Current Allergy and Asthma Reports

, Volume 13, Issue 3, pp 298–307 | Cite as

Virus/Allergen Interactions in Asthma

  • Monica L. Gavala
  • Hiba Bashir
  • James E. Gern


Understanding the underlying mechanisms that cause and exacerbate allergic asthmatic disease is of great clinical interest. Clinical studies have revealed that allergies and viral respiratory illnesses are strongly linked to the inception and exacerbation of asthma, and suggest the possibility that there are interactive inflammatory mechanisms. Recent work has revealed a number of mechanisms of virus and allergen cross-talk that may play a role in the pathophysiology of allergic asthma, including (1) deficiency in virus-induced interferon responses, (2) defective epithelial barrier function, (3) increased release of epithelium-derived cytokines (e.g., thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, IL-33), (4) dysregulation of lymphocytes [e.g., innate lymphoid cells (ILCs), regulatory T cells (Tregs)], and (5) altered activation of purinergic receptors. One or more of these processes may provide targets for new therapeutics to treat allergic asthma and prevent disease exacerbation.


Asthma Virus Allergen Atopy Interactions Rhinovirus Exacerbations eATP TSLP IL-33 IL-25 Treg ILC P2X7 FcεR1 Dendritic cells 


Conflict of Interest

Monica L. Gavala declares that she has no conflict of interest.

Hiba Bashir declares that she has no conflict of interest.

James E. Gern has served as a consultant for GlaxoSmithKline, Biota Pharmaceuticals, Centocor, Boehringer Ingelheim GmbH, MedImmune, Theraclone Sciences, Merck & Co., and Gilead Sciences, and has received grant support from AstraZeneca, GlaxoSmithKline, and Merck & Co.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Platts-Mills TA, Erwin EA, Woodfolk JA, Heymann PW. Environmental factors influencing allergy and asthma. Chem Immunol Allergy. 2006;91:3–15.PubMedCrossRefGoogle Scholar
  2. 2.
    Akinbami LJ, Moorman JE, Garbe PL, Sondik EJ. Status of childhood asthma in the United States, 1980-2007. Pediatrics. 2009;123 Suppl 3:S131–45.PubMedCrossRefGoogle Scholar
  3. 3.
    Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995;332:133–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Sigurs N, Gustafsson PM, Bjarnason R, Lundberg F, Schmidt S, Sigurbergsson F, et al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med. 2005;171:137–41.PubMedCrossRefGoogle Scholar
  5. 5.
    Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, Taussig LM, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999;354:541–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Wu P, Dupont WD, Griffin MR, Carroll KN, Mitchel EF, Gebretsadik T, et al. Evidence of a causal role of winter virus infection during infancy in early childhood asthma. Am J Respir Crit Care Med. 2008;178:1123–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Thomsen SF, van der Sluis S, Stensballe LG, Posthuma D, Skytthe A, Kyvik KO, et al. Exploring the association between severe respiratory syncytial virus infection and asthma: a registry-based twin study. Am J Respir Crit Care Med. 2009;179:1091–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Simoes EA, Carbonell-Estrany X, Rieger CH, Mitchell I, Fredrick L, Groothuis JR. The effect of respiratory syncytial virus on subsequent recurrent wheezing in atopic and nonatopic children. J Allergy Clin Immunol. 2010;126:256–62.PubMedCrossRefGoogle Scholar
  9. 9.
    Kotaniemi-Syrjanen A, Vainionpaa R, Reijonen TM, Waris M, Korhonen K, Korppi M. Rhinovirus-induced wheezing in infancy–the first sign of childhood asthma? J Allergy Clin Immunol. 2003;111:66–71.PubMedCrossRefGoogle Scholar
  10. 10.
    Jackson DJ, Gangnon RE, Evans MD, Roberg KA, Anderson EL, Pappas TE, et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med. 2008;178:667–72.PubMedCrossRefGoogle Scholar
  11. 11.
    Kusel MM, de Klerk NH, Kebadze T, Vohma V, Holt PG, Johnston SL, et al. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. J Allergy Clin Immunol. 2007;119:1105–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Sly PD, Boner AL, Bjorksten B, Bush A, Custovic A, Eigenmann PA, et al. Early identification of atopy in the prediction of persistent asthma in children. Lancet. 2008;372:1100–6.PubMedCrossRefGoogle Scholar
  13. 13.
    •• Jackson DJ, Evans MD, Gangnon RE, Tisler CJ, Pappas TE, Lee WM, et al. Evidence for a causal relationship between allergic sensitization and rhinovirus wheezing in early life. Am J Respir Crit Care Med. 2012;185:281–5. Provide evidence that exposure to allergens proceeds HRV-induced wheeze in a high risk prospective birth cohort.PubMedCrossRefGoogle Scholar
  14. 14.
    Murray CS, Poletti G, Kebadze T, Morris J, Woodcock A, Johnston SL, et al. Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children. Thorax. 2006;61:376–82.PubMedCrossRefGoogle Scholar
  15. 15.
    Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ. 1995;310:1225–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacerbations of asthma in adults. BMJ. 1993;307:982–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Heymann PW, Carper HT, Murphy DD, Platts-Mills TA, Patrie J, McLaughlin AP, et al. Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing. J Allergy Clin Immunol. 2004;114:239–47.PubMedCrossRefGoogle Scholar
  18. 18.
    • Miller EK, Hernandez JZ, Wimmenauer V, Shepherd BE, Hijano D, Libster R, et al. A mechanistic role for type III IFN-lambda1 in asthma exacerbations mediated by human rhinoviruses. Am J Respir Crit Care Med. 2012;185:508–16. A prospective study showing a correlation between increased HRV-induced IFN-λ release and asthma exacerbations in children.PubMedCrossRefGoogle Scholar
  19. 19.
    Denlinger LC, Sorkness RL, Lee WM, Evans MD, Wolff MJ, Mathur SK, et al. Lower airway rhinovirus burden and the seasonal risk of asthma exacerbation. Am J Respir Crit Care Med. 2011;184:1007–14.PubMedCrossRefGoogle Scholar
  20. 20.
    Green RM, Custovic A, Sanderson G, Hunter J, Johnston SL, Woodcock A. Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study. BMJ. 2002;324:763.PubMedCrossRefGoogle Scholar
  21. 21.
    Olenec JP, Kim WK, Lee WM, Vang F, Pappas TE, Salazar LE, et al. Weekly monitoring of children with asthma for infections and illness during common cold seasons. J Allergy Clin Immunol. 2010;125:1001–1006 e1.PubMedCrossRefGoogle Scholar
  22. 22.
    • Soto-Quiros M, Avila L, Platts-Mills TA, Hunt JF, Erdman DD, Carper H, et al. High titers of IgE antibody to dust mite allergen and risk for wheezing among asthmatic children infected with rhinovirus. J Allergy Clin Immunol. 2012;129:1499–1505 e5. Found HRV-induced wheeze correlated with high serum IgE.PubMedCrossRefGoogle Scholar
  23. 23.
    Johnston NW, Johnston SL, Duncan JM, Greene JM, Kebadze T, Keith PK, et al. The September epidemic of asthma exacerbations in children: a search for etiology. J Allergy Clin Immunol. 2005;115:132–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Johnston NW, Johnston SL, Norman GR, Dai J, Sears MR. The September epidemic of asthma hospitalization: school children as disease vectors. J Allergy Clin Immunol. 2006;117:557–62.PubMedCrossRefGoogle Scholar
  25. 25.
    Bizzintino J, Lee WM, Laing IA, Vang F, Pappas T, Zhang G, et al. Association between human rhinovirus C and severity of acute asthma in children. Eur Respir J Off J Eur Soc Clin Respir Physiol. 2011;37:1037–42.CrossRefGoogle Scholar
  26. 26.
    Khetsuriani N, Lu X, Teague WG, Kazerouni N, Anderson LJ, Erdman DD. Novel human rhinoviruses and exacerbation of asthma in children. Emerg Infect Dis. 2008;14:1793–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Miller EK, Edwards KM, Weinberg GA, Iwane MK, Griffin MR, Hall CB, et al. A novel group of rhinoviruses is associated with asthma hospitalizations. J Allergy Clin Immunol. 2009;123:98–104 e1.PubMedCrossRefGoogle Scholar
  28. 28.
    Iwane MK, Prill MM, Lu X, Miller EK, Edwards KM, Hall CB, et al. Human rhinovirus species associated with hospitalizations for acute respiratory illness in young US children. J Infect Dis. 2011;204:1702–10.PubMedCrossRefGoogle Scholar
  29. 29.
    • Lee WM, Lemanske Jr RF, Evans MD, Vang F, Pappas T, Gangnon R, et al. Human rhinovirus species and season of infection determine illness severity. Am J Respir Crit Care Med. 2012;186:886–91. Provide data that HRV-A and HRV-C groups cause more respiratory illnesses in infants, with season effecting HRV prevalence and virulence.PubMedCrossRefGoogle Scholar
  30. 30.
    DeMore JP, Weisshaar EH, Vrtis RF, Swenson CA, Evans MD, Morin A, et al. Similar colds in subjects with allergic asthma and nonatopic subjects after inoculation with rhinovirus-16. J Allergy Clin Immunol. 2009;124:245–52. 52 e1-3.PubMedCrossRefGoogle Scholar
  31. 31.
    Message SD, Laza-Stanca V, Mallia P, Parker HL, Zhu J, Kebadze T, et al. Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production. Proc Natl Acad Sci U S A. 2008;105:13562–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Calhoun WJ, Dick EC, Schwartz LB, Busse WW. A common cold virus, rhinovirus 16, potentiates airway inflammation after segmental antigen bronchoprovocation in allergic subjects. J Clin Investig. 1994;94:2200–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Avila PC, Abisheganaden JA, Wong H, Liu J, Yagi S, Schnurr D, et al. Effects of allergic inflammation of the nasal mucosa on the severity of rhinovirus 16 cold. J Allergy Clin Immunol. 2000;105:923–32.PubMedCrossRefGoogle Scholar
  34. 34.
    de Kluijver J, Evertse CE, Sont JK, Schrumpf JA, van Zeijl-van der Ham CJ, Dick CR, et al. Are rhinovirus-induced airway responses in asthma aggravated by chronic allergen exposure? Am J Respir Crit Care Med. 2003;168:1174–80.PubMedCrossRefGoogle Scholar
  35. 35.
    Kovac K, Dodig S, Tjesic-Drinkovic D, Raos M. Correlation between asthma severity and serum IgE in asthmatic children sensitized to Dermatophagoides pteronyssinus. Arch Med Res. 2007;38:99–105.PubMedCrossRefGoogle Scholar
  36. 36.
    Kraft S, Kinet JP. New developments in FcepsilonRI regulation, function and inhibition. Nat Rev Immunol. 2007;7:365–78.PubMedCrossRefGoogle Scholar
  37. 37.
    Dehlink E, Baker AH, Yen E, Nurko S, Fiebiger E. Relationships between levels of serum IgE, cell-bound IgE, and IgE-receptors on peripheral blood cells in a pediatric population. PLoS One. 2010;5:e12204.PubMedCrossRefGoogle Scholar
  38. 38.
    Gill MA, Bajwa G, George TA, Dong CC, Dougherty II, Jiang N, et al. Counterregulation between the FcepsilonRI pathway and antiviral responses in human plasmacytoid dendritic cells. J Immunol. 2010;184:5999–6006.PubMedCrossRefGoogle Scholar
  39. 39.
    • Durrani SR, Montville DJ, Pratt AS, Sahu S, DeVries MK, Rajamanickam V, et al. Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children. J Allergy Clin Immunol. 2012;130:489–95. Data reveal a role for IgE receptor activation on pDCs in attenuating anti-viral responses in asthmatic children.PubMedCrossRefGoogle Scholar
  40. 40.
    Cao W, Rosen DB, Ito T, Bover L, Bao M, Watanabe G, et al. Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilonRI gamma inhibits Toll-like receptor-induced interferon production. J Exp Med. 2006;203:1399–405.PubMedCrossRefGoogle Scholar
  41. 41.
    Cao W, Zhang L, Rosen DB, Bover L, Watanabe G, Bao M, et al. BDCA2/Fc epsilon RI gamma complex signals through a novel BCR-like pathway in human plasmacytoid dendritic cells. PLoS Biol. 2007;5:e248.PubMedCrossRefGoogle Scholar
  42. 42.
    Contoli M, Message SD, Laza-Stanca V, Edwards MR, Wark PA, Bartlett NW, et al. Role of deficient type III interferon-lambda production in asthma exacerbations. Nature Medicine. 2006;12:1023–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Papadopoulos NG, Stanciu LA, Papi A, Holgate ST, Johnston SL. A defective type 1 response to rhinovirus in atopic asthma. Thorax. 2002;57:328–32.PubMedCrossRefGoogle Scholar
  44. 44.
    Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med. 2005;201:937–47.PubMedCrossRefGoogle Scholar
  45. 45.
    Collison A, Hatchwell L, Verrills N, Wark PA, de Siqueira AP, Tooze M, et al. The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity. Nat Med. 2013.Google Scholar
  46. 46.
    Edwards MR, Regamey N, Vareille M, Kieninger E, Gupta A, Shoemark A, et al. Impaired innate interferon induction in severe therapy resistant atopic asthmatic children. Mucosal Immunol. 2012.Google Scholar
  47. 47.
    Sykes A, Edwards MR, Macintyre J, del Rosario A, Bakhsoliani E, Trujillo-Torralbo MB, et al. Rhinovirus 16-induced IFN-alpha and IFN-beta are deficient in bronchoalveolar lavage cells in asthmatic patients. J Allergy Clin Immunol. 2012;129:1506–1514 e6.PubMedCrossRefGoogle Scholar
  48. 48.
    Bochkov YA, Hanson KM, Keles S, Brockman-Schneider RA, Jarjour NN, Gern JE. Rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma. Mucosal Immunol. 2010;3:69–80.PubMedCrossRefGoogle Scholar
  49. 49.
    Lopez-Souza N, Favoreto S, Wong H, Ward T, Yagi S, Schnurr D, et al. In vitro susceptibility to rhinovirus infection is greater for bronchial than for nasal airway epithelial cells in human subjects. J Allergy Clin Immunol. 2009;123:1384–1390 e2.PubMedCrossRefGoogle Scholar
  50. 50.
    Bullens DM, Decraene A, Dilissen E, Meyts I, De Boeck K, Dupont LJ, et al. IFN-lambda mRNA expression in sputum of adult and school-aged asthmatics. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2008;38:1459–67.CrossRefGoogle Scholar
  51. 51.
    He S, Li T, Chen H, Ma W, Yao Q, Yang H, et al. CD14+ cell-derived IL-29 modulates proinflammatory cytokine production in patients with allergic airway inflammation. Allergy. 2011;66:238–46.PubMedCrossRefGoogle Scholar
  52. 52.
    • Baraldo S, Contoli M, Bazzan E, Turato G, Padovani A, Marku B, et al. Deficient antiviral immune responses in childhood: distinct roles of atopy and asthma. J Allergy Clin Immunol. 2012;130:1307–14. Show asthmatic children have greater epithelia damage and impaired HRV-induced cytokine production that correlates inversely with HRV replication.PubMedCrossRefGoogle Scholar
  53. 53.
    Sajjan U, Wang Q, Zhao Y, Gruenert DC, Hershenson MB. Rhinovirus disrupts the barrier function of polarized airway epithelial cells. Am J Respir Crit Care Med. 2008;178:1271–81.PubMedCrossRefGoogle Scholar
  54. 54.
    Vareille M, Kieninger E, Edwards MR, Regamey N. The airway epithelium: soldier in the fight against respiratory viruses. Clin Microbiol Rev. 2011;24:210–29.PubMedCrossRefGoogle Scholar
  55. 55.
    Jakiela B, Brockman-Schneider R, Amineva S, Lee WM, Gern JE. Basal cells of differentiated bronchial epithelium are more susceptible to rhinovirus infection. Am J Respir Cell Mol Biol. 2008;38:517–23.PubMedCrossRefGoogle Scholar
  56. 56.
    Lopez-Souza N, Dolganov G, Dubin R, Sachs LA, Sassina L, Sporer H, et al. Resistance of differentiated human airway epithelium to infection by rhinovirus. Am J Physiol Lung Cel Mol Physiol. 2004;286:L373–81.CrossRefGoogle Scholar
  57. 57.
    Holgate ST, Roberts G, Arshad HS, Howarth PH, Davies DE. The role of the airway epithelium and its interaction with environmental factors in asthma pathogenesis. Proc Am Thorac Soc. 2009;6:655–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Takai T. TSLP expression: cellular sources, triggers, and regulatory mechanisms. Allergol Int Off J Jpn Soc Allergol. 2012;61:3–17.CrossRefGoogle Scholar
  59. 59.
    Okayama Y, Okumura S, Sagara H, Yuki K, Sasaki T, Watanabe N, et al. FcepsilonRI-mediated thymic stromal lymphopoietin production by interleukin-4-primed human mast cells. Eur Respir J Off J Eur Soc Clin Respir Physiol. 2009;34:425–35.CrossRefGoogle Scholar
  60. 60.
    Calven J, Yudina Y, Hallgren O, Westergren-Thorsson G, Davies DE, Brandelius A, et al. Viral stimuli trigger exaggerated thymic stromal lymphopoietin expression by chronic obstructive pulmonary disease epithelium: role of endosomal TLR3 and cytosolic RIG-I-like helicases. J Innate Immun. 2012;4:86–99.PubMedCrossRefGoogle Scholar
  61. 61.
    Holtzman MJ. Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens. J Clin Investig. 2012;122:2741–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Shikotra A, Choy DF, Ohri CM, Doran E, Butler C, Hargadon B, et al. Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma. J Allergy Clin Immunol. 2012;129:104–11. e1-9.PubMedCrossRefGoogle Scholar
  63. 63.
    Xu G, Zhang L, Wang DY, Xu R, Liu Z, Han DM, et al. Opposing roles of IL-17A and IL-25 in the regulation of TSLP production in human nasal epithelial cells. Allergy. 2010;65:581–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Ying S, O'Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol. 2005;174:8183–90.PubMedGoogle Scholar
  65. 65.
    Ito T, Wang YH, Duramad O, Hori T, Delespesse GJ, Watanabe N, et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med. 2005;202:1213–23.PubMedCrossRefGoogle Scholar
  66. 66.
    Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3:673–80.PubMedCrossRefGoogle Scholar
  67. 67.
    Hanabuchi S, Ito T, Park WR, Watanabe N, Shaw JL, Roman E, et al. Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus. J Immunol. 2010;184:2999–3007.PubMedCrossRefGoogle Scholar
  68. 68.
    Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PLoS One. 2008;3:e3331.PubMedCrossRefGoogle Scholar
  69. 69.
    Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. 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. 2005;23:479–90.PubMedCrossRefGoogle Scholar
  70. 70.
    Borish L, Steinke JW. Interleukin-33 in asthma: how big of a role does it play? Curr Allergy Asthma Rep. 2011;11:7–11.PubMedCrossRefGoogle Scholar
  71. 71.
    Prefontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ, et al. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J Immunol. 2009;183:5094–103.PubMedCrossRefGoogle Scholar
  72. 72.
    Kouzaki H, Iijima K, Kobayashi T, O'Grady SM, Kita H. The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate Th2-type responses. J Immunol. 2011;186:4375–87.PubMedCrossRefGoogle Scholar
  73. 73.
    Le Goffic R, Arshad MI, Rauch M, L'Helgoualc'h A, Delmas B, Piquet-Pellorce C, et al. Infection with influenza virus induces IL-33 in murine lungs. Am J Respir Cell Mol Biol. 2011;45:1125–32.PubMedCrossRefGoogle Scholar
  74. 74.
    Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol. 2008;121:1484–90.PubMedCrossRefGoogle Scholar
  75. 75.
    Kim YH, Yang TY, Park CS, Ahn SH, Son BK, Kim JH, et al. Anti-IL-33 antibody has a therapeutic effect in a murine model of allergic rhinitis. Allergy. 2012;67:183–90.PubMedCrossRefGoogle Scholar
  76. 76.
    Wang YH, Angkasekwinai P, Lu N, Voo KS, Arima K, Hanabuchi S, et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J Exp Med. 2007;204:1837–47.PubMedCrossRefGoogle Scholar
  77. 77.
    Hams E, Fallon PG. Innate type 2 cells and asthma. Curr Opin Pharmacol. 2012;12:503–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Mjosberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM, Piet B, et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol. 2011;12:1055–62.PubMedCrossRefGoogle Scholar
  79. 79.
    Nandakumar S, Miller CW, Kumaraguru U. T regulatory cells: an overview and intervention techniques to modulate allergy outcome. Clin Mol Allergy CMA. 2009;7:5.CrossRefGoogle Scholar
  80. 80.
    Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012;30:531–64.PubMedCrossRefGoogle Scholar
  81. 81.
    Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med. 2004;199:1567–75.PubMedCrossRefGoogle Scholar
  82. 82.
    Nguyen KD, Vanichsarn C, Nadeau KC. TSLP directly impairs pulmonary Treg function: association with aberrant tolerogenic immunity in asthmatic airway. Allergy Asthma Clin Immunol Off J Can Soc Allergy Clin Immunol. 2010;6:4.CrossRefGoogle Scholar
  83. 83.
    Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Arbery J, et al. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet. 2004;363:608–15.PubMedCrossRefGoogle Scholar
  84. 84.
    Hartl D, Koller B, Mehlhorn AT, Reinhardt D, Nicolai T, Schendel DJ, et al. Quantitative and functional impairment of pulmonary CD4+CD25hi regulatory T cells in pediatric asthma. J Allergy Clin Immunol. 2007;119:1258–66.PubMedCrossRefGoogle Scholar
  85. 85.
    Keynan Y, Card CM, McLaren PJ, Dawood MR, Kasper K, Fowke KR. The role of regulatory T cells in chronic and acute viral infections. Clin Infect Dis Off Publ Infect Dis Soc Am. 2008;46:1046–52.CrossRefGoogle Scholar
  86. 86.
    Seyerl M, Kirchberger S, Majdic O, Seipelt J, Jindra C, Schrauf C, et al. Human rhinoviruses induce IL-35-producing Treg via induction of B7-H1 (CD274) and sialoadhesin (CD169) on DC. Eur J Immunol. 2010;40:321–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Krishnamoorthy N, Khare A, Oriss TB, Raundhal M, Morse C, Yarlagadda M, et al. Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nature Medicine. 2012;18:1525–30.PubMedCrossRefGoogle Scholar
  88. 88.
    Esther Jr CR, Alexis NE, Clas ML, Lazarowski ER, Donaldson SH, Ribeiro CM, et al. Extracellular purines are biomarkers of neutrophilic airway inflammation. Eur Respir J Off J Eur Soc Clin Respir Physiol. 2008;31:949–56.CrossRefGoogle Scholar
  89. 89.
    Idzko M, Hammad H, van Nimwegen M, Kool M, Willart MA, Muskens F, et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nature Medicine. 2007;13:913–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Bulanova E, Bulfone-Paus S. P2 receptor-mediated signaling in mast cell biology. Purinergic Signal. 2010;6:3–17.PubMedCrossRefGoogle Scholar
  91. 91.
    Denlinger LC, Manthei DM, Seibold MA, Ahn K, Bleecker E, Boushey HA, et al. P2X7-regulated protection from exacerbations and loss of control is independent of asthma maintenance therapy. Am J Respir Crit Care Med. 2013;187:28–33.PubMedCrossRefGoogle Scholar
  92. 92.
    Shi L, Manthei DM, Guadarrama AG, Lenertz LY, Denlinger LC. Rhinovirus-induced IL-1beta release from bronchial epithelial cells is independent of functional P2X7. Am J Respir Cell Mol Biol. 2012;47:363–71.PubMedCrossRefGoogle Scholar
  93. 93.
    Manthei DM, Jackson DJ, Evans MD, Gangnon RE, Tisler CJ, Gern JE, et al. Protection from asthma in a high-risk birth cohort by attenuated P2X(7) function. J Allergy Clin Immunol. 2012;130:496–502.PubMedCrossRefGoogle Scholar
  94. 94.
    Denlinger LC, Shi L, Guadarrama A, Schell K, Green D, Morrin A, et al. Attenuated P2X7 pore function as a risk factor for virus-induced loss of asthma control. Am J Respir Crit Care Med. 2009;179:265–70.PubMedCrossRefGoogle Scholar
  95. 95.
    Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176:1062–71.PubMedCrossRefGoogle Scholar
  96. 96.
    Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973–84.PubMedCrossRefGoogle Scholar
  97. 97.
    Johnston NW, Mandhane PJ, Dai J, Duncan JM, Greene JM, Lambert K, et al. Attenuation of the September epidemic of asthma exacerbations in children: a randomized, controlled trial of montelukast added to usual therapy. Pediatrics. 2007;120:e702–12.PubMedCrossRefGoogle Scholar
  98. 98.
    Kim CK, Choi J, Kim HB, Callaway Z, Shin BM, Kim JT, et al. A randomized intervention of montelukast for post-bronchiolitis: effect on eosinophil degranulation. J Pediatr. 2010;156:749–54.PubMedCrossRefGoogle Scholar
  99. 99.
    •• Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med. 2011;364:1005–15. Describe the benefits of anti-IgE (omalizumab) therapy for improved asthma control and reduced exacerbations in an inner-city children cohort.PubMedCrossRefGoogle Scholar
  100. 100.
    Chen H, Eisner MD, Haselkorn T, Trzaskoma B. Concomitant asthma medications in moderate-to-severe allergic asthma treated with omalizumab. Respir Med. 2013;107:60–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Monica L. Gavala
    • 1
  • Hiba Bashir
    • 2
  • James E. Gern
    • 3
  1. 1.Department of Biomolecular ChemistrySchool of Medicine and Public Health, University of Wisconsin-MadisonMadisonUSA
  2. 2.Department of MedicineUniversity of Wisconsin Medical SchoolMadisonUSA
  3. 3.Departments of Pediatrics and MedicineUniversity of Wisconsin Medical SchoolMadisonUSA

Personalised recommendations