Advertisement

Role of Type 2 Innate Lymphoid Cells in Allergic Diseases

  • Lorenzo Cosmi
  • Francesco Liotta
  • Laura Maggi
  • Francesco AnnunziatoEmail author
Immune Deficiency and Dysregulation (DP Huston and C Kuo, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Immune Deficiency and Dysregulation

Abstract

Purpose of Review

The adaptive immune response orchestrated by type 2 T helper (Th2) lymphocytes, strictly cooperates with the innate response of group 2 innate lymphoid cells (ILC2), in the protection from helminths infection, as well as in the pathogenesis of allergic disease. The aim of this review is to explore the pathogenic role of ILC2 in different type 2-mediated disorders.

Recent Findings

Recent studies have shown that epithelial cell-derived cytokines and their responding cells, ILC2, play a pathogenic role in bronchial asthma, chronic rhinosinusitis, and atopic dermatitis.

Summary

The growing evidences of the contribution of ILC2 in the induction and maintenance of allergic inflammation in such disease suggest the possibility to target them in therapy. Biological therapies blocking ILC2 activation or neutralizing their effector cytokines are currently under evaluation to be used in patients with type 2-dominated diseases.

Keywords

Innate lymphoid cells ILC2 T helper lymphocytes Th2 Asthma Rhinosinusitis Atopic dermatitis 

Notes

Acknowledgments

We thank Dr. Beatrice Rossettini and Dr. Gianni Montaini for their support in the preparation of the figure

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

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

  1. 1.
    Karta MR, Broide DH, Doherty TA. Insights into group 2 innate lymphoid cells in human airway disease. Curr Allergy Asthma Rep. 2016;16:8. doi: 10.1007/s11882-015-0581-6.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol. 2015;16:45–56.CrossRefPubMedGoogle Scholar
  3. 3.
    Licona-Limón P, Kim LK, Palm NW, Flavell RA. TH2, allergy and group 2 innate lymphoid cells. Nat Immunol. 2013;14:536–42.CrossRefPubMedGoogle Scholar
  4. 4.
    Lambrecht BN, Hammad H. The airway epithelium in asthma. Nat Med. 2012;18:684–92.CrossRefPubMedGoogle Scholar
  5. 5.
    • Maggi L, Montaini G, Mazzoni A, Rossettini B, Capone M, Rossi MC, et al. Human circulating group 2 innate lymphoid cells can express CD154 and promote IgE production. J Allergy Clin Immunol. 2017;139:964–76. ILC2s, once activated, express CD154 and produce type 2 cytokines, becoming able to induce IgE production in autologous B cells. It is also reported that ILC2 can be activated by ligands of Toll-like receptors 1, 4, and 6.Google Scholar
  6. 6.
    Halim TY. Group 2 innate lymphoid cells in disease. Int Immunol. 2016;28:13–22.PubMedGoogle Scholar
  7. 7.
    Nausch N, Mutapi F. Group 2 ILCs: a way of enhancing immune protection against human helminths? Parasite Immunol. 2017; doi: 10.1111/pim.12450.
  8. 8.
    Cosmi L, Annunziato F, Galli G, Iwasaki M, Maggi E, Manetti R, et al. CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease. Eur J Immunol. 2000;30:2972–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Annunziato F, Romagnani C, Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity. J Allergy Clin Immunol. 2015;135:626–35.CrossRefPubMedGoogle Scholar
  10. 10.
    Chackerian AA, Oldham ER, Murphy EE, Schmitz J, Pflanz S, Kastelein RA. IL-1 receptor accessory protein and ST2 comprise the IL- 33 receptor complex. J Immunol. 2007;179:2551–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Klose CS, Artis D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat Immunol. 2016;17:765–74.CrossRefPubMedGoogle Scholar
  12. 12.
    Cosmi L, Annunziato F. ILC2 are the earliest recruiters of eosinophils in lungs of allergic asthmatic patients. Am J Respir Crit Care Med. 2017; doi: 10.1164/rccm.201704-0799ED.
  13. 13.
    Oliphant CJ, Hwang YY, Walker JA, Salimi M, Wong SH, Brewer JM, et al. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4(+) T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity. 2014;41:283.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Gold MJ, Antignano F, Halim TY, Hirota JA, Blanchet MR, Zaph C, et al. Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures. J Allergy Clin Immunol. 2014;133:1142–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Zaiss DM, Yang L, Shah PR, Kobie JJ, Urban JF, Mosmann TR. Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. Science. 2006;314:1746.CrossRefPubMedGoogle Scholar
  16. 16.
    Mitchell PD, O'Byrne PM. Epithelial-derived cytokines in asthma. Chest. 2017;151:1338–44.CrossRefPubMedGoogle Scholar
  17. 17.
    Kubo M. Innate and adaptive type 2 immunity in lung allergic inflammation. Immunol Rev. 2017;278:162–17.CrossRefPubMedGoogle Scholar
  18. 18.
    Snelgrove RJ, Gregory LG, Peiró T, Akthar S, Campbell GA, Walker SA, et al. Alternaria-derived serine protease activity drives IL-33-mediated asthma exacerbations. J Allergy Clin Immunol. 2014;134:583–92.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Valero A, Quirce S, Dávila I, Delgado J, Domínguez-Ortega J. Allergic respiratory disease: different allergens, different symptoms. Allergy. 2017; doi: 10.1111/all.13141.
  20. 20.
    Vianello A, Caminati M, Crivellaro M, El Mazloum R, Snenghi R, Schiappoli M, et al. Fatal asthma; is it still an epidemic? World Allergy Organ J. 2016;9:42.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    • Smith SG, Chen R, Kjarsgaard M, Huang C, Oliveria JP, O'Byrne PM, et al. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016;137:75–86. Authors found greater numbers of total and type 2 cytokine-producing ILC2s in blood and sputum of patients with severe asthma compared to mild asthmatics, suggesting a possible pathogenic correlation between ILC2 and asthma.Google Scholar
  22. 22.
    Lombardi V, Beuraud C, Neukirch C, Moussu H, Morizur L, Horiot S, et al. Circulating innate lymphoid cells are differentially regulated in allergic and nonallergic subjects. J Allergy Clin Immunol. 2016;138:305–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Jia Y, Fang X, Zhu X, Bai C, Zhu L, Jin M, et al. IL-13+type 2 innate lymphoid cells correlate with asthma control status and treatment response. Am J Respir Cell Mol Biol. 2016;55:675–83.CrossRefPubMedGoogle Scholar
  24. 24.
    Kabata H, Moro K, Fukunaga K, Suzuki Y, Miyata J, Masaki K, et al. Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation. Nat Commun. 2013;4:2675.CrossRefPubMedGoogle Scholar
  25. 25.
    Chen R, Smith SG, Salter B, El-Gammal A, Oliveria JP, Obminski C, et al. Allergen-induced increases in sputum levels of group 2 innate lymphoid cells in asthmatic subjects. Am J Respir Crit Care Med. 2017; doi: 10.1164/rccm.201612-2427OC.
  26. 26.
    Varricchi G, Bagnasco D, Borriello F, Heffler E, Canonica GW. Interleukin-5 pathway inhibition in the treatment of eosinophilic respiratory disorders: evidence and unmet needs. Curr Opin Allergy Clin Immunol. 2016;16:186–200.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Gauvreau GM, O'Byrne PM, Boulet LP, Wang Y, Cockcroft D, Bigler J, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014 May 29;370:2102–10.CrossRefPubMedGoogle Scholar
  28. 28.
    Gonem S, Berair R, Singapuri A, Hartley R, Laurencin MF, Bacher G, et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med. 2016:699–707.Google Scholar
  29. 29.
    Nagarkar DR, Poposki JA, Tan BK, Comeau MR, Peters AT, Hulse KE, et al. Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis. J Allergy Clin Immunol. 2013;132:593–600.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Miljkovic D, Bassiouni A, Cooksley C, Ou J, Hauben E, Wormald PJ, et al. Association between group 2 innate lymphoid cells enrichment, nasal polyps and allergy in chronic rhinosinusitis. Allergy. 2014;69:1154–61.CrossRefPubMedGoogle Scholar
  31. 31.
    Poposki JA, Klingler AI, Tan BK, Soroosh P, Banie H, Lewis G, et al. Group 2 innate lymphoid cells are elevated and activated in chronic rhinosinusitis with nasal polyps. Immun Inflamm Dis. 2017; doi: 10.1002/iid3.161.
  32. 32.
    Feldman S, Kasjanski R, Poposki J, Hernandez D, Chen JN, Norton JE, et al. Chronic airway inflammation provides a unique environment for B cell activation and antibody production. Clin Exp Allergy. 2017;47:457–66.CrossRefPubMedGoogle Scholar
  33. 33.
    Lee TJ, Fu CH, Wang CH, Huang CC, Huang CC, Chang PH, et al. Impact of chronic rhinosinusitis on severe asthma patients. PLoS One. 2017;12:e0171047.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. NatGenet. 2006;38:441–6.Google Scholar
  35. 35.
    Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest. 2004;113:651–7.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Teunissen MB, Munneke JM, Bernink JH, Spuls PI, Res PC, Te Velde A, et al. Composition of innate lymphoid cell subsets in the human skin: enrichment of NCR ILC3 in lesional skin and blood of psoriasis patients. J Investig Dermatol. 2014;134:2351–60.CrossRefPubMedGoogle Scholar
  37. 37.
    • Salimi M, Barlow JL, Saunders SP, Xue L, Gutowska-Owsiak D, Wang X, et al. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med. 2013;210:2939–50. Authors show that E-cadherin ligation on human ILC2 inhibits IL-5 and IL-13 production. Being the down-regulation of E-cadherin characteristic of filaggrin insufficiency, both these features may concur to atopic dermatitis pathogenesis.Google Scholar
  38. 38.
    • Roediger B, Kyle R, Le Gros G, Weninger W. Dermal group 2 innate lymphoid cells in atopic dermatitis and allergy. Curr Opin Immunol. 2014;31:108–14. Exhaustive review on the possible role played by ILC2 in the physiology and pathology of mouse and human skin.Google Scholar
  39. 39.
    Imai Y, Yasuda K, Sakaguchi Y, Haneda T, Mizutani H, Yoshimoto T, et al. Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc Natl Acad Sci U S A. 2013;110:13921–6.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Roediger R, Kyle KH, Yip N, Sumaria TV, Guy BS, Kim AJ, et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat Immunol. 2013;14:564–73.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335–48.CrossRefPubMedGoogle Scholar
  42. 42.
    Kim BS, Siracusa MC, Saenz SA, Noti M, Monticelli LA, Sonnenberg GF, et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med. 2013;5(170):170ra16.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Lorenzo Cosmi
    • 1
  • Francesco Liotta
    • 1
  • Laura Maggi
    • 1
  • Francesco Annunziato
    • 1
    Email author
  1. 1.Department of Experimental and Clinical Medicine and DENOTHE CenterUniversity of FlorenceFlorenceItaly

Personalised recommendations