Allergic asthma is distinguished by sensitivity of allergen-specific CD4 ⁺ T cells and airway structural cells to type 2 inflammation

Abstract

Despite systemic sensitization, not all allergic individuals develop asthma symptoms upon airborne allergen exposure. Determination of the factors that lead to the asthma phenotype in allergic individuals could guide treatment and identify novel therapeutic targets. In this study, we utilized segmental allergen challenge (SAC) of allergic asthmatics (AA) and allergic non-asthmatic controls (AC) to determine if there are differences in the airway immune response or airway structural cells that could drive the development of asthma. Both groups developed prominent allergic airway inflammation in response to allergen. However, asthmatic subjects had markedly higher levels of innate type 2 receptors on allergen-specific CD4+ T cells recruited into the airway. There were also increased levels of type 2 cytokines, increased total mucin and increased MUC5AC in response to allergen in the airways of AA subjects. Furthermore, type 2 cytokine levels correlated with the mucin response in AA but not AC subjects, suggesting differences in the airway epithelial response to inflammation. Finally, AA subjects had increased airway smooth muscle mass at baseline measured in vivo using novel orientation-registered optical coherence tomography (OR-OCT). Our data demonstrate that the development of allergic asthma is dependent on the responsiveness of allergen-specific CD4+ T cells to innate type 2 mediators as well as increased sensitivity of airway epithelial cells and smooth muscle to type 2 inflammation.

Automated segmentation and quantification of airway mucus with endobronchial optical coherence tomography

“…Previously [26], as in this work, we reported on the correlation between mucus pixel intensity in OCT and mucin content, and found them to be reasonably well correlated (p = 0.03 for the 30 subjects included in this analysis). Although pixel intensity has been used to characterize fluid particulate in other OCT applications [30], it is nevertheless not ideal in analyzing mucus due to the fact that dense and heterogeneous distributions of mucus can cause strong scattering effects that can impact the accuracy of the measurements.…”

“…To evaluate our segmentation and mucus classification algorithms in human in vivo data sets, we analyzed data sets that had previously been obtained in a clinical study involving 18 allergic asthmatic and 22 allergic non-asthmatic subjects [26]. The clinical characteristics of the subjects and the details of this study, which involved a titrated allergen challenge, have been described elsewhere [26][27][28][29].…”

“…The clinical characteristics of the subjects and the details of this study, which involved a titrated allergen challenge, have been described elsewhere [26][27][28][29]. By analyzing data sets obtained before and after the delivery of allergen, we were able to assess our image segmentation and mucus characterization both under normal conditions and 24 hours after allergen exposure, which can have a dramatic effect on the airways in terms of mucus production, airway closure, and inflammation and edema.…”

Quantitative assessment of airway remodelling and response to allergen in asthma

“…All HC subjects had a negative reaction to skin test. Asthmatics were classified as previously described . All asthmatic volunteers had a PC20 (concentration of methacholine needed to produce a 20% fall of FEV 1 from baseline) of less than 20 mg/mL at baseline.…”

T cells in severe childhood asthma

“…One study that sampled the airways of adults with allergic asthma identified low numbers of allergen‐specific CD4 + T cells by tetramer staining that were enriched for cells that co‐expressed receptors for the alarmins IL‐33 (ST2), and IL‐25, and prostaglandin D2 (CRTH2). Receptor expression was enhanced after segmental allergen challenge . The same study reported a correlation between ST2 expression on allergen‐specific T cells and Th2 cytokine levels in BAL fluid, which would be consistent with IL‐33‐mediated triggering.…”