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Supplements Therapeutic Advances in the Management of Type 2 Inflammatory Disease

The Emerging Role of the Type 2 Inflammatory Cascade in Atopic Diseases

Numerous pharmacologic agents targeting various points in the type 2 inflammatory cascade are currently in development or have already been approved for the treatment of atopic asthma, especially in patients with Th2-high asthma endotype. One of the first targeted agents approved for the treatment of atopic asthma was omalizumab, which works primarily by depleting IgE and blocking its effect on dendritic cells.4 Agents that selectively bind to and block IL-5, including mepolizumab and reslizumab, inhibit eosinophilic inflammation and have demonstrated reductions in asthma exacerbations among patients with persistent eosinophilia despite other treatments.3 Other recent developments in targeted therapy include agents that selectively bind to and block either IL-13, including lebrikizumab and tralokinumab, or IL-4, including altrakincept; other agents more broadly inhibit the activity of both IL-4 and IL-13, such as dupilumab and pitrakinra.

Atopic Dermatitis

Importantly, not all atopic diseases are triggered by allergens or allergic exposure. The pathology of AD is multifaceted. It is a complex, chronic inflammatory disease process. Often preceding the onset of other inflammatory conditions, such as food allergy, asthma, and allergic rhinitis, AD is a systemic disease.21 Skin lesions have shown increased numbers of inflammatory cells including T-helper cells, IgE plasma cells, eosinophils, and mast cells.22 One hallmark of AD is skin barrier dysfunction, which leads to increased water loss and allows for the penetration of noxious environmental stimulants, in turn triggering the immune response pathway.22 Barrier dysfunction in AD-affected skin can be attributed to a deficiency of filaggrin, along with other abnormalities. Filaggrin loss is associated with poor skin hydration and enhanced penetration of allergens through the skin.21

Early immune response has been found to be type 2–mediated, with AD skin having a high expression of IL-4, IL-13, IL-25, and IL-33.22 IL-4 and IL-13 stimulate eosinophil recruitment, IgE class switching, and induce Th2 cell survival and activation.22 IL-4 and IL-13 also play a role in keratinocyte differentiation and downregulate the production of filaggrin and cell adhesion molecules, leading to a defective skin barrier.22 The immune response has been confirmed by findings which show that patients with severe AD experience significant improvement when treated with dupilumab, a humanized antibody that inhibits IL-4 and IL-13 and was approved by the FDA in 2017.23 IL-23 appears to play an important role in immune pathway activation of AD, as well, because it differentiates between Th17 and Th22 cells, both of which produce IL-22 and inhibit keratinocyte differentiation. Thus, early case reports suggest that inhibiting IL-23 can lead to improvement of severe AD.22

Importantly, significant heterogeneity has been observed in AD immune responses, with age, race, and severity of disease being associated with different patterns of immune activation. For example, severe types of AD are often characterized by selective expansions of circulating Th2 and Th22.23


The pathology of CRSwNP is complex and involves dysregulation of the host immune response as well as extrinsic factors. The most prevalent endotype of CRSwNP demonstrates a type 2 mediated inflammatory response and is characterized by a high prevalence of eosinophils, mast cells, and basophils, as well as elevated type 2 cytokines (IL-4, IL-5, IL-13, IL-25, and IL-33) and Th2 cells.18,24

Moreover, a defective epithelial barrier indicates a role for proinflammatory cytokines in the pathogenesis of the disease.25 Thus, type 2 inflammatory involvement in CRSnWP is believed to have a driving role in the disease process.18,26 This can be attributed to a lack of regulatory T-cell function, local IgE production induced by IL-4 and IL-13, and eosinophilic inflammation induced by IL-4 and IL-13 as well as by IL-5.


The chronic illnesses reviewed in this article have a common underlying pathology involving the type 2 inflammatory pathway, which may explain, in part, the frequency of these conditions coexisting with each other.1 This is echoed by presence of barrier dysfunction in all of these diseases. In particular, IL-4 and IL-13 appear to be integral in the downregulation of filaggrin and epithelial resistance, both of which are critical drivers of barrier dysfunction.20,22

The involvement of this specific immune response allows for the premise of precision medicine to be applied to emerging treatment approaches. The next article in this publication will review the current and emerging therapeutics in type 2 inflammatory diseases, with an emphasis on targeting specific inflammatory pathways to enable more refined and efficacious approaches to disease management.

  1. Brunner PM, Silverberg JI, Guttman-Yassky E, et al; Councilors of the International Eczema Council. Increasing comorbidities suggest that atopic dermatitis is a systemic disorder. J Invest Dermatol. 2017;137(1):18-25. doi: 10.1016/j.jid.2016.08.022
  2. Pawankar R. Allergic diseases and asthma: a global public health concern and a call to action. World Allergy Organ J. 2014;7(1):12. doi: 10.1186/1939-4551-7-12.
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  8. Bhakta NR, Woodruff PG. Human asthma phenotypes: from the clinic, to cytokines, and back again. Immunol Rev. 2011;242(1):220-232. doi: 10.1111/j.1600-065X.2011.01032.x.
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  12. FastStats: asthma. CDC / National Center for Health Statistics website. Updated January 19, 2017. Accessed April 4, 2019.
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  17. Filanovsky MG, Pootongkam S, Tamburro JE, Smith MC, Ganocy SJ, Nedorost ST. The financial and emotional impact of atopic dermatitis on children and their families. J Pediatr. 2016;169:284-290.e5. doi: 10.1016/j.jpeds.2015.10.077.
  18. Stevens WW, Schleimer RP, Kern RC. Chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol Pract. 2016;4(4):565-572. doi: 10.1016/j.jaip.2016.04.012.
  19. Humeniuk P, Dubiela P, Hoffmann-Sommergruber K. Dendritic cells and their role in allergy: uptake, proteolytic processing and presentation of allergens. Int J Mol Sci. 2017;18(7):E1491. doi: 10.3390/ijms18071491.
  20. Wise SK, Laury AM, Katz EH, Den Beste KA, Parkos CA, Nusrat A. Interleukin-4 and interleukin-13 compromise the sinonasal epithelial barrier and perturb intercellular junction protein expression. Int Forum Allergy Rhinol. 2014;4(5):361-370. doi: 10.1002/alr.21298.
  21. Leung DY. Clinical implications of new mechanistic insights into atopic dermatitis. Curr Opin Pediatr. 2016;28(4):456-462. doi: 10.1097/MOP.0000000000000374.
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