Effects of Type 2 Inflammation in Allergic Disease: Visible, Invisible, Complex

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There has been a huge shift forward in the understanding of innate and adaptive immune mechanisms that provoke type 2 inflammation in atopic disease and eosinophilic esophagitis, according to a CHEST Annual Meeting 2021 speaker.

There is a much broader understanding of the role of type 2 inflammation in asthma and allergic disease, with results strikingly similar across different areas of the body, according to a presenter who spoke at the CHEST Annual Meeting 2021.

Geoffrey Chupp, MD, a pulmonologist and director of the Yale Center for Asthma and Airways Disease and director of the Pulmonary Function Laboratory at Yale-New Haven Hospital in Connecticut, gave an overview of type 2 inflammation, including how it manifests in different diseases and the role of the epithelial barrier.

Type 2 inflammation results from interactions among triggers, the epithelium, and innate and adaptive immunity, he said.

“In a lot of these patients, there is allergic inflammation,” Chupp said, characterized by Th2-type cytokines, or adaptive response, which itself is characterized by memory t cells linked with the production of immunoglobulin E (IgE) against a specific allergen.

In eosinophilic inflammation, innate cells, such as dendritic or lymphoid cells, can be programmed to produce cytokines such as interleukin 13 (IL-13) and IL-5, but because there is not as much IL-4 involved, IgE reactions are not as common.

The combination of environmental factors and host factors can lead to irreversible tissue remodeling, whether the epithelial tissue affected is the skin, as in atopic dermatitis (AD); the lungs, as in asthma; or the gastrointestinal (GI) tract, when it triggers eosinophilic esophagitis (EoE).


Asthma is 1 of 2 phenotypes, allergic or eosinophilic, and both phenotypes share similarities of a type 2–high profile, including:

  • The same immune pathway expressing IL-4, IL-5, and IL-13
  • A variable response to corticosteroids
  • Elevated blood and sputum eosinophils (EOS) are commonly elevated
  • Tissue remodeling provoked by IL-4 and IL-13, including mucus overproduction and airway hyperesponsiveness

What is different between the two, however, is that the allergic phenotype is associated with onset in early childhood, with specific IgE sensitivity to certain allergens and various atopic comorbidities. The eosinophilic phenotype usually starts in adulthood, is nonspecific with respect to IgE, and the main comorbidity is chronic rhinusitis with nasal polyps.

Chronically elevated type 2 inflammation can contribute to multiple disease manifestations, and these diseases frequently coexist, Chupp noted. For example, for individuals with a primary diagnosis of asthma, 30% to 80% also have a diagnosis of allergic rhinitis (AR). And in patients with EoE, up to 93% may have AR, up to 55% might have AD, and up to 66% might have asthma.

Epithelial barrier dysfunction contributes to the cycle of damage in type 2 inflammation, Chupp pointed out. As it becomes permeable and leaky due to attacks by allergens, microbes, and other invaders, cytokines called alarmins, namely IL-33, IL-25, and thymic stromal lymphopoietin are released, not only triggering the inflammation but also adding proteases and hormones into the mix that further contribute to the cycle of dysfunction.

This cycle is what leads to fibrosis and tissue remodeling in the lungs, GI tract, or the skin.

As far as targeting therapy to patients, 3 biomarkers are typically elevated in type 2 inflammation—fractional exhaled nitric oxide (FeNO), blood EOS, and serum IgE—and Chupp said type 2 inflammation should be considered by a clinician if any or all of these factors are present while a patient is taking high-dose inhaled corticosteroids or daily oral corticosteroids (OCS):

  • Blood EOS ≥ 150 mcL
  • FeNO ≥ 20 ppb
  • Sputum EOS ≥ 2%
  • Asthma that is clinically driven

Patients needing maintenance OCS may also have underlying type 2 inflammation, he said.