Ryan H. Dougherty, MD, Sukhvinder S

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Presentation transcript:

Accumulation of intraepithelial mast cells with a unique protease phenotype in TH2-high asthma Ryan H. Dougherty, MD, Sukhvinder S. Sidhu, PhD, Kavita Raman, PhD, Margaret Solon, BA, Owen D. Solberg, PhD, George H. Caughey, MD, Prescott G. Woodruff, MD, MPH, John V. Fahy, MD, MSc Journal of Allergy and Clinical Immunology Volume 125, Issue 5, Pages 1046-1053.e8 (May 2010) DOI: 10.1016/j.jaci.2010.03.003 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Epithelial gene expression of mast cell proteases, as determined by means of gene array (top row) and qPCR (bottom row). Lines represent median values. A, Asthmatic; H, healthy. ∗P < .0001. Journal of Allergy and Clinical Immunology 2010 125, 1046-1053.e8DOI: (10.1016/j.jaci.2010.03.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Heat map showing genes in cluster number 24 from unsupervised hierarchical clustering of gene expression data from epithelial brushings of asthmatic subjects (TH2 high, n = 22; TH2 low, n = 20) and healthy control subjects (n = 28). The color bar along the top indicates subject status: green, healthy; blue, TH2-low asthma; red, TH2-high asthma. Journal of Allergy and Clinical Immunology 2010 125, 1046-1053.e8DOI: (10.1016/j.jaci.2010.03.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Baseline mast cell protease gene expression is positively correlated with improvement in lung function from ICSs. Baseline (pretreatment) tryptase(A) and CPA3(B) mRNA expression levels (as measured by means of qPCR) in subjects subsequently randomized to inhaled fluticasone correlated with treatment-related improvements in lung function at 4 weeks. Journal of Allergy and Clinical Immunology 2010 125, 1046-1053.e8DOI: (10.1016/j.jaci.2010.03.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Density of mast cells within airway epithelium among subjects stratified by disease status (A) and TH2 subgroup (B). Lines represent median values, and boxes represent interquartile ranges. A, Asthmatic; H, healthy. ∗P = .011, Kruskal-Wallis test. Journal of Allergy and Clinical Immunology 2010 125, 1046-1053.e8DOI: (10.1016/j.jaci.2010.03.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Immunohistochemistry in endobronchial biopsy specimens for mast cells and basophils. A and B, Serial sections show tryptase-positive cells within the epithelium (arrows; Fig 5, A) and absence of basophils (Fig 5, B). C and D, Serial sections show tryptase-positive cells within the epithelium (arrow; Fig 5, C) and chymase-positive cells in the submucosa (arrow; Fig 5, D). E, Anti-CPA3 shows CPA3-positive cells (arrows). Additional immunostaining is shown in Fig E5. Journal of Allergy and Clinical Immunology 2010 125, 1046-1053.e8DOI: (10.1016/j.jaci.2010.03.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 IL-13 induces epithelial cell production of SCF. qPCR (A) and protein (B) levels in basal media after 4 days of treatment with control (Grey media), IL-13, TNF-α, and IL-1β. Results are shown as the fold induction over control averaged across 4 different donor cell lines. ∗P = .02 and ∗∗P = .004 versus control. Journal of Allergy and Clinical Immunology 2010 125, 1046-1053.e8DOI: (10.1016/j.jaci.2010.03.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 CM from IL-13–treated epithelial cells suppresses mast cell chymase but not tryptase or CPA3. Cord blood–derived mast cells were grown in CM from human epithelial cells treated with control media or IL-13 (10 ng/mL; CM/IL-13). A and B, qPCR data (means ± SDs). C, Immunostaining of mast cells for tryptase, CPA3, and chymase. ∗P = .002. Journal of Allergy and Clinical Immunology 2010 125, 1046-1053.e8DOI: (10.1016/j.jaci.2010.03.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Ratio of CPA3 to tryptase epithelial gene expression, as determined by means of qPCR. There was a trend toward slightly higher CPA3/tryptase ratios in subjects with TH2-high asthma compared with those seen in subjects with TH2-low asthma and healthy control subjects (H). P = .135, Kruskal-Wallis test (P = .054 for subjects with TH2-high asthma vs healthy control subjects). Journal of Allergy and Clinical Immunology 2010 125, 1046-1053.e8DOI: (10.1016/j.jaci.2010.03.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Correlations between tryptase- and IL-13–responsive genes (periostin, CLCA1, and serpin B2). Pearson correlations with microarray normalized intensity values are shown. Journal of Allergy and Clinical Immunology 2010 125, 1046-1053.e8DOI: (10.1016/j.jaci.2010.03.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

SCF epithelial gene expression by microarray SCF epithelial gene expression by microarray. SCF expression is significantly higher in subjects with TH2-high asthma compared with that seen in subjects with TH2-low asthma and healthy control subjects (H). P = .0019, Kruskal-Wallis test. ∗P < .001, subjects with TH2-high asthma versus healthy control subjects. ∗∗P < .01, subjects with TH2-high asthma versus subjects with TH2-low asthma. Journal of Allergy and Clinical Immunology 2010 125, 1046-1053.e8DOI: (10.1016/j.jaci.2010.03.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Immunostaining of a section of lung tissue from lungs of a patient who died from status asthmaticus. The finding of scattered BB1-positive cells in the submucosa (examples highlighted with arrows) agrees with the findings of Kepley et al.E9 These data serve as a positive control for the BB1 immunostaining data in the mucosal biopsy specimens from patients with mild-to-moderate asthma. Journal of Allergy and Clinical Immunology 2010 125, 1046-1053.e8DOI: (10.1016/j.jaci.2010.03.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Immunostaining for tryptase (AA1 antibody) and CPA3 (CPA3 antibody) in a lung section from a patient with fatal asthma shows colocalization of tryptase and CPA3 in the airway epithelium. Journal of Allergy and Clinical Immunology 2010 125, 1046-1053.e8DOI: (10.1016/j.jaci.2010.03.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions