Asthma is a common disease that affects 300 million people worldwide. Given the large number of eosinophils in the airways of people with mild asthma, and verified by data from murine models, asthma was long considered the hallmark T helper type 2 (TH2) disease of the airways. It is now known that some asthmatic inflammation is neutrophilic, controlled by the TH17 subset of helper T cells, and that some eosinophilic inflammation is controlled by type 2 innate lymphoid cells (ILC2 cells) acting together with basophils. Here we discuss results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and describe the extraordinary heterogeneity of asthma.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
RNY3 modulates cell proliferation and IL13 mRNA levels in a T lymphocyte model: a possible new epigenetic mechanism of IL-13 regulation
Journal of Physiology and Biochemistry Open Access 12 September 2022
Effects of human adipose tissue- and bone marrow-derived mesenchymal stem cells on airway inflammation and remodeling in a murine model of chronic asthma
Scientific Reports Open Access 14 July 2022
Nature Communications Open Access 04 July 2022
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Simpson, A. et al. Beyond atopy: multiple patterns of sensitization in relation to asthma in a birth cohort study. Am. J. Respir. Crit. Care Med. 181, 1200–1206 (2010).
Spergel, J.M. & Paller, A.S. Atopic dermatitis and the atopic march. J. Allergy Clin. Immunol. 112 (suppl.), S118–S127 (2003).
Anderson, G.P. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 372, 1107–1119 (2008).
Woodruff, P.G. et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 180, 388–395 (2009).
Wu, W. et al. Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J. Allergy Clin. Immunol. 133, 1280–1288 (2014).
Wenzel, S.E. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat. Med. 18, 716–725 (2012).
Brusselle, G.G., Joos, G.F. & Bracke, K.R. New insights into the immunology of chronic obstructive pulmonary disease. Lancet 378, 1015–1026 (2011).
De Monchy, J.G.R. et al. Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am. Rev. Respir. Dis. 131, 373–376 (1985).
Humbert, M., Durham, S.R. & Ying, S. IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and non-atopic asthma: evidence against “intrinsic” asthma being a distinct immunopathologic entity. Am. J. Respir. Crit. Care Med. 154, 1497–1504 (1996).
Bentley, A.M. et al. Activated T-lymphocytes and eosinophils in the bronchial mucosa in isocyanate-induced asthma. J. Allergy Clin. Immunol. 89, 821–829 (1992).
Bousquet, J. et al. Eosinophilic inflammation in asthma. N. Engl. J. Med. 323, 1033–1039 (1990).
Robinson, D.S. et al. Predominant Th2-like bronchoalveolar T lymphocyte population in atopic asthma. N. Engl. J. Med. 326, 298–304 (1992).
Woodruff, P.G. et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc. Natl. Acad. Sci. USA 104, 15858–15863 (2007).
Cheng, D. et al. Epithelial interleukin-25 is a key mediator in TH2-high, corticosteroid-responsive asthma. Am. J. Respir. Crit. Care Med. 190, 639–648 (2014).
Cohn, L., Homer, R.J., Niu, N. & Bottomly, K. T helper 1 cells and interferon gamma regulate allergic airway inflammation and mucus production. J. Exp. Med. 190, 1309–1318 (1999).
Cohn, L. et al. TH2-induced airway mucus production is dependent on IL-4Rα, but not on eosinophils. J. Immunol. 162, 6178–6183 (1999).
Cohn, L., Homer, R.J., Marinov, A., Rankin, J. & Bottomly, K. Induction of airway mucus production By T helper 2 (TH2) cells: a critical role for interleukin 4 in cell recruitment but not mucus production. J. Exp. Med. 186, 1737–1747 (1997).
Doherty, T.A., Soroosh, P., Broide, D.H. & Croft, M. CD4+ cells are required for chronic eosinophilic lung inflammation but not airway remodeling. Am. J. Physiol. Lung Cell. Mol. Physiol. 296, L229–L235 (2009).
Gavett, S.H. et al. Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and TH2 cytokine expression in mice. J. Exp. Med. 182, 1527–1536 (1995).
Brusselle, G.G. et al. Attenuation of allergic airway inflammation in IL-4 deficient mice. Clin. Exp. Allergy 24, 73–80 (1994).
Corry, D.B. et al. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J. Exp. Med. 183, 109–117 (1996).
Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).
Grünig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science [see comments] 282, 2261–2263 (1998).
Wenzel, S. et al. Dupilumab in persistent asthma with elevated eosinophil levels. N. Engl. J. Med. 368, 2455–2466 (2013).
Corren, J. et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088–1098 (2011).
Coyle, A.J., Perretti, F., Manzini, S. & Irvin, C.G. Cationic protein-induced sensory nerve activation: role of substance P in airway hyperresponsiveness and plasma protein extravasation. J. Clin. Invest. 94, 2301–2306 (1994).
Coyle, A.J., Ackerman, S.J., Burch, R., Proud, D. & Irvin, C.G. Human eosinophil-granule major basic protein and synthetic polycations induce airway hyperresponsiveness in vivo dependent on bradykinin generation. J. Clin. Invest. 95, 1735–1740 (1995).
Chu, D.K. et al. Indigenous enteric eosinophils control DCs to initiate a primary TH2 immune response in vivo. J. Exp. Med. 211, 1657–1672 (2014).
van Rijt, L.S. et al. Airway eosinophils accumulate in the mediastinal lymph nodes but lack antigen-presenting potential for naive T cells. J. Immunol. 171, 3372–3378 (2003).
Song, D.J. et al. Anti-Siglec-F antibody reduces allergen-induced eosinophilic inflammation and airway remodeling. J. Immunol. 183, 5333–5341 (2009).
Fattouh, R. et al. Eosinophils are dispensable for allergic remodeling and immunity in a model of house dust mite-induced airway disease. Am. J. Respir. Crit. Care Med. 183, 179–188 (2011).
Dworski, R., Simon, H.U., Hoskins, A. & Yousefi, S. Eosinophil and neutrophil extracellular DNA traps in human allergic asthmatic airways. J. Allergy Clin. Immunol. 127, 1260–1266 (2011).
Yousefi, S., Simon, D. & Simon, H.U. Eosinophil extracellular DNA traps: molecular mechanisms and potential roles in disease. Curr. Opin. Immunol. 24, 736–739 (2012).
Ortega, H.G. et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N. Engl. J. Med. 371, 1198–1207 (2014).
Bel, E.H. et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N. Engl. J. Med. 371, 1189–1197 (2014).
Flood-Page, P. et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J. Clin. Invest. 112, 1029–1036 (2003).
Laviolette, M. et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J. Allergy Clin. Immunol. 132, 1086–1096 (2013).
Fallon, P.G. et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 203, 1105–1116 (2006).
Fort, M.M. et al. IL-25 induces IL-4, IL-5, and IL-13 and TH2-associated pathologies in vivo. Immunity 15, 985–995 (2001).
Kang, Z. et al. Epithelial cell-specific Act1 adaptor mediates interleukin-25-dependent helminth expulsion through expansion of Lin-c-Kit+ innate cell population. Immunity 36, 821–833 (2012).
Walker, J.A., Barlow, J.L. & McKenzie, A.N. Innate lymphoid cells–how did we miss them? Nat. Rev. Immunol. 13, 75–87 (2013).
Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).
Barlow, J.L. et al. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J. Allergy Clin. Immunol. 129, 191–198 (2012).
Bartemes, K.R. et al. IL-33-responsive lineage- CD25+ CD44hi lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J. Immunol. 188, 1503–1513 (2012).
Yasuda, K. et al. Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc. Natl. Acad. Sci. USA 109, 3451–3456 (2012).
Halim, T.Y., Krauss, R.H., Sun, A.C. & Takei, F. Lung natural helper cells are a critical source of TH2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36, 451–463 (2012).
Doherty, T.A. et al. Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. J. Allergy Clin. Immunol. 132, 205–213 (2013).
Chang, Y.J. et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat. Immunol. 12, 631–638 (2011).
Hong, J.Y. et al. Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells. J. Allergy Clin. Immunol. 134, 429–439 (2014).
Gorski, S.A., Hahn, Y.S. & Braciale, T.J. Group 2 innate lymphoid cell production of IL-5 is regulated by NKT cells during influenza virus infection. PLoS Pathog. 9, e1003615 (2013).
Klein Wolterink, R.G. et al. 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 (2012).
Gold, M.J. et al. Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures. J. Allergy Clin. Immunol. 133, 1142–1148 (2014).
Halim, T.Y. et al. Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation. Immunity 37, 463–474 (2012).
Halim, T.Y. et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40, 425–435 (2014).
Xue, L. et al. Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J. Allergy Clin. Immunol. 133, 1184–1194 (2014).
Doherty, T.A. et al. STAT6 regulates natural helper cell proliferation during lung inflammation initiated by Alternaria. Am. J. Physiol. Lung Cell. Mol. Physiol. 303, L577–L588 (2012).
Barnig, C. et al. Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma. Sci. Transl. Med. 5, 174ra126 (2013).
Juncadella, I.J. et al. Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation. Nature 493, 547–551 (2013).
McSorley, H.J., Blair, N.F., Smith, K.A., McKenzie, A.N. & Maizels, R.M. Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy. Mucosal Immunol. 7, 1068–1078 (2014).
Van Dyken, S.J. et al. Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ T cells. Immunity 40, 414–424 (2014).
Oliphant, C.J. et al. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 41, 283–295 (2014).
Zaiss, D.M. et al. Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. Science 314, 1746 (2006).
Monticelli, L.A. et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054 (2011).
Porter, P.C. et al. Airway surface mycosis in chronic TH2-associated airway disease. J. Allergy Clin. Immunol. 134, 325–331 (2014).
Mjösberg, J. et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37, 649–659 (2012).
Mjösberg, J.M. et al. 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 (2011).
Kabata, H. et al. Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation. Nat. Commun. 4, 2675 (2013).
McKinley, L. et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J. Immunol. 181, 4089–4097 (2008).
Shaw, D.E. et al. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest 132, 1871–1875 (2007).
Manni, M.L. et al. The complex relationship between inflammation and lung function in severe asthma. Mucosal Immunol. 7, 1186–1198 (2014).
Schnyder-Candrian, S. et al. Interleukin-17 is a negative regulator of established allergic asthma. J. Exp. Med. 203, 2715–2725 (2006).
Wakashin, H. et al. IL-23 and TH17 cells enhance TH2-cell-mediated eosinophilic airway inflammation in mice. Am. J. Respir. Crit. Care Med. 178, 1023–1032 (2008).
Besnard, A.G. et al. Dual role of IL-22 in allergic airway inflammation and its cross-talk with IL-17A. Am. J. Respir. Crit. Care Med. 183, 1153–1163 (2011).
Brandt, E.B. et al. Diesel exhaust particle induction of IL-17A contributes to severe asthma. J. Allergy Clin. Immunol. 132, 1194–1204 (2013).
Bellini, A. et al. Interleukin (IL)-4, IL-13, and IL-17A differentially affect the profibrotic and proinflammatory functions of fibrocytes from asthmatic patients. Mucosal Immunol. 5, 140–149 (2011).
Zhao, J., Lloyd, C.M. & Noble, A. TH17 responses in chronic allergic airway inflammation abrogate regulatory T-cell-mediated tolerance and contribute to airway remodeling. Mucosal Immunol. 6, 335–346 (2012).
Kudo, M. et al. IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat. Med. 18, 547–554 (2012).
Busse, W.W. et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am. J. Respir. Crit. Care Med. 188, 1294–1302 (2013).
Berry, M.A. et al. Evidence of a role of tumor necrosis factor α in refractory asthma. N. Engl. J. Med. 354, 697–708 (2006).
Wenzel, S.E. et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-α blockade in severe persistent asthma. Am. J. Respir. Crit. Care Med. 179, 549–558 (2009).
Morjaria, J.B. et al. The role of a soluble TNFα receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax 63, 584–591 (2008).
Porter, P.C. et al. Necessary and sufficient role for T helper cells to prevent fungal dissemination in allergic lung disease. Infect. Immun. 79, 4459–4471 (2011).
Wang, Y.H. et al. A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma. J. Exp. Med. 207, 2479–2491 (2010).
Sutherland, T.E. et al. Chitinase-like proteins promote IL-17 mediated neutrophilia in a tradeoff between nematode killing and host damage. Nat. Immunol. 15, 1116–1125 (2014).
Irvin, C. et al. Increased frequency of dual-positive T2/T17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J. Allergy Clin. Immunol. doi:10.1016/j.jaci.2014.05.038 (18 July 2014).
Randolph, D.A., Stephens, R., Carruthers, C.J. & Chaplin, D.D. Cooperation between TH1 and TH2 cells in a murine model of eosinophilic airway inflammation. J. Clin. Invest. 104, 1021–1029 (1999).
Hansen, G., Berry, G., Dekruyff, R.H. & Umetsu, D.T. Allergen-specific TH1 cells fail to counterbalance TH2 cell-induced airway hyperreactivity but cause severe airway inflammation. J. Clin. Invest. 103, 175–183 (1999).
Ford, J.G. et al. IL-13 and IFN-γ: Interactions in lung inflammation. J. Immunol. 167, 1769–1777 (2001).
Hessel, E.M. et al. Development of airway hyperresponsiveness is dependent on interferon-γ and independent of eosinophil infiltration. Am. J. Respir. Cell Mol. Biol. 16, 325–334 (1997).
Sugimoto, T. et al. Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse. J. Exp. Med. 199, 535–545 (2004).
Krug, N. et al. T-cell cytokine profile evaluated at the single cell level in BAL and blood in allergic asthma. Am. J. Respir. Cell Mol. Biol. 14, 319–326 (1996).
Corrigan, C.J. & Kay, A.B. CD4 T-lymphocyte activation in acute severe asthma. Am. Rev. Respir. Dis. 141, 970–977 (1990).
Schmitt, E. et al. IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF- and IL-4, and is inhibited by IFN-γ. J. Immunol. 153, 3989–3996 (1994).
O'Garra, A., Stockinger, B. & Veldhoen, M. Differentiation of human TH17 cells does require TGF-β!. Nat. Immunol. 9, 588–590 (2008).
Yao, W. et al. Interleukin-9 is required for allergic airway inflammation mediated by the cytokine TSLP. Immunity 38, 360–372 (2013).
Elyaman, W. et al. Notch receptors and Smad3 signaling cooperate in the induction of interleukin-9-producing T cells. Immunity 36, 623–634 (2012).
Xiao, X. et al. OX40 signaling favors the induction of TH9 cells and airway inflammation. Nat. Immunol. 13, 981–990 (2012).
Chang, H.C. et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat. Immunol. 11, 527–534 (2011).
Liao, W. et al. Opposing actions of IL-2 and IL-21 on TH9 differentiation correlate with their differential regulation of BCL6 expression. Proc. Natl. Acad. Sci. USA 111, 3508–3513 (2014).
Yang, X.O. et al. The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation. Nat. Immunol. 14, 732–740 (2013).
Staudt, V. et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33, 192–202 (2010).
Kearley, J. et al. IL-9 governs allergen-induced mast cell numbers in the lung and chronic remodeling of the airways. Am. J. Respir. Crit. Care Med. 183, 865–875 (2011).
Erpenbeck, V.J. et al. Segmental allergen challenge in patients with atopic asthma leads to increased IL-9 expression in bronchoalveolar lavage fluid lymphocytes. J. Allergy Clin. Immunol. 111, 1319–1327 (2003).
Kerzerho, J. et al. Programmed cell death ligand 2 regulates TH9 differentiation and induction of chronic airway hyperreactivity. J. Allergy Clin. Immunol. 131, 1048–1057 (2013).
Wilhelm, C. et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat. Immunol. 12, 1071–1077 (2011).
Turner, J.E. et al. IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J. Exp. Med. 210, 2951–2965 (2013).
Parker, J.M. et al. Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma. BMC Pulm. Med. 11, 14 (2011).
Ostroukhova, M. et al. Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3. J. Clin. Invest. 114, 28–38 (2004).
Josefowicz, S.Z. et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395–399 (2012).
Weiss, J.M. et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med. 209, 1723–1742 (2012).
Lewkowich, I.P. et al. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J. Exp. Med. 202, 1549–1561 (2005).
Huang, M.T. et al. Regulatory T cells negatively regulate neovasculature of airway remodeling via DLL4-Notch signaling. J. Immunol. 183, 4745–4754 (2009).
Whitehead, G.S. et al. IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J. Allergy Clin. Immunol. 129, 207–215 (2012).
Mamessier, E. et al. T-cell activation during exacerbations: a longitudinal study in refractory asthma. Allergy 63, 1202–1210 (2008).
Hartl, D. et al. Quantitative and functional impairment of pulmonary CD4+CD25hi regulatory T cells in pediatric asthma. J. Allergy Clin. Immunol. 119, 1258–1266 (2007).
Smyth, L.J., Eustace, A., Kolsum, U., Blaikely, J. & Singh, D. Increased airway T regulatory cells in asthmatic subjects. Chest 138, 905–912 (2010).
Barczyk, A. et al. Decreased percentage of CD4+Foxp3+TGF-β+ and increased percentage of CD4+IL-17+ cells in bronchoalveolar lavage of asthmatics. J. Inflamm. (Lond.) 11, 22 (2014).
Joller, N. et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory TH1 and TH17 cell responses. Immunity 40, 569–581 (2014).
Lambrecht, B.N. & Hammad, H. Lung dendritic cells in respiratory viral infection and asthma: from protection to immunopathology. Annu. Rev. Immunol. 30, 243–270 (2012).
Plantinga, M. et al. Conventional and monocyte-derived CD11b+ dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity 38, 322–335 (2013).
Williams, J.W. et al. Transcription factor IRF4 drives dendritic cells to promote TH2 differentiation. Nat. Commun. 4, 2990 (2013).
Raymond, M. et al. Selective control of SIRP-α-positive airway dendritic cell trafficking through CD47 is critical for the development of TH2-mediated allergic inflammation. J. Allergy Clin. Immunol. 124, 1333–1342 (2009).
Semmrich, M. et al. Directed antigen targeting in vivo identifies a role for CD103+ dendritic cells in both tolerogenic and immunogenic T-cell responses. Mucosal Immunol. 5, 150–160 (2012).
Khare, A. et al. Cutting edge: inhaled antigen upregulates retinaldehyde dehydrogenase in lung CD103+ but not plasmacytoid dendritic cells to induce Foxp3 de novo in CD4+ T cells and promote airway tolerance. J. Immunol. 191, 25–29 (2013).
de Heer, H.J. et al. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J. Exp. Med. 200, 89–98 (2004).
Kool, M. et al. An anti-inflammatory role for plasmacytoid dendritic cells in allergic airway inflammation. J. Immunol. 183, 1074–1082 (2009).
Lambrecht, B.N. & Hammad, H. The airway epithelium in asthma. Nat. Med. 18, 684–692 (2012).
Millien, V.O. et al. Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4. Science 341, 792–796 (2013).
Hammad, H. et al. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat. Med. 15, 410–416 (2009).
Willart, M.A. et al. Interleukin-1α controls allergic sensitization to inhaled house dust mite via the epithelial release of GM-CSF and IL-33. J. Exp. Med. 209, 1505–1517 (2012).
Herre, J. et al. Allergens as immunomodulatory proteins: the cat dander protein Fel d 1 enhances TLR activation by lipid ligands. J. Immunol. 191, 1529–1535 (2013).
Kool, M. et al. 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 (2011).
Idzko, M. et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat. Med. 13, 913–919 (2007).
Ullah, M.A. et al. Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation. J. Allergy Clin. Immunol. 134, 440–450 (2014).
Barrett, N.A. et al. Dectin-2 mediates TH2 immunity through the generation of cysteinyl leukotrienes. J. Exp. Med. 208, 593–604 (2011).
Norimoto, A. et al. Dectin-2 promotes house dust mite-induced TH2 and TH17 cell differentiation and allergic airway inflammation in mice. Am. J. Respir. Cell Mol. Biol. 51, 201–209 (2014).
Besnard, A.G. et al. IL-33-activated dendritic cells are critical for allergic airway inflammation. Eur. J. Immunol. 41, 1675–1686 (2011).
Bell, B.D. et al. The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses. Nat. Immunol. 14, 364–371 (2013).
Chu, D.K. et al. IL-33, but not thymic stromal lymphopoietin or IL-25, is central to mite and peanut allergic sensitization. J. Allergy Clin. Immunol. 131, 187–200 (2013).
Huh, J.C. et al. Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma. J. Exp. Med. 198, 19–30 (2003).
Thornton, E.E. et al. Spatiotemporally separated antigen uptake by alveolar dendritic cells and airway presentation to T cells in the lung. J. Exp. Med. 209, 1183–1199 (2012).
van Rijt, L.S. et al. in vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med. 201, 981–991 (2005).
van Rijt, L.S. et al. Persistent activation of dendritic cells after resolution of allergic airway inflammation breaks tolerance to inhaled allergens in mice. Am. J. Respir. Crit. Care Med. 184, 303–311 (2011).
Gauvreau, G.M. et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N. Engl. J. Med. 370, 2102–2110 (2014).
Yu, M. et al. Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma. J. Clin. Invest. 121, 3133–3143 (2011).
Heger, K. et al. A20-deficient mast cells exacerbate inflammatory responses in vivo. PLoS Biol. 12, e1001762 (2014).
Williams, C.M. & Galli, S.J. Mast cells can amplify airway reactivity and features of chronic inflammation in an asthma model in mice. J. Exp. Med. 192, 455–462 (2000).
Motomura, Y. et al. Basophil-derived interleukin-4 controls the function of natural helper cells, a member of ILC2s, in lung inflammation. Immunity 40, 758–771 (2014).
Brightling, C.E. et al. Mast-cell infiltration of airway smooth muscle in asthma. N. Engl. J. Med. 346, 1699–1705 (2002).
Dougherty, R.H. et al. Accumulation of intraepithelial mast cells with a unique protease phenotype in TH2-high asthma. J. Allergy Clin. Immunol. 125, 1046–1053 (2010).
Hammad, H. et al. 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 (2010).
Tang, H. et al. The T helper type 2 response to cysteine proteases requires dendritic cell-basophil cooperation via RAS-mediated signaling. Nat. Immunol. 11, 608–617 (2010).
Ohnmacht, C. et al. Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity 33, 364–374 (2010).
Wakahara, K. et al. Basophils are recruited to inflamed lungs and exacerbate memory TH2 responses in mice and humans. Allergy 68, 180–189 (2013).
Holgate, S., Smith, N., Massanari, M. & Jimenez, P. Effects of omalizumab on markers of inflammation in patients with allergic asthma. Allergy 64, 1728–1736 (2009).
Maurer, D. et al. Peripheral blood dendritic cells express Fc ɛ RI as a complex composed of Fc ɛ RI α- and Fc ɛ RI γ-chains and can use this receptor for IgE-mediated allergen presentation. J. Immunol. 157, 607–616 (1996).
Bieber, T. et al. Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (Fc ɛ RI). J. Exp. Med. 175, 1285–1290 (1992).
Maurer, D. et al. Fc ɛ receptor I on dendritic cells delivers IgE-bound multivalent antigens into a cathepsin S-dependent pathway of MHC class II presentation. J. Immunol. 161, 2731–2739 (1998).
Khan, S.H. & Grayson, M.H. Cross-linking IgE augments human conventional dendritic cell production of CC chemokine ligand 28. J. Allergy Clin. Immunol. 125, 265–267 (2010).
Sallmann, E. et al. High-affinity IgE receptors on dendritic cells exacerbate TH2-dependent inflammation. J. Immunol. 187, 164–171 (2011).
Grayson, M.H. et al. Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J. Exp. Med. 204, 2759–2769 (2007).
Novak, N., Bieber, T. & Katoh, N. Engagement of Fc ɛ RI on human monocytes induces the production of IL-10 and prevents their differentiation in dendritic cells. J. Immunol. 167, 797–804 (2001).
Platzer, B. et al. Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites. Mucosal Immunol. doi:10.1038/mi.2014.85 (17 September 2014).
Jackson, D.J. et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am. J. Respir. Crit. Care Med. 178, 667–672 (2008).
Calşkan, M. et al. Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. N. Engl. J. Med. 368, 1398–1407 (2013).
Papi, A. et al. Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor κB and c-Jun N-terminal kinase activation. J. Allergy Clin. Immunol. 132, 1075–1085 (2013).
Zhu, J. et al. Airway inflammation and illness severity in response to experimental rhinovirus infection in asthma. Chest 145, 1219–1229 (2014).
Bartlett, N.W. et al. Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation. Nat. Med. 14, 199–204 (2008).
Collison, A. et al. The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity. Nat. Med. 19, 232–237 (2013).
Kim, E.Y. et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat. Med. 14, 633–640 (2008).
Kaiko, G.E. et al. Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice. J. Allergy Clin. Immunol. 131, 1331–1339 (2013).
Wark, P.A. et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J. Exp. Med. 201, 937–947 (2005).
Contoli, M. et al. Role of deficient type III interferon-λ production in asthma exacerbations. Nat. Med. 12, 1023–1026 (2006).
Edwards, M.R. et al. Impaired innate interferon induction in severe therapy resistant atopic asthmatic children. Mucosal Immunol. 6, 797–806 (2013).
Kennedy, J.L. et al. Comparison of viral load in individuals with and without asthma during infections with rhinovirus. Am. J. Respir. Crit. Care Med. 189, 532–539 (2014).
Bochkov, Y.A. et al. Rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma. Mucosal Immunol. 3, 69–80 (2010).
Spann, K.M. et al. Viral and host factors determine innate immune responses in airway epithelial cells from children with wheeze and atopy. Thorax 69, 918–925 (2014).
Durrani, S.R. et al. Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children. J. Allergy Clin. Immunol. 130, 489–495 (2012).
Gill, M.A. et al. Counterregulation between the FcɛRI pathway and antiviral responses in human plasmacytoid dendritic cells. J. Immunol. 184, 5999–6006 (2010).
Tversky, J.R. et al. Human blood dendritic cells from allergic subjects have impaired capacity to produce interferon-α via Toll-like receptor 9. Clin. Exp. Allergy 38, 781–788 (2008).
Mathur, S.K. et al. Interaction between allergy and innate immunity: model for eosinophil regulation of epithelial cell interferon expression. Ann. Allergy Asthma Immunol. 111, 25–31 (2013).
Osborne, L.C. et al. Coinfection. Virus-helminth coinfection reveals a microbiota-independent mechanism of immunomodulation. Science 345, 578–582 (2014).
Ober, C. et al. Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function. N. Engl. J. Med. 358, 1682–1691 (2008).
Djukanovicć´, R. et al. The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. A randomized trial. Am. J. Respir. Crit. Care Med. 190, 145–154 (2014).
Brusselle, G.G., Maes, T. & Bracke, K.R. Eosinophils in the spotlight: eosinophilic airway inflammation in nonallergic asthma. Nat. Med. 19, 977–979 (2013).
Supported by the European Union European Research Council (B.N.L.), the European Union Framework Programme 7 (MedALL and EUBIOPRED to B.N.L.), the University of Ghent Multidisciplinary Research Platform (Group-ID, to B.N.L.) and Fonds Wetenschappelijk Onderzoek Vlaanderen (B.N.L. and H.H.).
The authors declare no competing financial interests.
About this article
Cite this article
Lambrecht, B., Hammad, H. The immunology of asthma. Nat Immunol 16, 45–56 (2015). https://doi.org/10.1038/ni.3049
This article is cited by
Nature Communications (2022)
Nature Cardiovascular Research (2022)
Mucosal Immunology (2022)
Effects of human adipose tissue- and bone marrow-derived mesenchymal stem cells on airway inflammation and remodeling in a murine model of chronic asthma
Scientific Reports (2022)
FoxO1 suppresses IL-10 producing B cell differentiation via negatively regulating Blimp-1 expression and contributes to allergic asthma progression
Mucosal Immunology (2022)