Identification of novel immune phenotypes for allergic and nonallergic childhood asthma Diana Raedler, PhD, Nikolaus Ballenberger, PhD, Elisabeth Klucker,

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Presentation transcript:

Identification of novel immune phenotypes for allergic and nonallergic childhood asthma Diana Raedler, PhD, Nikolaus Ballenberger, PhD, Elisabeth Klucker, MD, Andreas Böck, PhD, Ragna Otto, MD, Olivia Prazeres da Costa, Otto Holst, PhD, Thomas Illig, PhD, Thorsten Buch, PhD, Erika von Mutius, MD, Bianca Schaub, MD Journal of Allergy and Clinical Immunology Volume 135, Issue 1, Pages 81-91 (January 2015) DOI: 10.1016/j.jaci.2014.07.046 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Enrollment flow chart. From 275 children from the Clinical Asthma Research Association (CLARA), 202 steroid-naive 4- to 15-year-old German children (HCs, patients with AA, and patients with NA) with complete epidemiologic and core immunologic data were included. Additional exclusions were due to infections or chronic diseases, transient or episodic wheezing, or allergy without asthma. Journal of Allergy and Clinical Immunology 2015 135, 81-91DOI: (10.1016/j.jaci.2014.07.046) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Microarray and cytokine LDA plots of group discrimination. A scatterplot (A-C; patients with AA/patients with NA/HCs) with the first 2 linear discriminants (LD1/2) depicted on the x-axis and y-axis and a histogram (D-F, 2 groups) with the first linear discriminant depicted on the x-axis and density on the y-axis are shown. Fig 2, A, Top 600 microarray genes. Fig 2, B, Thirty-one microarray genes validated by means of qRT-PCR. Fig 2, C, Cytokines. Cytokine levels were compared between 2 groups: patients with AA versus HCs (Fig 2, D); patients with NA versus HCs (Fig 2, E); and patients with NA versus patients with AA (Fig 2, F). PCR: HCs/patients with AA/patients with NA, n = 14/14/8. Cytokines: HCs/patients with AA/patients with NA, n = 72/60/11. Journal of Allergy and Clinical Immunology 2015 135, 81-91DOI: (10.1016/j.jaci.2014.07.046) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Treg cell numbers, function, and expression of innate immunity genes. A and B, Treg cells (unstimulated [U]) characterized as CD4+CD25+FOXP3+CD49d− lymphocytes (Fig 3, A) and CD4+ upper 10% CD25+FOXP3+ lymphocytes (Fig 3, B). ANOVA: HCs/patients with AA/patients with NA, n = 58/62/11. C, Forrest plot of IL-5, IL-13, and IFN-γ geometric mean ratios (after Treg cell addition/no Treg cell addition) in HCs, patients with AA, and patients with NA. The dots and horizontal line show the geometric mean ratio and 95% CI. The solid vertical line denotes the geometric mean ratio of 1; values of less than 1 describe Treg cell–mediated suppression of the respective cytokine, and values of greater than 1 describe increased secretion. The x-axis shows the log scale, and labels reflect original units. Cytokines were measured in supernatants from Treg cell suppression assays both with and without Treg cells (effector T/Treg cells = 1:0.5). p(i), P value for interaction. HCs/patients with AA/patients with NA, n = 10/12/7. D and E, mRNA expression of CLIC4 (LpA; Fig 3, D) and TSC1 (main effect; Fig 3, E). Higher Δ cycle threshold (CT) values reflect lower expression (inverted y-axis scale). Tobit regression analysis (geometric mean ± SE): HCs/patients with AA/patients with NA, n = 14/14/8. Journal of Allergy and Clinical Immunology 2015 135, 81-91DOI: (10.1016/j.jaci.2014.07.046) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Inflammatory and IL-17–related immune profile. A, IL-1β (in picograms per milliliter; LpA). B-D, mRNA expression (main effect) of IL1B, IL37, and PSTPIP2; higher values reflect lower expression (inverted y-axis scale). E, IL-17 (in picograms per milliliter; LpA). F-H, Cytokine ratios (LpA) of IL-17/TNF-α (Fig 4, F), IL-17/IL-13 (Fig 4, G), and IL-17/IFN-γ (Fig 4, H). Results of Tobit regression analysis are shown as geometric means ± SEs. Cytokines: HCs/patients with AA/patients with NA, n = 72/60/11; PCR: HCs/patients with AA/patients with NA, n = 14/14/8. Journal of Allergy and Clinical Immunology 2015 135, 81-91DOI: (10.1016/j.jaci.2014.07.046) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2015 135, 81-91DOI: (10.1016/j.jaci.2014.07.046) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2015 135, 81-91DOI: (10.1016/j.jaci.2014.07.046) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2015 135, 81-91DOI: (10.1016/j.jaci.2014.07.046) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2015 135, 81-91DOI: (10.1016/j.jaci.2014.07.046) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2015 135, 81-91DOI: (10.1016/j.jaci.2014.07.046) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions