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Type 2 inflammation in asthma — present in most, absent in many

A Corrigendum to this article was published on 19 January 2015

This article has been updated

Abstract

Asthma is one of the most common chronic immunological diseases in humans, affecting people from childhood to old age. Progress in treating asthma has been relatively slow and treatment guidelines have mostly recommended empirical approaches on the basis of clinical measures of disease severity rather than on the basis of the underlying mechanisms of pathogenesis. An important molecular mechanism of asthma is type 2 inflammation, which occurs in many but not all patients. In this Opinion article, I explore the role of type 2 inflammation in asthma, including lessons learnt from clinical trials of inhibitors of type 2 inflammation. I consider how dichotomizing asthma according to levels of type 2 inflammation — into 'T helper 2 (TH2)-high' and 'TH2-low' subtypes (endotypes) — has shaped our thinking about the pathobiology of asthma and has generated new interest in understanding the mechanisms of disease that are independent of type 2 inflammation.

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Figure 1: Type 2 immune responses in asthma.
Figure 2: Airway pathology in asthma.
Figure 3: Asthma can be divided into TH2-low and TH2-high subgroups.
Figure 4: Asthma as a core disease of smooth muscle that is modified by inflammation.

Change history

  • 19 January 2015

    In the version of this article that was originally published, the targeted epitope of lebrikizumab was listed as "IL‑4Rα" in Table 1 but this should be "IL‑13 (IL‑4Rα‑binding epitope)”. Also, for the main effects of lebrikizumab in human asthma trials, the citation of reference 44 should be reference 48. The author apologizes for these errors, which have now been corrected online.

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Acknowledgements

The author would like to thank the following colleagues and collaborators who have contributed to his understanding of type 2 inflammation in asthma: P. Woodruff, M. Peters, E. Gordon, N. Bhakta, S. Christenson, H. Boushey, S. Lazarus, R. Locksley and M. Ansel (all at the University of California, San Francisco, USA), and M. Seibold (National Jewish Health, Denver, Colorado, USA) and J. Arron (Genentech Inc., South San Francisco, California, USA).

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Correspondence to John V. Fahy.

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Competing interests

The author is a named inventor on a patent application for periostin as a biomarker in asthma. He has consulted for Amgen, Merck, Regeneron, Boehringer Ingelheim and MedImmune.

PowerPoint slides

Glossary

Asthma control questionnaire

A tool for measuring quality of life and symptoms in patients with asthma. It assesses whether an individual wakes in the mornings with symptoms, the limitations of daily activities, shortness of breath and wheeze.

Atopy

A tendency to develop IgE-mediated allergic disease, such as asthma, eczema (atopic dermatitis), allergic rhinitis (hay fever) or allergic conjunctivitis.

Bronchial hyperresponsiveness

(BHR). A state in which the airways are hyperreactive to various bronchoconstrictor stimuli, including methacholine, histamine, hypertonic saline, distilled water, exercise or eucapnic hyperventilation. Hyperresponsiveness in this context means a bronchoconstrictor response at 'doses' that normally have no bronchoconstrictor effect.

FEV1

(Forced expired volume in 1 second). A measure of airflow. Decreases in FEV1 are characteristic of asthma and are one metric of asthma severity.

Glucocorticoids

Steroid hormones that are produced in the adrenal glands. Synthetic analogues are available as anti-inflammatory drugs that are particularly effective in suppressing type 2 immune responses.

Group 2 innate lymphoid cells

(ILC2s). ILC2s are a subtype of innate lymphoid cells, which are a novel family of haematopoietic effector cells with heterogeneous location, cytokine production and effector functions. ILC2s specifically produce type 2 cytokines and depend on GATA-binding protein 3 and retinoic acid receptor-related orphan receptor-α for their development and function.

SARP

(Severe Asthma Research Program). A network of seven asthma research centres and one data coordination centre in the United States. SARP aims to improve understanding of the heterogeneity of asthma, including asthma endotypes, with the ultimate goal of better treatments. It is funded by the US National Heart, Lung and Blood Institute.

U-BIOPRED

(Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes). A European-wide project that aims to uncover biomarkers of asthma and to identify mechanisms of disease subtypes to improve the treatment of asthma. It is funded by the Innovative Medicine Initiative (IMI) and the European Federation of Pharmaceutical Industries and Associations (EFPIA).

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Fahy, J. Type 2 inflammation in asthma — present in most, absent in many. Nat Rev Immunol 15, 57–65 (2015). https://doi.org/10.1038/nri3786

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