Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33 Susana Castanhinha, MD, Rebekah Sherburn, MSc, Simone Walker,

Slides:

Advertisements

Similar presentations

Dysregulation of type 2 innate lymphoid cells and TH2 cells impairs pollutant-induced allergic airway responses Katrien C. De Grove, MSc, Sharen Provoost,

Advertisements

Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function Cecilia K. Andersson, PhD, Alexandra Adams, MBBS, Prasad.

Exposure to allergen and diesel exhaust particles potentiates secondary allergen- specific memory responses, promoting asthma susceptibility Eric B. Brandt,

Sejal Saglani, MD, Stephen Lui, PhD, Nicola Ullmann, MD, Gaynor A

Epoxyeicosatrienoic acids are involved in the C70 fullerene derivative–induced control of allergic asthma Sarah K. Norton, PhD, Dayanjan S. Wijesinghe,

IL-4 induces IL-13–independent allergic airway inflammation

Weiguo Chen, PhD, Umasundari Sivaprasad, PhD, Aaron M

Effective prevention and therapy of experimental allergic asthma using a GATA-3– specific DNAzyme Serdar Sel, MD, Michael Wegmann, PhD, Tanja Dicke, MSc,

The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF- like (BATF), regulates lymphocyte- and mast cell–driven immune.

Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model Sylvie Amu, PhD, Sean P.

The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF- like (BATF), regulates lymphocyte- and mast cell–driven immune.

Robert J. Snelgrove, PhD, Lisa G

Increased airway smooth muscle in preschool wheezers who have asthma at school age Ruth O'Reilly, MBChBBAO, Nicola Ullmann, MD, Samantha Irving, BSc,

Allergy prevention starts before conception: Maternofetal transfer of tolerance protects against the development of asthma Tobias Polte, PhD, Christian.

Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function Cecilia K. Andersson, PhD, Alexandra Adams, MBBS, Prasad.

Innate IL-13–producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity Jillian L. Barlow, PhD, Agustin Bellosi,

Frank Kirstein, PhD, Natalie E

Maternal house dust mite exposure during pregnancy enhances severity of house dust mite–induced asthma in murine offspring Phoebe K. Richgels, MS, Amnah.

Exposure to allergen and diesel exhaust particles potentiates secondary allergen- specific memory responses, promoting asthma susceptibility Eric B. Brandt,

Nazanin Farhadi, MSc, Laura Lambert, BA, Chiara Triulzi, PhD, Peter J

Pentraxin 3 deletion aggravates allergic inflammation through a TH17-dominant phenotype and enhanced CD4 T-cell survival Jyoti Balhara, MSc, Lianyu Shan,

Type 2 innate lymphoid cells in induced sputum from children with severe asthma Prasad Nagakumar, MBBS, Laura Denney, PhD, Louise Fleming, MD, Andrew.

IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs Chien-Chang Chen, PhD, Takao Kobayashi, PhD, Koji Iijima,

Airway inflammation after epicutaneous sensitization of mice requires protease activity of low-dose allergen inhalation Izumi Nishioka, MD, PhD, Toshiro.

Restoration of T-box–containing protein expressed in T cells protects against allergen- induced asthma Jung Won Park, MD, Hyun Jung Min, MS, Jung Ho Sohn,

CD1d restricted natural killer T cells are not required for allergic skin inflammation Abdallah Elkhal, PhD, Muriel Pichavant, PhD, Rui He, PhD, Jordan.

Β-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses Zhonghua Zhang, MD, Jocelyn.

Allergic airway disease is unaffected by the absence of IL-4Rα–dependent alternatively activated macrophages Natalie E. Nieuwenhuizen, PhD, Frank Kirstein,

Signaling through FcRγ-associated receptors on dendritic cells drives IL-33–dependent TH2-type responses Melissa Y. Tjota, BA, Cara L. Hrusch, PhD, Kelly.

Activin A and TGF-β promote TH9 cell–mediated pulmonary allergic pathology Carla P. Jones, PhD, Lisa G. Gregory, PhD, Benjamin Causton, BSc, Gaynor A.

Notch signaling in T cells is essential for allergic airway inflammation, but expression of the Notch ligands Jagged 1 and Jagged 2 on dendritic cells.

Prime role of IL-17A in neutrophilia and airway smooth muscle contraction in a house dust mite–induced allergic asthma model Julie Chesné, PhD, Faouzi.

CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling Jennifer Kearley, PhD, Douglas S. Robinson,

Volume 43, Issue 5, Pages (November 2015)

Experimental gastrointestinal allergy enhances pulmonary responses to specific and unrelated allergens Eric B. Brandt, PhD, Troy A. Scribner, MD, Hiroko.

Frank Kirstein, PhD, Natalie E

Inhibition of house dust mite–induced allergic airways disease by antagonism of microRNA-145 is comparable to glucocorticoid treatment Adam Collison,

Requirements for allergen-induced airway inflammation and hyperreactivity in CD4- deficient and CD4-sufficient HLA-DQ transgenic mice Svetlana P. Chapoval,

Stephan Löser, MSc, Lisa G

Pediatric severe asthma is characterized by eosinophilia and remodeling without TH2 cytokines Cara J. Bossley, MBChB, Louise Fleming, MD, Atul Gupta,

Takao Kobayashi, PhD, Koji Iijima, PhD, Alexander L

Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells Elizabeth.

Regulation of allergic airway inflammation by class I–restricted allergen presentation and CD8 T-cell infiltration James W. Wells, PhD, Christopher J.

Pre-pregnancy exposure to diesel exhaust predisposes offspring to asthma through IL- 1β and IL-17A Jerica Lenberg, BS, Qian Qian, PhD, Zehua Sun, PhD,

Janus kinase 1/3 signaling pathways are key initiators of TH2 differentiation and lung allergic responses Shigeru Ashino, PhD, Katsuyuki Takeda, MD,

Prophylactic and therapeutic inhibition of allergic airway inflammation by probiotic Escherichia coli O83 Christian Zwicker, MSc, Priya Sarate, MSc,

CD4-mediated regulatory T-cell activation inhibits the development of disease in a humanized mouse model of allergic airway disease Helen Martin, MS,

Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity Sean.

Dysregulation of type 2 innate lymphoid cells and TH2 cells impairs pollutant-induced allergic airway responses Katrien C. De Grove, MSc, Sharen Provoost,

Does reduced zona pellucida binding protein 2 (ZPBP2) expression on chromosome 17q21 protect against asthma? Marina Miller, MD, PhD, Christine Vuong,

Role of B cells in TH cell responses in a mouse model of asthma

Sarita Sehra, PhD, Weiguo Yao, PhD, Evelyn T. Nguyen, MS, Nicole L

Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33–basophil axis in mice Nicholas Venturelli, BS, Willem S. Lexmond, MD,

Stephan Löser, MSc, Lisa G

Susceptibility to allergic lung disease regulated by recall responses of dual-receptor memory T cells∗ Mark A. Aronica, MD, Shadi Swaidani, MS, Yan H.

Diesel exhaust particles exert acute effects on airway inflammation and function in murine allergen provocation models Minqi Hao, MD, PhD, Stephania.

Stephanie A. Shore, PhD, Raya D

IL-10–treated dendritic cells decrease airway hyperresponsiveness and airway inflammation in mice Toshiyuki Koya, MD, PhD, Hiroyuki Matsuda, MD, PhD,

Duy Pham, PhD, Sarita Sehra, PhD, Xin Sun, PhD, Mark H. Kaplan, PhD

Unique and overlapping gene expression patterns driven by IL-4 and IL-13 in the mouse lung Christina C. Lewis, PhD, Bruce Aronow, PhD, John Hutton, MD,

Effects of diesel exhaust on allergic airway inflammation in mice

Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma

David S. Southam, BSc, Natasha Widmer, Russ Ellis, BSc, Jeremy A

MicroRNA-155 is essential for TH2-mediated allergen-induced eosinophilic inflammation in the lung Carina Malmhäll, BSc, Sahar Alawieh, BSc, You Lu, PhD,

Eric B. Brandt, PhD, Melissa K. Mingler, MS, Michelle D

The extra domain A of fibronectin is essential for allergen-induced airway fibrosis and hyperresponsiveness in mice Martin Kohan, MSc, Andres F. Muro,

IL-33 is not critical for initiation of allergic airways disease phenotype. IL-33 is not critical for initiation of allergic airways disease phenotype.

TNF can contribute to multiple features of ovalbumin-induced allergic inflammation of the airways in mice Susumu Nakae, PhD, Carolina Lunderius, PhD,

In response to allergen, T cells and ILCs are equally important sources of IL-13. In response to allergen, T cells and ILCs are equally important sources.

T cell–derived IL-13 is essential for the inception of AHR.

Presentation transcript:

Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33 Susana Castanhinha, MD, Rebekah Sherburn, MSc, Simone Walker, BSc, Atul Gupta, MD(Res), Cara J. Bossley, MD(Res), James Buckley, PhD, Nicola Ullmann, MD, Ruth Grychtol, MD, Gaynor Campbell, PhD, Marco Maglione, MD, Sergio Koo, MPH, Louise Fleming, MD, Lisa Gregory, PhD, Robert J. Snelgrove, PhD, Andrew Bush, MD, Clare M. Lloyd, PhD, Sejal Saglani, MD Journal of Allergy and Clinical Immunology Volume 136, Issue 2, Pages 312-322.e7 (August 2015) DOI: 10.1016/j.jaci.2015.01.016 Copyright © 2015 The Authors Terms and Conditions

Fig 1 Increased IL-33 levels (A) and MMP-9 activity (B) in BAL fluid and increased submucosal IL-33+ cell numbers in endobronchial biopsy specimens (C) from children with STRA and SAFS compared with those without fungal sensitization (no SAFS). There were 18 specimens for BAL data, and 33 specimens for biopsy data. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology 2015 136, 312-322.e7DOI: (10.1016/j.jaci.2015.01.016) Copyright © 2015 The Authors Terms and Conditions

Fig 2 Fungal exposure in neonatal mice resulted in more severe atopy and inflammation than HDM exposure, but AHR was similar with both allergens. Neonatal BALB/c mice were challenged with intranasal HDM (20 μg for the first 2 weeks and then 25 μg) or A alternata (Alt; 5 μg for the first 2 weeks and then 10 μg) for 3 weeks (A), and assessments of AHR (B), total serum IgE levels (C), allergen-specific IgE levels (D), total pulmonary inflammation (E), and eosinophilic inflammation (F) were made. Data are representative of 2 experiments (n = 4-8 per group). *P < .05 and **P < .01. ns, Not significant. Journal of Allergy and Clinical Immunology 2015 136, 312-322.e7DOI: (10.1016/j.jaci.2015.01.016) Copyright © 2015 The Authors Terms and Conditions

Fig 3 A alternata exposure resulted in significantly increased lung IL-33 levels, but lung IL-13 levels were similar to those after HDM exposure. Pulmonary IL-4 (A), IL-5 (B), IL-13 (C), and IL-33 (D) levels; BAL fluid MMP-9 levels (E); IL-13+ Lin−CD45+ICOS+ ILC numbers (F); and IL-13+CD3+CD4+ T-cell numbers (G) in neonatal BALB/c mice exposed to intranasal saline (PBS), HDM, or A alternata (Alt) for 3 weeks are shown. Data are representative of 2 experiments (n = 4-8 per group). *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2015 136, 312-322.e7DOI: (10.1016/j.jaci.2015.01.016) Copyright © 2015 The Authors Terms and Conditions

Fig 4 Neonatal ST2−/− mice have significantly reduced allergic airways disease after A alternata exposure compared with wild-type mice. Neonatal mice were exposed to intermittent intranasal A alternata (Alt; 5 μg for the first 2 weeks and then 10 μg) or saline (PBS) from day 3 of life for 3 weeks. AHR (A and B), total serum IgE levels (C), pulmonary IL-13 levels (D), and IL-13+Lin−CD45+ICOS+ ILCs (E) and IL-13+CD3+CD4+ T cells (F) were assessed. Data are representative of 2 experiments (n = 6-8 per group). *P < .05 and **P < .01. MCh, Methacholine; ns, not significant. Journal of Allergy and Clinical Immunology 2015 136, 312-322.e7DOI: (10.1016/j.jaci.2015.01.016) Copyright © 2015 The Authors Terms and Conditions

Fig 5 AHR is unaffected by steroids after A alternata exposure, whereas inflammation and serum IgE levels are reduced. A, Neonatal BALB/c mice were exposed to intranasal (I-N) saline (PBS), HDM, or A alternata (Alt) from day 3 of life for 3 weeks, with concomitant intranasal budesonide (0.6 mg/kg) or PBS from day 10 of life for 2 weeks (prevention regimen). B-G, AHR (Fig 5, B and C), total lung inflammation (Fig 5, D), BAL inflammation (Fig 5, E), and serum immunoglobulin levels (Fig 5, F and G) were assessed (n = 4-6 per group [PBS] or n = 6-8 per group [HDM or Alt]. *P < .05 and **P < .01. MCh, Methacholine; ns, not significant. Journal of Allergy and Clinical Immunology 2015 136, 312-322.e7DOI: (10.1016/j.jaci.2015.01.016) Copyright © 2015 The Authors Terms and Conditions

Fig 6 Steroids did not reduce IL-33 levels. Lung IL-13 levels and IL-13+ ILC and IL-13+ T-cell numbers only remained increased after steroids with A alternata exposure. Neonatal BALB/c mice were exposed to intranasal saline (PBS), HDM, or A alternata (Alt) for 3 weeks from day 3 of life, with either concomitant intranasal budesonide or saline (PBS). Lung IL-13+Lin−CD45+ICOS+ ILCs (A) and IL-13+CD3+CD4+ T cells (B) were quantified by means of flow cytometry. Levels of pulmonary IL-13 (C) and IL-33 (D) were measured by means of ELISA. There were 4 to 6 per group for the PBS group and 6 to 8 per group for the HDM or A alternata groups. *P < .05, **P < .01, and ***P < .001. ns, Not significant. Journal of Allergy and Clinical Immunology 2015 136, 312-322.e7DOI: (10.1016/j.jaci.2015.01.016) Copyright © 2015 The Authors Terms and Conditions

Fig E1 IL-33 levels were quantified in BAL fluid by means of Western blotting (A), and IL-33+ cells stained by means of immunohistochemistry were quantified in the submucosa of endobronchial biopsy specimens (B; n = 14 children). Group differences were assessed by using the Mann-Whitney U test: *P < .05. ns, Not significant. Journal of Allergy and Clinical Immunology 2015 136, 312-322.e7DOI: (10.1016/j.jaci.2015.01.016) Copyright © 2015 The Authors Terms and Conditions

Fig E2 Endobronchial biopsy specimens from children aged 6 to 16 years with severe asthma receiving high-dose inhaled steroids only were stained by using immunohistochemistry for IL-33 expression. IL-33+ cells in the submucosa were counted and expressed per area of submucosa in children with SAFS compared with children with severe asthma without fungal sensitization (no-SAFS; n = 2). Group differences were assessed by using the Mann-Whitney U test: **P < .01. Journal of Allergy and Clinical Immunology 2015 136, 312-322.e7DOI: (10.1016/j.jaci.2015.01.016) Copyright © 2015 The Authors Terms and Conditions

Fig E3 Neonatal BALB/c mice were exposed to intermittent intranasal A alternata (Alt), HDM, or saline (PBS) for 3 weeks. Total BAL fluid IL-13 levels were measured by means of ELISA (A), and numbers of Lin−CD45+ICOS+ ILCs (B) and CD3+CD4+ T cells (C) were quantified by means of flow cytometry. *P < .05, **P < .01, and ***P < .001. ns, Not significant. Journal of Allergy and Clinical Immunology 2015 136, 312-322.e7DOI: (10.1016/j.jaci.2015.01.016) Copyright © 2015 The Authors Terms and Conditions

Fig E4 Neonatal ST2−/− and wild-type mice were exposed to intermittent intranasal A alternata (Alt; 5 μg for the first 2 weeks and then 10 μg) or saline (PBS) from day 3 of life for 3 weeks. Levels of IL-4 (A), IL-5 (B), IL-33 (C), and MMP-9 (D) were measured in lung homogenates (LH) by means of ELISA. Data are representative of 2 experiments (n = 6-8 per group). *P < .05. Journal of Allergy and Clinical Immunology 2015 136, 312-322.e7DOI: (10.1016/j.jaci.2015.01.016) Copyright © 2015 The Authors Terms and Conditions

Fig E5 Neonatal BALB/c mice were exposed to intranasal saline (PBS), HDM, or A alternata (Alt) from day 3 of life for 3 weeks, with concomitant intranasal budesonide (0.6 mg/kg) or PBS from day 10 of life for 2 weeks (prevention regimen). These data relate to the same experiment shown in Fig 5. Numbers of eosinophils were quantified by means of flow cytometry in lung digests after A alternata exposure (A) and HDM exposure (B) with and without budesonide (Bud; n = 4-6 per group for PBS and n = 6-8 per group for HDM or A alternata. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2015 136, 312-322.e7DOI: (10.1016/j.jaci.2015.01.016) Copyright © 2015 The Authors Terms and Conditions

Fig E6 Endobronchial biopsy specimens from children aged 6 to 16 years with severe asthma were stained by means of immunohistochemistry for IL-13 expression. A, IL-13+ cells in the submucosa were counted and expressed per area of submucosa in children with SAFS compared with children with severe asthma without fungal sensitization (no SAFS). B-E, IL-13 (Fig E6, B), IL-5 (Fig E6, C), IL-6 (Fig E6, D), and IL-8 (Fig E6, E) levels in BAL fluid from children with SAFS and non-SAFS were quantified by using the Luminex multiplex assay (Bio-Rad). ns, Not significant. Journal of Allergy and Clinical Immunology 2015 136, 312-322.e7DOI: (10.1016/j.jaci.2015.01.016) Copyright © 2015 The Authors Terms and Conditions