T-helper Type 2–driven Inflammation Defines Major Subphenotypes of Asthma

Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, CA 94143-0111, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 05/2009; 180(5):388-95. DOI: 10.1164/rccm.200903-0392OC
Source: PubMed


T-helper type 2 (Th2) inflammation, mediated by IL-4, IL-5, and IL-13, is considered the central molecular mechanism underlying asthma, and Th2 cytokines are emerging therapeutic targets. However, clinical studies increasingly suggest that asthma is heterogeneous.
To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation.
Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects, we classified subjects with asthma based on high or low expression of IL-13-inducible genes. We then validated this classification and investigated its clinical implications through analyses of cytokine expression in bronchial biopsies, markers of inflammation and remodeling, responsiveness to inhaled corticosteroids, and reproducibility on repeat examination.
Gene expression analyses identified two evenly sized and distinct subgroups, "Th2-high" and "Th2-low" asthma (the latter indistinguishable from control subjects). These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness, serum IgE, blood and airway eosinophilia, subepithelial fibrosis, and airway mucin gene expression (all P < 0.03). The lung function improvements expected with inhaled corticosteroids were restricted to Th2-high asthma, and Th2 markers were reproducible on repeat evaluation.
Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma. Furthermore, current models do not adequately explain non-Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapies.

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Available from: Alexander R Abbas, Sep 30, 2015
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    • "The pathophysiology of allergic asthma is mostly sustained by T-helper 2 (Th2) lymphocytes, which orchestrate and coordinate the immune inflammatory response of asthmatic airways. This “Th2-high” signature of bronchial inflammation is the result of multiple interactions between the innate and adaptive branches of the immune system.4,5 Indeed, aeroallergens responsible for allergic asthma derive from both seasonal and perennial triggers, penetrate into the airway epithelium, and stimulate Toll-like receptors, which belong to the so-called “pattern recognition receptors” operating in innate immune responses. "
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    ABSTRACT: Simultaneously with the steady progress towards a better knowledge of the pathobiology of asthma, the potential usefulness of anticytokine therapies is emerging as one of the key concepts in the newly developing treatments of this widespread airway disease. In particular, given the key role played by interleukin (IL)-4 and IL-13 in the pathophysiology of the most typical aspects of asthma, such as chronic airway inflammation, tissue remodeling, and bronchial hyperresponsiveness, these pleiotropic cytokines are now considered as suitable therapeutic targets. Among the recently developed antiasthma biologic drugs, the monoclonal antibody dupilumab is very promising because of its ability to inhibit the biological effects of both IL-4 and IL-13. Indeed, dupilumab prevents IL-4/13 interactions with the α-subunit of the IL-4 receptor complex. A recent trial showed that in patients with difficult-to-control asthma, dupilumab can markedly decrease asthma exacerbations and improve respiratory symptoms and lung function; these effects were paralleled by significant reductions in T-helper 2-associated inflammatory biomarkers. However, further larger and longer trials are required to extend and validate these preliminary results, and also to carefully study the safety and tolerability profile of dupilumab.
    Journal of Asthma and Allergy 09/2014; 7:123-30. DOI:10.2147/JAA.S52387
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    • "The type-2 cytokines, interleukin (IL)-4, IL-5, IL-9, and IL-13, are the major drivers of allergic asthma and studies [1–4], in both mice and humans, have indicated that they regulate many inflammatory processes, including bronchoconstriction, mucus production, eosinophilia, and immunoglobulin E class switching by B cells. This understanding has been essential for the development of two new potential asthma treatments, lebrikizumab (anti-IL-13) and mepolizumab (anti-IL-5) [5,6]. "
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    ABSTRACT: Purpose of review Recent decades have seen allergic diseases become endemic in a number of developed countries. Understanding the inflammatory processes that dictate these allergic responses is therefore important. Recent findings Critical to many allergic responses is the inappropriate release of the type-2 immune-regulatory cytokines: interleukin-4, interleukin-5, interleukin-9, and interleukin-13. The study of these inflammatory mediators has led directly to the development of two new asthma treatments: anti-interleukin-5 and anti-interleukin-13. Until recently, T helper 2 cells were considered to be the major cellular source of type-2 cytokines; however, a paradigm shift occurred with the discovery of a novel population, type-2 innate lymphoid cells (ILC2s), that can produce huge levels of type-2 cytokines and are sufficient to induce allergy in mice. This discovery raises interesting questions about how innate and adaptive type-2 immunity might interact to induce relapsing and remitting episodes of allergy in patients. Summary It is essential that alongside the mechanistic investigation using model organisms, the roles of ILC2s in human disease be explored. Here, we discuss how ILC2 traits, discovered in mouse models, have informed research in humans and how newly identified human ILC2 pathways might provide potential therapeutic benefits in the future.
    Current Opinion in Allergy and Clinical Immunology 08/2014; 14(5). DOI:10.1097/ACI.0000000000000090 · 3.57 Impact Factor
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    • "Healthy or asthmatic subjects were enrolled and tested for airway hyper-responsiveness as measured by airway hyper-responsiveness upon methacholine challenge and allergies as measured by serum IgE. Th2 skew was categorized by methods from Woodruff et al. [21]. Age and FEV % predicted are shown as mean ± SD. "
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    ABSTRACT: Dendritic cells (DCs) significantly contribute to the pathology of several mouse lung disease models. However, little is known of the contribution of DCs to human lung diseases. In this study, we examined infiltration with BDCA1+ DCs of human lungs in patients with interstitial lung diseases or asthma. Using flow cytometry, we found that these DCs increased by 5∼6 fold in the lungs of patients with idiopathic pulmonary fibrosis or hypersensitivity pneumonitis, which are both characterized by extensive fibrosis in parenchyma. The same DC subset also significantly increased in the lung parenchyma of patients with chronic obstructive pulmonary disease, although the degree of increase was relatively modest. By employing immunofluorescence microscopy using FcεRI and MHCII as the specific markers for BDCA1+ DCs, we found that the numbers of BDCA1+ DCs also significantly increased in the airway epithelium of Th2 inflammation-associated asthma. These findings suggest a potential contribution of BDCA1+ DCs in human lung diseases associated with interstitial fibrosis or Th2 airway inflammation.
    PLoS ONE 06/2014; 9(6):e99084. DOI:10.1371/journal.pone.0099084 · 3.23 Impact Factor
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