Asthma and lower airway disease
Identification of novel immune phenotypes for allergic and nonallergic childhood asthma

https://doi.org/10.1016/j.jaci.2014.07.046Get rights and content

Background

Childhood asthma is classified into allergic asthma (AA) and nonallergic asthma (NA), yet both are treated identically, with only partial success.

Objective

We sought to identify novel immune phenotypes for childhood AA and NA.

Methods

The Clinical Asthma Research Association cohort study includes 275 steroid-naive 4- to 15-year-old German children (healthy control subjects [HCs], patients with AA, and patients with NA). In PBMCs both quantitative and functional analysis of regulatory T (Treg) and TH17 cells (flow cytometry/Treg cell suppression) before/after anti-CD3/CD28, lipid A, and peptidoglycan stimulation were performed. Cytokines and gene expression, as assessed by using Luminex or transcriptomics/quantitative real-time RT-PCR, were analyzed by means of regression analysis. Linear discriminant analysis was applied to discriminate between phenotypes.

Results

The 3 phenotypes were immunologically well discriminated by means of microarray and protein analysis with linear discriminant analysis. Patients with AA were characterized by increased Treg cells compared with those in HCs but not those in patients with NA. Treg cells from patients with AA, but not patients with NA, significantly suppressed IL-5, IL-13, and IFN-γ secretion. Patients with AA had decreased expression of chloride intracellular channel 4 (CLIC4) and tuberous sclerosis 1 (TSC1), important innate immunity regulators. Patients with NA were characterized by increased proinflammatory IL-1β levels, neutrophil counts, and IL-17–shifted immunity. In parallel, expressions of anti-inflammatory IL37, proline-serine-threonine phosphatase–interacting protein 2 (PSTPIP2), and the neutrophil-associated genes CD93, triggering receptor expressed on myeloid cells 1 (TREM1), and regulator of G-protein signaling 13 (RGS13) were increased in patients with NA. A shared TH2 immunity was present in both asthma phenotypes.

Conclusion

Novel immune-regulatory mechanisms in childhood asthma identified increased Treg cells in patients with AA compared with those in HCs but not those in NA and decreased innate immunity genes for patients with AA, the first potentially indicating a counterregulatory mechanism to suppress cytokines yet not sufficient to control allergic inflammation. Very distinctly, patients with NA showed an IL-17–shifted proinflammatory immunity, promoting neutrophil inflammation and less functional Treg cells. Identification of these unique pathways provides a profound basis for future strategies for individualized prediction of asthma development, disease course, and prevention.

Section snippets

Study population

Two hundred seventy-five children (age, 4-15 years) were recruited in the Munich Clinical Asthma Research Association study during a visit to an asthma clinic (January 2009-July 2014), which was registered at the DRKS German study registry (no. DRKS00004635; http://drks-neu.uniklinik-freiburg.de/drks_web/). Parents completed a detailed questionnaire assessing health data on allergy, asthma, and socioeconomic factors. The study population contained healthy control subjects (HCs) and patients

Clinical differentiation between HCs, patients with AA, and patients with NA

For the Clinical Asthma Research Association study, 275 children were recruited, and 202 children with complete epidemiologic and core immunologic data were included in this article (Fig 1). After exclusion of 12 children because of infections or pulmonary or autoimmune diseases, 13 because of transient or episodic wheeze, and 4 because of allergy without asthma, 74 patients with AA, 18 patients with NA, and 81 HCs were finally analyzed (Fig 1).

The 3 groups were significantly different

Discussion

Patients with AA, as characterized by pulmonary obstruction and allergic inflammation indicated by increased eosinophil counts and specific IgE levels, exhibited increased Treg cells compared with those seen in HCs but not those seen in patients with NA, with efficient suppression of TH2 and TH1 cytokines compared with insufficient suppression by patients with NA. In parallel, expression of CLIC4 and TSC1, 2 important regulators of innate immunity, was decreased in patients with AA. In

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    Supported by the German Research Foundation (DFG, TRR 22/2 and 22/3, SFB-TR22; to D.R., N.B., E.K., A.B., B.S., O.P.d.C., and T.B.), GPA, WAO (to B.S.), a grant from GlaxoSmithKline, Forschungsstipendium für Klinische Pneumologie 2013 (D.R.), FöFoLe Reg.Nr. 839 (DR), and the German Centre for Lung Research (DZL) as part of the Comprehensive Pneumology Centre in Munich (CPC-M; to D.R., B.S., and E.v.M.).

    Disclosure of potential conflict of interest: T. Buch has received research support from DFG, is employed by the Technical University of Munich, and has stock in biotechs within ETFs. E. von Mutius is an Associate Editor for the Journal of Allergy and Clinical Immunology; has consultant arrangements with GlaxoSmithKline, Novartis, ALK-Abelló, and Astellas Pharma Europe Ltd; has provided expert testimony for the UK Research Excellence Framework; and has received research support from FrieslandCampina. B. Schaub has received research support from DFG and is employed by University Children's Hospital Munich. The rest of the authors declare that they have no relevant conflicts of interest.

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