Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The immunology of asthma and chronic rhinosinusitis

Nature Reviews Immunology volume 25, pages 569–587 (2025)Cite this article

Subjects

Abstract

Asthma and chronic rhinosinusitis (CRS) are common chronic inflammatory diseases of the respiratory tract that have increased in prevalence over the past five decades. The clinical relationship between asthma and CRS has been well recognized, suggesting a common pathogenesis between these diseases. Both diseases are driven by complex airway epithelial cell and immune cell interactions that occur in response to environmental triggers such as allergens, microorganisms and irritants. Advances, including a growing understanding of the biology of the cells involved in the disease, the application of multiomics technologies and the performance of large-scale clinical studies, have led to a better understanding of the pathophysiology and heterogeneity of asthma and CRS. This research has promoted the concept that these diseases consist of several endotypes, in which airway epithelial cells, innate lymphoid cells, T cells, B cells, granulocytes and their mediators are distinctly involved in the immunopathology. Identification of the disease heterogeneity and immunological markers has also greatly improved the protocols for biologic therapies and the clinical outcomes in certain subsets of patients. However, many clinical and research questions remain. In this Review, we discuss recent advances in characterizing the immunological mechanisms of asthma and CRS, with a focus on the main cell types and molecules involved in these diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Roles and alterations in the epithelium in asthma and CRS.
Fig. 2: Immunological mechanisms of type 2 asthma and chronic rhinosinusitis.
Fig. 3: Immunological mechanisms of non-type 2 asthma and chronic rhinosinusitis.

Similar content being viewed by others

References

  1. Eder, W., Ege, M. J. & von Mutius, E. The asthma epidemic. N. Engl. J. Med. 355, 2226–2235 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396, 1204–1222 (2020).

  3. Bai, T. R., Vonk, J. M., Postma, D. S. & Boezen, H. M. Severe exacerbations predict excess lung function decline in asthma. Eur. Respir. J. 30, 452–456 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Nurmagambetov, T., Kuwahara, R. & Garbe, P. The economic burden of asthma in the United States, 2008-2013. Ann. Am. Thorac. Soc. 15, 348–356 (2018).

    Article  PubMed  Google Scholar 

  5. Meltzer, E. O. et al. Rhinosinusitis: establishing definitions for clinical research and patient care. J. Allergy Clin. Immunol. 114, 155–212 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hirsch, A. G. et al. Radiologic sinus inflammation and symptoms of chronic rhinosinusitis in a population-based sample. Allergy 75, 911–920 (2020).

    Article  CAS  PubMed  Google Scholar 

  7. Orlandi, R. R. et al. International consensus statement on allergy and rhinology: rhinosinusitis 2021. Int. Forum Allergy Rhinol. 11, 213–739 (2021).

    Article  PubMed  Google Scholar 

  8. Bachert, C., Bhattacharyya, N., Desrosiers, M. & Khan, A. H. Burden of disease in chronic rhinosinusitis with nasal polyps. J. Asthma Allergy 14, 127–134 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Laidlaw, T. M. & Boyce, J. A. Aspirin-exacerbated respiratory disease-new prime suspects. N. Engl. J. Med. 374, 484–488 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Cohn, L., Elias, J. A. & Chupp, G. L. Asthma: mechanisms of disease persistence and progression. Annu. Rev. Immunol. 22, 789–815 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Guarnieri, M. & Balmes, J. R. Outdoor air pollution and asthma. Lancet 383, 1581–1592 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Akdis, C. A. Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions? Nat. Rev. Immunol. 21, 739–751 (2021).

    Article  CAS  PubMed  Google Scholar 

  13. Moffatt, M. F. et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pividori, M., Schoettler, N., Nicolae, D. L., Ober, C. & Im, H. K. Shared and distinct genetic risk factors for childhood-onset and adult-onset asthma: genome-wide and transcriptome-wide studies. Lancet Respir. Med. 7, 509–522 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kaur, R. & Chupp, G. Phenotypes and endotypes of adult asthma: moving toward precision medicine. J. Allergy Clin. Immunol. 144, 1–12 (2019).

    Article  PubMed  Google Scholar 

  16. Ray, A., Camiolo, M., Fitzpatrick, A., Gauthier, M. & Wenzel, S. E. Are we meeting the promise of endotypes and precision medicine in asthma? Physiol. Rev. 100, 983–1017 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bleecker, E. R. et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur. Respir. J. 52, 1800936 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gauvreau, G. M. et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N. Engl. J. Med. 370, 2102–2110 (2014).

    Article  PubMed  Google Scholar 

  19. Wenzel, S., Wilbraham, D., Fuller, R., Getz, E. B. & Longphre, M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 370, 1422–1431 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Agache, I., Akdis, C., Jutel, M. & Virchow, J. C. Untangling asthma phenotypes and endotypes. Allergy 67, 835–846 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Peters, M. C. et al. Evidence for exacerbation-prone asthma and predictive biomarkers of exacerbation frequency. Am. J. Respir. Crit. Care Med. 202, 973–982 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Östling, J. et al. IL-17-high asthma with features of a psoriasis immunophenotype. J. Allergy Clin. Immunol. 144, 1198–1213 (2019).

    Article  PubMed  Google Scholar 

  23. Liu, W. et al. Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma. J. Allergy Clin. Immunol. 139, 1548–1558.e4 (2017).

    Article  CAS  PubMed  Google Scholar 

  24. Raundhal, M. et al. High IFN-γ and low SLPI mark severe asthma in mice and humans. J. Clin. Invest. 125, 3037–3050 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Won, H. K. et al. Age-related prevalence of chronic rhinosinusitis and nasal polyps and their relationships with asthma onset. Ann. Allergy Asthma Immunol. 120, 389–394 (2018).

    Article  PubMed  Google Scholar 

  26. Hamilos, D. L. et al. Evidence for distinct cytokine expression in allergic versus nonallergic chronic sinusitis. J. Allergy Clin. Immunol. 96, 537–544 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Van Zele, T. et al. Differentiation of chronic sinus diseases by measurement of inflammatory mediators. Allergy 61, 1280–1289 (2006).

    Article  PubMed  Google Scholar 

  28. Poposki, J. A. et al. Elevation of activated neutrophils in chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 149, 1666–1674 (2022).

    Article  CAS  PubMed  Google Scholar 

  29. Stevens, W. W. et al. Associations between inflammatory endotypes and clinical presentations in chronic rhinosinusitis. J. Allergy Clin. Immunol. Pract. 7, 2812–2820.e3 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Wang, X. et al. Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: a multicenter study in Europe, Asia, and Oceania. J. Allergy Clin. Immunol. 138, 1344–1353 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Lou, H., Zhang, N., Bachert, C. & Zhang, L. Highlights of eosinophilic chronic rhinosinusitis with nasal polyps in definition, prognosis, and advancement. Int. Forum Allergy Rhinol. 8, 1218–1225 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Tomassen, P. et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J. Allergy Clin. Immunol. 137, 1449–1456.e4 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Lal, D. et al. Genetics and epigenetics of chronic rhinosinusitis. J. Allergy Clin. Immunol. 151, 848–868 (2023).

    Article  CAS  PubMed  Google Scholar 

  34. Rackley, C. R. & Stripp, B. R. Building and maintaining the epithelium of the lung. J. Clin. Invest. 122, 2724–2730 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Krausgruber, T. et al. Structural cells are key regulators of organ-specific immune responses. Nature 583, 296–302 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Saglani, S. et al. Inception of early-life allergen-induced airway hyperresponsiveness is reliant on IL-13+CD4+ T cells. Sci Immunol 3, eaan4128 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Zhu, Z. et al. Nasopharyngeal airway dual-transcriptome of infants with severe bronchiolitis and risk of childhood asthma: a multicenter prospective study. J. Allergy Clin. Immunol. 150, 806–816 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ebina-Shibuya, R. & Leonard, W. J. Role of thymic stromal lymphopoietin in allergy and beyond. Nat. Rev. Immunol. 23, 24–37 (2023).

    Article  CAS  PubMed  Google Scholar 

  39. Andreasson, L. M. et al. Airway hyperresponsiveness correlates with airway TSLP in asthma independent of eosinophilic inflammation. J. Allergy Clin. Immunol. 153, 988–997.e11 (2024).

    Article  CAS  PubMed  Google Scholar 

  40. Dwyer, G. K., D’Cruz, L. M. & Turnquist, H. R. Emerging functions of IL-33 in homeostasis and immunity. Annu. Rev. Immunol. 40, 15–43 (2022).

    Article  CAS  PubMed  Google Scholar 

  41. Lloyd, C. M. IL-33 family members and asthma — bridging innate and adaptive immune responses. Curr. Opin. Immunol. 22, 800–806 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kobayashi, T., Iijima, K., Checkel, J. L. & Kita, H. IL-1 family cytokines drive Th2 and Th17 cells to innocuous airborne antigens. Am. J. Respir. Cell Mol. Biol. 49, 989–998 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Xu, M. & Dong, C. IL-25 in allergic inflammation. Immunol. Rev. 278, 185–191 (2017).

    Article  CAS  PubMed  Google Scholar 

  44. Borowczyk, J., Shutova, M., Brembilla, N. C. & Boehncke, W. H. IL-25 (IL-17E) in epithelial immunology and pathophysiology. J. Allergy Clin. Immunol. 148, 40–52 (2021).

    Article  CAS  PubMed  Google Scholar 

  45. Bankova, L. G. et al. The cysteinyl leukotriene 3 receptor regulates expansion of IL-25-producing airway brush cells leading to type 2 inflammation. Sci. Immunol. 3, eaat9453 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Van Dyken, S. J. et al. A tissue checkpoint regulates type 2 immunity. Nat. Immunol. 17, 1381–1387 (2016). This paper provides insight into how epithelium-derived cytokines, including TSLP, IL-33 and IL-25, affect type 2 immunity and lung inflammation.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Vannella, K. M. et al. Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis. Sci. Transl. Med. 8, 337ra365 (2016).

    Article  Google Scholar 

  48. Kato, A., Schleimer, R. P. & Bleier, B. S. Mechanisms and pathogenesis of chronic rhinosinusitis. J. Allergy Clin. Immunol. 149, 1491–1503 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kato, A., Favoreto, S. Jr, Avila, P. C. & Schleimer, R. P. TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells. J. Immunol. 179, 1080–1087 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Nadjsombati, M. S. et al. Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit. Immunity 49, 33–41.e7 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Arifuzzaman, M. et al. Inulin fibre promotes microbiota-derived bile acids and type 2 inflammation. Nature 611, 578–584 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gandhi, V. D., Shrestha Palikhe, N. & Vliagoftis, H. Protease-activated receptor-2: Role in asthma pathogenesis and utility as a biomarker of disease severity. Front. Med. 9, 954990 (2022).

    Article  Google Scholar 

  54. Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020).

    Article  CAS  PubMed  Google Scholar 

  55. Uchida, M. et al. Oxidative stress serves as a key checkpoint for IL-33 release by airway epithelium. Allergy 72, 1521–1531 (2017).

    Article  CAS  PubMed  Google Scholar 

  56. Srisomboon, Y. et al. Airway exposure to polyethyleneimine nanoparticles induces type 2 immunity by a mechanism involving oxidative stress and ATP release. Int. J. Mol. Sci. 22, 9017 (2021).

    Article  Google Scholar 

  57. Perdijk, O. et al. Antibiotic-driven dysbiosis in early life disrupts indole-3-propionic acid production and exacerbates allergic airway inflammation in adulthood. Immunity 57, 1939–1954.e7 (2024).

    Article  CAS  PubMed  Google Scholar 

  58. Weng, C. M. et al. Aryl hydrocarbon receptor activation by diesel exhaust particles mediates epithelium-derived cytokines expression in severe allergic asthma. Allergy 73, 2192–2204 (2018).

    Article  CAS  PubMed  Google Scholar 

  59. O’Grady, S. M. & Kita, H. ATP functions as a primary alarmin in allergen-induced type 2 immunity. Am. J. Physiol. Cell Physiol 325, C1369–C1386 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Kouzaki, H., Iijima, K., Kobayashi, T., O’Grady, S. M. & 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. 186, 4375–4387 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Ualiyeva, S. et al. Airway brush cells generate cysteinyl leukotrienes through the ATP sensor P2Y2. Sci. Immunol. 5, eaax7224 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen, W. et al. Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion. Nat. Immunol. 23, 1021–1030 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Brusilovsky, M. et al. Environmental allergens trigger type 2 inflammation through ripoptosome activation. Nat. Immunol. 22, 1316–1326 (2021). Along with Chen et al. (2022), illustrates how airway epithelium responds to allergen exposure and releases IL-33 into the extracellular space.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang, B. F. et al. Evidence that oncostatin M synergizes with IL-4 signaling to induce TSLP expression in chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 151, 1379–1390.e11 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nagarkar, D. R. et al. Airway epithelial cells activate TH2 cytokine production in mast cells through IL-1 and thymic stromal lymphopoietin. J. Allergy Clin. Immunol. 130, 225–232.e4 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Aegerter, H. & Lambrecht, B. N. The pathology of asthma: what is obstructing our view? Annu. Rev. Pathol. 18, 387–409 (2023).

    Article  CAS  PubMed  Google Scholar 

  67. Contoli, M. et al. Role of deficient type III interferon-λ production in asthma exacerbations. Nat. Med. 12, 1023–1026 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Jin, M. et al. Real-time imaging of asthmatic epithelial cells identifies migratory deficiencies under type-2 conditions. J. Allergy Clin. Immunol. 149, 579–588 (2022).

    Article  CAS  PubMed  Google Scholar 

  69. Tieu, D. D., Kern, R. C. & Schleimer, R. P. Alterations in epithelial barrier function and host defense responses in chronic rhinosinusitis. J. Allergy Clin. Immunol. 124, 37–42 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Alladina, J. et al. A human model of asthma exacerbation reveals transcriptional programs and cell circuits specific to allergic asthma. Sci. Immunol. 8, eabq6352 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Jackson, N. D. et al. Single-cell and population transcriptomics reveal pan-epithelial remodeling in type 2-high asthma. Cell Rep. 32, 107872 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ordovas-Montanes, J. et al. Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560, 649–654 (2018). This study provides insight into how type 2 airway inflammation modifies the function and composition of respiratory epithelium in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kotas, M. E. et al. IL-13-associated epithelial remodeling correlates with clinical severity in nasal polyposis. J. Allergy Clin. Immunol. 151, 1277–1285 (2023). This study provides evidence that IL-13 responses in epithelial cells are associated with epithelial cell subsets and clinical severity of patients with chronic rhinosinusitis with nasal polyps.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Takabayashi, T. et al. Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression. Am. J. Respir. Crit. Care Med. 187, 49–57 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Chen, C. L. et al. Common fibrin deposition and tissue plasminogen activator downregulation in nasal polyps with distinct inflammatory endotypes. J. Allergy Clin. Immunol. 146, 677–681 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Xu, Z. et al. The multi-omics single-cell landscape of sinus mucosa in uncontrolled severe chronic rhinosinusitis with nasal polyps. Clin. Immunol. 256, 109791 (2023).

    Article  CAS  PubMed  Google Scholar 

  77. Nakajima, T. et al. ACC1-expressing pathogenic T helper 2 cell populations facilitate lung and skin inflammation in mice. J. Exp. Med. 218, e20210639 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zou, X. et al. Hypoxia-inducible factor 2α promotes pathogenic polarization of stem-like Th2 cells via modulation of phospholipid metabolism.Immunity 57, 2808–2826.e8 (2024).

    Article  CAS  PubMed  Google Scholar 

  79. Morimoto, Y. et al. Amphiregulin-producing pathogenic memory T helper 2 cells instruct eosinophils to secrete osteopontin and facilitate airway fibrosis. Immunity 49, 134–150.e6 (2018).

    Article  CAS  PubMed  Google Scholar 

  80. Onrust-van Schoonhoven, A. et al. 3D chromatin reprogramming primes human memory TH2 cells for rapid recall and pathogenic dysfunction. Sci. Immunol. 8, eadg3917 (2023).

    Article  CAS  PubMed  Google Scholar 

  81. Wambre, E. et al. A phenotypically and functionally distinct human TH2 cell subpopulation is associated with allergic disorders. Sci. Transl. Med. 9, eaam9171 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Seumois, G. et al. Single-cell transcriptomic analysis of allergen-specific T cells in allergy and asthma. Sci. Immunol. 5, eaba6087 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Vieira Braga, F. A. et al. A cellular census of human lungs identifies novel cell states in health and in asthma. Nat. Med. 25, 1153–1163 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Tibbitt, C. A. et al. Single-cell RNA sequencing of the T helper cell response to house dust mites defines a distinct gene expression signature in airway Th2 cells. Immunity 51, 169–184.e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  85. Ma, J. et al. Single-cell analysis pinpoints distinct populations of cytotoxic CD4+ T cells and an IL-10+CD109+ TH2 cell population in nasal polyps. Sci. Immunol. 6, eabg6356 (2021). Along with Wambre et al. (2017), Seumois et al. (2020), Vieira Braga et al. (2019) and Tibbitt et al. (2019), demonstrates heterogeneity of antigen-specific TH2 cells and their contribution to asthma and chronic rhinosinusitis.

    Article  CAS  PubMed  Google Scholar 

  86. Zhang, Y. N. et al. Nasal IL-4+CXCR5+CD4+ T follicular helper cell counts correlate with local IgE production in eosinophilic nasal polyps. J. Allergy Clin. Immunol. 137, 462–473 (2016).

    Article  CAS  PubMed  Google Scholar 

  87. Kaplan, M. H., Hufford, M. M. & Olson, M. R. The development and in vivo function of T helper 9 cells. Nat. Rev. Immunol. 15, 295–307 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Micossé, C. et al. Human “TH9” cells are a subpopulation of PPAR-γ+ TH2 cells. Sci. Immunol. 4, eaat5943 (2019).

    Article  PubMed  Google Scholar 

  89. Fu, Y. et al. An IL-9-pulmonary macrophage axis defines the allergic lung inflammatory environment. Sci. Immunol. 7, eabi9768 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bick, F. et al. Interleukin-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma. J. Allergy Clin. Immunol. 154, 1129–1145 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Masopust, D. & Soerens, A. G. Tissue-resident T cells and other resident leukocytes. Annu. Rev. Immunol. 37, 521–546 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Corris, P. A. & Dark, J. H. Aetiology of asthma: lessons from lung transplantation. Lancet 341, 1369–1371 (1993).

    Article  CAS  PubMed  Google Scholar 

  93. Ramirez, S. I. et al. Immunological memory diversity in the human upper airway. Nature 632, 630–636 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kobayashi, T., Iijima, K., Matsumoto, K., Lama, J. K. & Kita, H. Lung-resident CD69+ST2+ TH2 cells mediate long-term type 2 memory to inhaled antigen in mice. J. Allergy Clin. Immunol. 152, 167–181.e6 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hondowicz, B. D. et al. Interleukin-2-dependent allergen-specific tissue-resident memory cells drive asthma. Immunity 44, 155–166 (2016).

    Article  CAS  PubMed  Google Scholar 

  96. Dahlgren, M. W. et al. Adventitial stromal cells define group 2 innate lymphoid cell tissue niches. Immunity 50, 707–722.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Rahimi, R. A., Nepal, K., Cetinbas, M., Sadreyev, R. I. & Luster, A. D. Distinct functions of tissue-resident and circulating memory Th2 cells in allergic airway disease. J. Exp. Med. 217, e20190865 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  98. He, K. et al. Spatial microniches of IL-2 combine with IL-10 to drive lung migratory TH2 cells in response to inhaled allergen. Nat. Immunol. 25, 2124–2139 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Cautivo, K. M. et al. Interferon gamma constrains type 2 lymphocyte niche boundaries during mixed inflammation. Immunity 55, 254–271.e7 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Branchett, W. J. et al. A T cell-myeloid IL-10 axis regulates pathogenic IFN-γ-dependent immunity in a mouse model of type 2-low asthma. J. Allergy Clin. Immunol. 145, 666–678.e9 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gauthier, M. et al. CCL5 is a potential bridge between type 1 and type 2 inflammation in asthma. J. Allergy Clin. Immunol. 152, 94–106.e12 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Camiolo, M. J. et al. High-dimensional profiling clusters asthma severity by lymphoid and non-lymphoid status. Cell Rep. 35, 108974 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rha, M. S. et al. Type 1/17 CD103+CD4+ nasal-resident memory T cells in non-eosinophilic chronic rhinosinusitis with nasal polyps. Allergy 79, 1996–1999 (2024).

    Article  CAS  PubMed  Google Scholar 

  104. Newcomb, D. C. & Peebles, R. S. Jr Th17-mediated inflammation in asthma. Curr. Opin. Immunol. 25, 755–760 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Bapat, S. P. et al. Obesity alters pathology and treatment response in inflammatory disease. Nature 604, 337–342 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Irvin, C. et al. Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J. Allergy Clin. Immunol. 134, 1175–1186.e7 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chowdhury, N. U. et al. Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation. J. Clin. Invest. 134, e177242 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Rha, M. S. et al. IL-17A-producing sinonasal MAIT cells in patients with chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 149, 599–609.e7 (2022).

    Article  CAS  PubMed  Google Scholar 

  110. Na, H. et al. Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor-related orphan receptor γt. J. Allergy Clin. Immunol. 141, 2061–2073.e5 (2018).

    Article  CAS  PubMed  Google Scholar 

  111. Choy, D. F. et al. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci. Transl. Med. 7, 301ra129 (2015).

    Article  PubMed  Google Scholar 

  112. Scharschmidt, T. C. et al. A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity 43, 1011–1021 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lloyd, C. M. & Hawrylowicz, C. M. Regulatory T cells in asthma. Immunity 31, 438–449 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Josefowicz, S. Z. et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395–399 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Faustino, L. D. et al. Interleukin-33 activates regulatory T cells to suppress innate γδ T cell responses in the lung. Nat. Immunol. 21, 1371–1383 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Chen, C. C., Kobayashi, T., Iijima, K., Hsu, F. C. & Kita, H. IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs. J. Allergy Clin. Immunol. 140, 1351–1363.e7 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Krishnamoorthy, N. et al. Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nat. Med. 18, 1525–1530 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kato, A., Hulse, K. E., Tan, B. K. & Schleimer, R. P. B-lymphocyte lineage cells and the respiratory system. J. Allergy Clin. Immunol. 131, 933–957 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hulse, K. E. et al. Chronic rhinosinusitis with nasal polyps is characterized by B-cell inflammation and EBV-induced protein 2 expression. J. Allergy Clin. Immunol. 131, 1075–1083 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Buchheit, K. M. et al. IL-5Rα marks nasal polyp IgG4- and IgE-expressing cells in aspirin-exacerbated respiratory disease. J. Allergy Clin. Immunol. 145, 1574–1584 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Bai, J. et al. Prognostic factors for polyp recurrence in chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 150, 352–361.e7 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Jarick, K. J. et al. Non-redundant functions of group 2 innate lymphoid cells. Nature 611, 794–800 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Spits, H. & Mjösberg, J. Heterogeneity of type 2 innate lymphoid cells. Nat. Rev. Immunol. 22, 701–712 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Bartemes, K. R. & Kita, H. Roles of innate lymphoid cells (ILCs) in allergic diseases: the 10-year anniversary for ILC2s. J. Allergy Clin. Immunol. 147, 1531–1547 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Sui, P. et al. Pulmonary neuroendocrine cells amplify allergic asthma responses. Science 360, eaan8546 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Sudo, T. et al. Group 2 innate lymphoid cells support hematopoietic recovery under stress conditions. J. Exp. Med. 218, e20200817 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Chi, L. et al. Sexual dimorphism in skin immunity is mediated by an androgen-ILC2-dendritic cell axis. Science 384, eadk6200 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Christianson, C. A. et al. Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33. J. Allergy Clin. Immunol. 136, 59–68.e14 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. von Moltke, J. et al. Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s. J. Exp. Med. 214, 27–37 (2017).

    Article  Google Scholar 

  132. Zhou, W. et al. COX inhibition increases Alternaria-induced pulmonary group 2 innate lymphoid cell responses and IL-33 release in mice. J. Immunol. 205, 1157–1166 (2020).

    Article  CAS  PubMed  Google Scholar 

  133. Stier, M. T. et al. Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin. J. Allergy Clin. Immunol. 138, 814–824.e1 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Liu, S. et al. Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: the role of thymic stromal lymphopoietin. J. Allergy Clin. Immunol. 141, 257–268.e6 (2018).

    Article  CAS  PubMed  Google Scholar 

  135. Liu, S. et al. Optimal identification of human conventional and nonconventional (CRTH2−IL7Rα−) ILC2s using additional surface markers. J. Allergy Clin. Immunol. 146, 390–405 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Poposki, J. A. et al. Group 2 innate lymphoid cells are elevated and activated in chronic rhinosinusitis with nasal polyps. Immun. Inflamm. Dis. 5, 233–243 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Tojima, I. et al. Group 2 innate lymphoid cells are increased in nasal polyps in patients with eosinophilic chronic rhinosinusitis. Clin. Immunol. 170, 1–8 (2016).

    Article  CAS  PubMed  Google Scholar 

  138. Eastman, J. J. et al. Group 2 innate lymphoid cells are recruited to the nasal mucosa in patients with aspirin-exacerbated respiratory disease. J. Allergy Clin. Immunol. 140, 101–108.e3 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Stevens, W. W. & Kato, A. Group 2 innate lymphoid cells in nasal polyposis. Ann. Allergy Asthma Immunol. 126, 110–117 (2021).

    Article  CAS  PubMed  Google Scholar 

  140. Buchheit, K. M. et al. Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease. J. Allergy Clin. Immunol. 137, 1566–1576.e5 (2016).

    Article  CAS  PubMed  Google Scholar 

  141. Ogasawara, N. et al. Role of RANK-L as a potential inducer of ILC2-mediated type 2 inflammation in chronic rhinosinusitis with nasal polyps. Mucosal Immunol. 13, 86–95 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Bernink, J. H. et al. c-Kit-positive ILC2s exhibit an ILC3-like signature that may contribute to IL-17-mediated pathologies. Nat. Immunol. 20, 992–1003 (2019).

    Article  CAS  PubMed  Google Scholar 

  143. Golebski, K. et al. Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response. Immunity 54, 291–307.e7 (2021). This paper provides insight into the heterogeneity of human ILC2s in response to allergen immunotherapy and their roles in clinical responses.

    Article  CAS  PubMed  Google Scholar 

  144. Califano, D. et al. Transcription factor Bcl11b controls identity and function of mature type 2 innate lymphoid cells. Immunity 43, 354–368 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Bal, S. M. et al. IL-1β, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs. Nat. Immunol. 17, 636–645 (2016).

    Article  CAS  PubMed  Google Scholar 

  146. Kato, A. Group 2 innate lymphoid cells in airway diseases. Chest 156, 141–149 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Filley, W. V., Holley, K. E., Kephart, G. M. & Gleich, G. J. Identification by immunofluorescence of eosinophil granule major basic protein in lung tissues of patients with bronchial asthma. Lancet 2, 11–16 (1982).

    Article  CAS  PubMed  Google Scholar 

  148. Gleich, G. J., Adolphson, C. R. & Leiferman, K. M. The biology of the eosinophilic leukocyte. Annu. Rev. Med. 44, 85–101 (1993).

    Article  CAS  PubMed  Google Scholar 

  149. Dunican, E. M. et al. Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J. Clin. Invest. 128, 997–1009 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Lee, J. J. et al. Defining a link with asthma in mice congenitally deficient in eosinophils. Science 305, 1773–1776 (2004).

    Article  CAS  PubMed  Google Scholar 

  151. Haldar, P. et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 360, 973–984 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Leung, C. et al. A novel air trapping segment score identifies opposing effects of obesity and eosinophilia on air trapping in asthma. Am. J. Respir. Crit. Care Med. 209, 1196–1207 (2024).

    Article  PubMed  Google Scholar 

  153. Gevaert, E. et al. Charcot-Leyden crystals promote neutrophilic inflammation in patients with nasal polyposis. J. Allergy Clin. Immunol. 145, 427–430.e4 (2020).

    Article  PubMed  Google Scholar 

  154. Persson, E. K. et al. Protein crystallization promotes type 2 immunity and is reversible by antibody treatment. Science 364, eaaw4295 (2019). This paper describes the roles of eosinophil CLC protein in promoting airway inflammation in asthma.

    Article  CAS  PubMed  Google Scholar 

  155. Liu, Z., Hong, J., Huang, X. & Wu, D. Olfactory cleft mucus galectin-10 predicts olfactory loss in chronic rhinosinusitis. Ann. Allergy Asthma Immunol. 130, 317–324.e1 (2023).

    Article  CAS  PubMed  Google Scholar 

  156. Ueki, S. et al. Eosinophil extracellular trap cell death-derived DNA traps: their presence in secretions and functional attributes. J. Allergy Clin. Immunol. 137, 258–267 (2016).

    Article  CAS  PubMed  Google Scholar 

  157. Choi, Y. et al. Eosinophil extracellular traps activate type 2 innate lymphoid cells through stimulating airway epithelium in severe asthma. Allergy 75, 95–103 (2020).

    Article  CAS  PubMed  Google Scholar 

  158. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Jacobsen, E. A., Lee, N. A. & Lee, J. J. Re-defining the unique roles for eosinophils in allergic respiratory inflammation. Clin. Exp. Allergy 44, 1119–1136 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. LeSuer, W. E. et al. Eosinophils promote effector functions of lung group 2 innate lymphoid cells in allergic airway inflammation in mice. J. Allergy Clin. Immunol. 152, 469–485.e10 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Drake, M. G. et al. Eosinophil and airway nerve interactions in asthma. J. Leukoc. Biol. 104, 61–67 (2018).

    Article  CAS  PubMed  Google Scholar 

  162. Mesnil, C. et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J. Clin. Invest. 126, 3279–3295 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Iwasaki, N. et al. Single cell RNA sequencing of human eosinophils from nasal polyps reveals eosinophil heterogeneity in chronic rhinosinusitis tissue. J. Allergy Clin. Immunol. 154, 952-964 (2024). This study performed scRNA-seq analysis successfully in human eosinophils and defined the single-cell transcriptome of eosinophils in tissue and peripheral blood.

    Article  CAS  PubMed  Google Scholar 

  164. Chupp, G. L. et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir. Med. 5, 390–400 (2017).

    Article  PubMed  Google Scholar 

  165. Han, J. K. et al. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir. Med. 9, 1141–1153 (2021).

    Article  CAS  PubMed  Google Scholar 

  166. Laidlaw, T. M. et al. Dexpramipexole depletes blood and tissue eosinophils in nasal polyps with no change in polyp size. Laryngoscope 129, E61–E66 (2019).

    Article  CAS  PubMed  Google Scholar 

  167. Lee, J. J. et al. Human versus mouse eosinophils: “that which we call an eosinophil, by any other name would stain as red”. J. Allergy Clin. Immunol. 130, 572–584 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Moore, W. C. et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J. Allergy Clin. Immunol. 133, 1557–1563.e5 (2014).

    Article  PubMed  Google Scholar 

  169. Sur, S. et al. Sudden-onset fatal asthma. A distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am. Rev. Respir. Dis. 148, 713–719 (1993).

    Article  CAS  PubMed  Google Scholar 

  170. Peters, M. C. et al. Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir. Med. 4, 574–584 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Robinson, P. F. M. et al. Lower airway microbiota associates with inflammatory phenotype in severe preschool wheeze. J. Allergy Clin. Immunol. 143, 1607–1610.e3 (2019).

    Article  PubMed  Google Scholar 

  172. Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 18, 134–147 (2018).

    Article  CAS  PubMed  Google Scholar 

  173. Siwicki, M. & Kubes, P. Neutrophils in host defense, healing, and hypersensitivity: dynamic cells within a dynamic host. J. Allergy Clin. Immunol. 151, 634–655 (2023).

    Article  CAS  PubMed  Google Scholar 

  174. Toussaint, M. et al. Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation. Nat. Med. 23, 681–691 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Krishnamoorthy, N. et al. Neutrophil cytoplasts induce TH17 differentiation and skew inflammation toward neutrophilia in severe asthma. Sci. Immunol. 3, eaao4747 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  176. 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).

    Article  CAS  PubMed  Google Scholar 

  177. O’Byrne, P. M. et al. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir. Med. 4, 797–806 (2016).

    Article  PubMed  Google Scholar 

  178. Chalmers, J. D. et al. Phase 2 trial of the DPP-1 inhibitor brensocatib in bronchiectasis. N. Engl. J. Med. 383, 2127–2137 (2020).

    Article  CAS  PubMed  Google Scholar 

  179. Takabayashi, T. et al. Glandular mast cells with distinct phenotype are highly elevated in chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 130, 410–420.e5 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Galli, S. J. & Tsai, M. IgE and mast cells in allergic disease. Nat. Med. 18, 693–704 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Allakhverdi, Z. et al. 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 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Dwyer, D. F. et al. Human airway mast cells proliferate and acquire distinct inflammation-driven phenotypes during type 2 inflammation. Sci. Immunol. 6, eabb7221 (2021). This study reveals the proliferation of mast cells in nasal polys and links mast cell subsets with phenotypes of type 2 airway inflammation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Casale, T. B. et al. Omalizumab effectiveness by biomarker status in patients with asthma: evidence from PROSPERO, a prospective real-world study. J. Allergy Clin. Immunol. Pract. 7, 156–164.e1 (2019).

    Article  PubMed  Google Scholar 

  184. Gevaert, P. et al. Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials. J. Allergy Clin. Immunol. 146, 595–605 (2020).

    Article  CAS  PubMed  Google Scholar 

  185. Bousquet, J. et al. Real-world effectiveness of omalizumab in severe allergic asthma: a meta-analysis of observational studies. J. Allergy Clin. Immunol. Pract. 9, 2702–2714 (2021).

    Article  CAS  PubMed  Google Scholar 

  186. Leckie, M. J. et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356, 2144–2148 (2000).

    Article  CAS  PubMed  Google Scholar 

  187. Pilette, C. et al. REALITI-a study: real-world oral corticosteroid-sparing effect of mepolizumab in severe asthma. J. Allergy Clin. Immunol. Pract. 10, 2646–2656 (2022).

    Article  CAS  PubMed  Google Scholar 

  188. Bjermer, L. et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest 150, 789–798 (2016).

    Article  PubMed  Google Scholar 

  189. Ibrahim, H. et al. The effectiveness of reslizumab in severe asthma treatment: a real-world experience. Respir. Res. 20, 289 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. FitzGerald, J. M. et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 388, 2128–2141 (2016).

    Article  CAS  PubMed  Google Scholar 

  191. Bachert, C. et al. Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: a randomized, placebo-controlled trial. J. Allergy Clin. Immunol. 149, 1309–1317.e12 (2022).

    Article  CAS  PubMed  Google Scholar 

  192. Castro, M. et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N. Engl. J. Med. 378, 2486–2496 (2018). This study shows the efficacy and safety of blocking the IL-4Rα pathway to treat patients with severe asthma.

    Article  CAS  PubMed  Google Scholar 

  193. Domingo, C. et al. Dupilumab efficacy in steroid-dependent severe asthma by baseline oral corticosteroid dose. J. Allergy Clin. Immunol. Pract. 10, 1835–1843 (2022).

    Article  CAS  PubMed  Google Scholar 

  194. Hanania, N. A. et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir. Med. 4, 781–796 (2016).

    Article  CAS  PubMed  Google Scholar 

  195. Panettieri, R. A. Jr et al. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respir. Med. 6, 511–525 (2018).

    Article  CAS  PubMed  Google Scholar 

  196. Bachert, C. et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet 394, 1638–1650 (2019).

    Article  CAS  PubMed  Google Scholar 

  197. Brightling, C. E., Nair, P., Cousins, D. J., Louis, R. & Singh, D. Risankizumab in severe asthma — a phase 2a, placebo-controlled trial. N. Engl. J. Med. 385, 1669–1679 (2021).

    Article  CAS  PubMed  Google Scholar 

  198. Oh, C. K. et al. A randomized, controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma. Respir. Res. 14, 93 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Corren, J. et al. Tezepelumab in adults with uncontrolled asthma. N. Engl. J. Med. 377, 936–946 (2017).

    Article  CAS  PubMed  Google Scholar 

  200. Menzies-Gow, A. et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N. Engl. J. Med. 384, 1800–1809 (2021). This study shows that TSLP-targeting therapy is beneficial to treat both TH2high and TH2low patients with asthma.

    Article  CAS  PubMed  Google Scholar 

  201. Wechsler, M. E. et al. Efficacy and safety of itepekimab in patients with moderate-to-severe asthma. N. Engl. J. Med. 385, 1656–1668 (2021).

    Article  CAS  PubMed  Google Scholar 

  202. Kelsen, S. G. et al. Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: a randomized clinical trial. J. Allergy Clin. Immunol. 148, 790–798 (2021).

    Article  CAS  PubMed  Google Scholar 

  203. Pavord, I. D. et al. After asthma: redefining airways diseases. Lancet 391, 350–400 (2018).

    Article  PubMed  Google Scholar 

  204. Bangert, C. et al. Persistence of mature dendritic cells, TH2A, and Tc2 cells characterize clinically resolved atopic dermatitis under IL-4Rα blockade. Sci. Immunol. 6, eabe2749 (2021).

    Article  CAS  PubMed  Google Scholar 

  205. Sampath, V., Aguilera, J., Prunicki, M. & Nadeau, K. C. Mechanisms of climate change and related air pollution on the immune system leading to allergic disease and asthma. Semin. Immunol. 67, 101765 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Menzies-Gow, A. et al. Long-term safety and efficacy of tezepelumab in people with severe, uncontrolled asthma (DESTINATION): a randomised, placebo-controlled extension study. Lancet Respir. Med. 11, 425–438 (2023).

    Article  CAS  PubMed  Google Scholar 

  207. Laidlaw, T. M. et al. Tezepelumab efficacy in patients with severe, uncontrolled asthma with comorbid nasal polyps in NAVIGATOR. J. Asthma Allergy 16, 915–932 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Crim, C. et al. IL-33 receptor inhibition in subjects with uncontrolled asthma: a randomized, placebo-controlled trial. J. Allergy Clin. Immunol. Glob. 1, 198–208 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Passalacqua, G., Ciprandi, G. & Canonica, G. W. The nose-lung interaction in allergic rhinitis and asthma: united airways disease. Curr. Opin. Allergy Clin. Immunol. 1, 7–13 (2001).

    CAS  PubMed  Google Scholar 

  210. Mullol, J. et al. Management of united airway disease focused on patients with asthma and chronic rhinosinusitis with nasal polyps: a systematic review. J. Allergy Clin. Immunol. Pract. 10, 2438–2447.e9 (2022).

    Article  PubMed  Google Scholar 

  211. Cho, H. J. et al. Differences and similarities between the upper and lower airway: focusing on innate immunity. Rhinology 59, 441–450 (2021).

    PubMed  Google Scholar 

  212. Wang, M. et al. Distinct type 2-high inflammation associated molecular signatures of chronic rhinosinusitis with nasal polyps with comorbid asthma. Clin. Transl. Allergy 10, 26 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Ek, A. et al. Chronic rhinosinusitis in asthma is a negative predictor of quality of life: results from the Swedish GA(2)LEN survey. Allergy 68, 1314–1321 (2013).

    Article  CAS  PubMed  Google Scholar 

  214. Volpe, S. et al. Viral infections and chronic rhinosinusitis. J. Allergy Clin. Immunol. 152, 819–826 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Kicic, A. et al. Assessing the unified airway hypothesis in children via transcriptional profiling of the airway epithelium. J. Allergy Clin. Immunol. 145, 1562–1573 (2020).

    Article  CAS  PubMed  Google Scholar 

  216. Yao, Y. et al. Proteomic and metabolomic proof of concept for unified airways in chronic rhinosinusitis and asthma. Ann. Allergy Asthma Immunol. 132, 713–722.e4 (2024).

    Article  CAS  PubMed  Google Scholar 

  217. Maspero, J. F. et al. Dupilumab efficacy in uncontrolled, moderate-to-severe asthma with self-reported chronic rhinosinusitis. J. Allergy Clin. Immunol. Pract. 8, 527–539.e9 (2020).

    Article  PubMed  Google Scholar 

  218. Nolasco, S. et al. Benralizumab effectiveness in severe eosinophilic asthma with and without chronic rhinosinusitis with nasal polyps: a real-world multicenter study. J. Allergy Clin. Immunol. Pract. 9, 4371–4380.e4 (2021).

    Article  CAS  PubMed  Google Scholar 

  219. Stokholm, J. et al. Maturation of the gut microbiome and risk of asthma in childhood. Nat. Commun. 9, 141 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Bach, J. F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002).

    Article  PubMed  Google Scholar 

  221. Riedler, J. et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 358, 1129–1133 (2001).

    Article  CAS  PubMed  Google Scholar 

  222. Braun-Fahrländer, C. et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N. Engl. J. Med. 347, 869–877 (2002).

    Article  PubMed  Google Scholar 

  223. Arrieta, M. C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl. Med. 7, 307ra152 (2015).

    Article  PubMed  Google Scholar 

  224. Depner, M. et al. Maturation of the gut microbiome during the first year of life contributes to the protective farm effect on childhood asthma. Nat. Med. 26, 1766–1775 (2020).

    Article  CAS  PubMed  Google Scholar 

  225. Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–166 (2014).

    Article  CAS  PubMed  Google Scholar 

  226. Stein, M. M. et al. Innate immunity and asthma risk in Amish and Hutterite farm children. N. Engl. J. Med. 375, 411–421 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Schuijs, M. J. et al. Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells. Science 349, 1106–1110 (2015).

    Article  CAS  PubMed  Google Scholar 

  228. von Mutius, E. The “Hygiene Hypothesis” and the lessons learnt from farm studies. Front. Immunol. 12, 635522 (2021).

    Article  Google Scholar 

  229. Durack, J. et al. Distinct associations of sputum and oral microbiota with atopic, immunologic, and clinical features in mild asthma. J. Allergy Clin. Immunol. 146, 1016–1026 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Huang, Y. J. et al. The airway microbiome in patients with severe asthma: associations with disease features and severity. J. Allergy Clin. Immunol. 136, 874–884 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  231. Bachert, C. et al. Adult chronic rhinosinusitis. Nat. Rev. Dis. Primers 6, 86 (2020).

    Article  PubMed  Google Scholar 

  232. Ma, J. et al. Laboratory mice with a wild microbiota generate strong allergic immune responses. Sci. Immunol. 8, eadf7702 (2023).

    Article  CAS  PubMed  Google Scholar 

  233. Block, K. E. et al. Physiological microbial exposure transiently inhibits mouse lung ILC2 responses to allergens. Nat. Immunol. 23, 1703–1713 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Huh, J. R. & Veiga-Fernandes, H. Neuroimmune circuits in inter-organ communication. Nat. Rev. Immunol. 20, 217–228 (2020).

    Article  CAS  PubMed  Google Scholar 

  235. Barnes, P. J. Neural control of human airways in health and disease. Am. Rev. Respir. Dis. 134, 1289–1314 (1986).

    CAS  PubMed  Google Scholar 

  236. Gosens, R., Zaagsma, J., Meurs, H. & Halayko, A. J. Muscarinic receptor signaling in the pathophysiology of asthma and COPD. Respir. Res. 7, 73 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  237. Phelan, K. J. et al. Airway transcriptome networks identify susceptibility to frequent asthma exacerbations in children. J. Allergy Clin. Immunol. 152, 73–83 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  238. Wessler, I., Kirkpatrick, C. J. & Racké, K. The cholinergic ‘pitfall’: acetylcholine, a universal cell molecule in biological systems, including humans. Clin. Exp. Pharmacol. Physiol. 26, 198–205 (1999).

    Article  CAS  PubMed  Google Scholar 

  239. Cox, M. A. et al. Choline acetyltransferase-expressing T cells are required to control chronic viral infection. Science 363, 639–644 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Chu, C. et al. The ChAT-acetylcholine pathway promotes group 2 innate lymphoid cell responses and anti-helminth immunity. Sci. Immunol. 6, eabe3218 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Schneider, C., O’Leary, C. E. & Locksley, R. M. Regulation of immune responses by tuft cells. Nat. Rev. Immunol. 19, 584–593 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Krasteva, G. et al. Cholinergic chemosensory cells in the trachea regulate breathing. Proc. Natl Acad. Sci. USA 108, 9478–9483 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Perniss, A. et al. Chemosensory cell-derived acetylcholine drives tracheal mucociliary clearance in response to virulence-associated formyl peptides. Immunity 52, 683–699.e11 (2020).

    Article  CAS  PubMed  Google Scholar 

  244. Barrios, J. et al. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. FASEB J. 31, 4117–4128 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Hayashi, R. et al. Cholinergic sensing of allergen exposure by airway epithelium promotes type 2 immunity in the lungs. J. Allergy Clin. Immunol. 153, 793–808.e2 (2024).

    Article  CAS  PubMed  Google Scholar 

  246. Pollack, C. E. et al. Association of a housing mobility program with childhood asthma symptoms and exacerbations. JAMA 329, 1671–1681 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  247. Rosenkranz, M. A. et al. Neuroimaging and biomarker evidence of neurodegeneration in asthma. J. Allergy Clin. Immunol. 149, 589–598.e6 (2022).

    Article  CAS  PubMed  Google Scholar 

  248. Dill-McFarland, K. A. et al. Molecular pathways underlying lung-brain axis signaling in asthma: relevance for psychopathology and neuroinflammation. J. Allergy Clin. Immunol. 153, 111–121 (2024).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are deeply grateful to all the scientists, physicians and patients who have contributed to the development of this area of research and apologize to the investigators whose work was not cited in this Review due to space limitations. This work was supported by grants from the National Institutes of Health (P01AI145818 for A.K. and R37AI71106, R01AI128729, R01AI169530, and R56AI181754 for H.K.) and the Mayo Foundation (for H.K.).

Author information

Authors and Affiliations

  1. Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Atsushi Kato

  2. Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Atsushi Kato

  3. Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic Arizona, Scottsdale, AZ, USA

    Hirohito Kita

  4. Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ, USA

    Hirohito Kita

Authors
  1. Atsushi Kato
    View author publications

    Search author on:PubMed Google Scholar

  2. Hirohito Kita
    View author publications

    Search author on:PubMed Google Scholar

Contributions

A.K. and H.K. designed the concept of this article, wrote the manuscript, and approved the final version of the manuscript.

Corresponding author

Correspondence to Hirohito Kita.

Ethics declarations

Competing interests

A.K. has served on an advisory board for AstraZeneca. A.K. has received research grants from Regeneron Pharmaceuticals and AstraZeneca. H.K. received a royalty from Aiolos Bio and GlaxoSmithKline.

Peer review

Peer review information

Nature Reviews Immunology thanks C. Akdis and W.-J. Song for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Adventitial cuff

A perivascular interstitial space that provides vascular support. The adventitial cuff is rich in extracellular matrix proteins, fibroblasts, small blood vessels, lymphatics, neurons and immune cells.

Charcot–Leyden crystal

(CLC). Crystals comprising the eosinophil-derived protein galectin 10 and which have been found to accumulate in the tissues of individuals with allergic diseases.

Dexpramipexole

A small-molecule drug that causes depletion of eosinophils by inhibiting their maturation and release from the bone marrow.

Goblet cell

Mucus-producing cells found in the epithelium lining the intestines and lungs.

Mucosal-associated invariant T cells

A population of innate-like T cells found at mucosal surfaces. Mucosal-associated invariant T cells express a semi-invariant T cell receptor and can rapidly respond to infections without prior sensitization.

Neutrophil extracellular traps

(NETs). NETs are large, extracellular, web-like structures composed of cytosolic and granule proteins that are assembled on chromatin scaffolds. They are released by activated neutrophils and can drive tissue inflammation.

Ripoptosome

A multi-protein signalling complex that regulates cell death pathways, most notably apoptosis and necroptosis. It typically assembles in response to cellular stress, DNA damage or the absence of certain survival signals.

T helper 2 (TH2) cell response

TH2 cells produce cytokines that regulate IgE synthesis (IL-4), eosinophil proliferation (IL-5), mast cell proliferation (IL-9) and airway hyper-responsiveness (IL-13). A TH2 cell response is commonly observed in allergic inflammation and parasitic infections, conditions that are both associated with IgE production and eosinophilia.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kato, A., Kita, H. The immunology of asthma and chronic rhinosinusitis. Nat Rev Immunol 25, 569–587 (2025). https://doi.org/10.1038/s41577-025-01159-0

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41577-025-01159-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research