  CAS  Google Scholar 

  273. Pavord ID et al (2012) Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380:651–659. https://doi.org/10.1016/S0140-6736(12)60988-X

    Article  PubMed  CAS  Google Scholar 

  274. Ortega H et al (2014) Cluster analysis and characterization of response to mepolizumab. A step closer to personalized medicine for patients with severe asthma. Ann Am Thorac Soc 11:1011–1017. https://doi.org/10.1513/AnnalsATS.201312-454OC

    Article  PubMed  Google Scholar 

  275. Leonard WJ (2002) TSLP: finally in the limelight. Nat Immunol 3:605–607. https://doi.org/10.1038/ni0702-605

    Article  PubMed  CAS  Google Scholar 

  276. Corren J et al (2017) Tezepelumab in adults with uncontrolled asthma. N Engl J Med 377:936–946. https://doi.org/10.1056/NEJMoa1704064

    Article  PubMed  CAS  Google Scholar 

  277. Kuo CS et al (2017) T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur Respir J 49. https://doi.org/10.1183/13993003.02135-2016

  278. Mitchell PD, O’Byrne PM (2017) Epithelial-derived cytokines in asthma. Chest 151:1338–1344. https://doi.org/10.1016/j.chest.2016.10.042

    Article  PubMed  Google Scholar 

  279. Mitchell PD, O'Byrne PM (2017) Biologics and the lung: TSLP and other epithelial cell-derived cytokines in asthma. Pharmacol Ther 169:104–112. https://doi.org/10.1016/j.pharmthera.2016.06.009

    Article  PubMed  CAS  Google Scholar 

  280. Striz I (2017) Cytokines of the IL-1 family: recognized targets in chronic inflammation underrated in organ transplantations. Clin Sci (Lond) 131:2241–2256. https://doi.org/10.1042/CS20170098

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Medicine, University of California at Davis, Davis, CA, USA

    Cameron H. Flayer, Sarah S. Killingbeck, Erik Larson & Angela Haczku

  2. The Research Institute of the McGill University Health Centre, Montreal, Québec, Canada

    Zoulfia Allakhverdi

Authors
  1. Cameron H. Flayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah S. Killingbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erik Larson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zoulfia Allakhverdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Angela Haczku
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Angela Haczku .

Editor information

Editors and Affiliations

  1. Department of Medicine, Section of Pharmacology, University of Perugia, Perugia, Italy

    Carlo Riccardi

  2. Pharmacology and Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    Francesca Levi-Schaffer

  3. Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Ekaterini Tiligada

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Flayer, C.H., Killingbeck, S.S., Larson, E., Allakhverdi, Z., Haczku, A. (2018). Adaptive Immunity of Airway Inflammation in Asthma. In: Riccardi, C., Levi-Schaffer, F., Tiligada, E. (eds) Immunopharmacology and Inflammation. Springer, Cham. https://doi.org/10.1007/978-3-319-77658-3_3

Download citation

Publish with us

Policies and ethics

Search

Navigation