Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia Steven.

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Presentation transcript:

Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia Steven G. Smith, PhD, Ruchong Chen, MD, Melanie Kjarsgaard, RRT, Chynna Huang, RRT, John-Paul Oliveria, BSc, Paul M. O'Byrne, MD, Gail M. Gauvreau, PhD, Louis-Philippe Boulet, MD, Catherine Lemiere, MD, James Martin, MD, DSc, Parameswaran Nair, MD, PhD, Roma Sehmi, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 1, Pages 75-86.e8 (January 2016) DOI: 10.1016/j.jaci.2015.05.037 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Multigating strategy for ILC2 enumeration from sputum. Representative plots from a patient with severe asthma show sequential gating of sputum cells to identified Lin− (region R1), CD45+ (region R2), and CD127+ST2+ cells (region R3; A) and intracellular IL-5+, IL-13+, and IL-5+IL-13+ ILC2 quantification (B) by using a 98% confidence limit. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Absolute ILC2 numbers in asthmatic patients. A, Absolute numbers of ILC2s were significantly increased in the blood of patients with severe asthma compared (n = 25) with values in those with mild asthma (n = 19). B, Similar findings were observed in sputum samples from the same subjects (severe asthma, n = 15; mild asthma, n = 18). Absolute cell numbers enumerated by means of flow cytometry are presented as cells per milliliter, and the bars represent the median values of each data set. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Levels of intracellular cytokine expression by ILC2s in blood and sputum. A, Absolute numbers of ILC2s expressing intracellular IL-5, IL-13, or both were significantly greater in the blood of patients with severe asthma (n = 25) compared with values in those with mild asthma (n = 9). B, In sputum only the absolute number of IL-5+ ILC2s was significantly greater in patients with severe asthma (n = 15) compared with those in patients with mild asthma (n = 9). Data are presented as cells per milliliter, and the bars represent median values of each data set. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Comparison of absolute and intracellular cytokine expression in CD4+ lymphocytes. A, Significantly greater absolute numbers of CD4+ cells were detected in sputum of patients with severe asthma (n = 13) compared with those in patients with mild asthma (n = 9). B, No significant between-group differences were found for CD4+ cells expressing intracellular TH2 cytokines, except for IL-5+ CD4 cells, numbers of which were lower in the blood of patients with severe asthma (n = 11) compared with those in patients with mild (n = 10) asthma. Data are presented as cells per milliliter, and the bars represent median values of each data set. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Comparison of absolute and intracellular cytokine expression levels of EoPs. A, Significantly higher CD34+CD45+IL-5Rα+ cell numbers were detected in blood and sputum of patients with severe asthma (n = 13) compared with value sin those with mild asthma (n = 9). B, Significantly greater numbers of EoPs expressing IL-5, IL-13, and both were found in the blood but not sputum of patients with severe asthma. Data are presented as cells per milliliter, and the bars represent median values of each data set. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Absolute numbers and TH2 cytokine expression by type 2 cells in patients with severe asthma. A, CD4+ lymphocytes were more abundant than ILC2s, HPCs, and EoPs in both blood (n = 11) and sputum (n = 13). B, Proportionally, ILC2s are the predominant source of IL-5 and IL-13 in blood and sputum. The bars represent median values of each data set. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Heterogeneity of ILC2 activation. A, Patients with severe asthma, all with controlled blood eosinophil numbers of less than 0.3 × 106/mL, were grouped into those with controlled airway eosinophilia (<3% sputum eosinophils, n = 5) or uncontrolled airway eosinophilia (>3% sputum eosinophils, n = 6). B, Significantly higher numbers of ILC2s expressing IL-5 and IL-13 were detected in the sputum of patients with uncontrolled asthma compared with those in patients with controlled asthma. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 Diagrammatic representation of the predominant mechanisms promoting airway eosinophilia in patients with severe asthma versus those with mild asthma. We propose that in patients with prednisone-dependent severe asthma, in response to disruptive agents, epithelial cells release alarmins that activate ILC2s, which can drive in situ eosinophilopoiesis within the lung, likely through local production of IL-5 and IL-13. CD4 lymphocyte–mediated release of TH2 cytokines stimulating lung homing of mature and immature eosinophils appears to be steroid sensitive and thus diminished in patients with severe asthma but not those with mild asthma, in whom we have previously shown that IL-4 and IL-13 prime migrational responses of progenitor cells and mature eosinophils to various chemoattractants. SDF-1, Stromal cell–derived factor 1. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 CD3+CD4+ lymphocyte gating strategy in sputum. A, identification of CD45+CD3+CD4+ lymphocytes by using FlowJo software. B, IL-5, IL-13, or both intracellular cytokine expression compared with the isotype control, as assessed with a 98% confidence limit. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Sequential multigating strategy. A, Identification of HPCs (CD34+CD45+ cells) by using FlowJo software. Scatter plots show side scatter, and the CD45 region R1 identifies nucleated white blood cells. Region R2 identifies the CD34+ marker. True CD34+ cells are further isolated based on low granularity and low CD45+ marker expression (region R3). HPCs are characterized by medium size (medium forward scatter [FSC]) and low granularity (low side scatter [SSC]) region R4. B, EoPs are identified as HPCs expressing CD125 compared with the isotype control with a 98% confidence limit. C, Intracellular cytokine expression of IL-5, IL-13, or both compared with isotype control assessed with a 98% confidence limit. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Multigating strategy for ILC2 enumeration from blood. Representative plots from 1 patient in whom, by means of sequential gating, blood-derived low-density mononuclear cells were identified as (A) Lin− (region R1), CD45+ (region R2), and CD127+ST2+ cells (region R3; B) and intracellular IL-5+, IL-13+, and IL-5+IL-13+ ILCs were enumerated (B) compared with isotype control by using a 98% confidence limit. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Multigating strategy for receptor expression on sputum ILC2s. Cells identified as Lin−CD45+CD127+ST2+ cells (as in Fig 1) coexpress chemoattractant receptor–homologous molecule expressed on TH2 lymphocytes (CRTH2; A), c-Kit (CD117; B), and CD125 (IL-5Rα; C) compared with the isotype control. Gating was set at a 99% confidence limit. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Comparisons of absolute numbers of type 2 cells expressing TH2 cytokines in patients with severe asthma. Compared with ILC2s, HPCs, and EoPs, significantly greater absolute numbers of CD4+ lymphocytes expressing IL-5, IL-13, or both were found in the blood and CD4+IL-5+ in the sputum of patients with severe asthma (n = 13). Bars represent median values of each data set. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 ILC2 levels in blood of patients with controlled and those with uncontrolled severe asthma. Patients with severe asthma, all with controlled blood eosinophils of less than 0.3 × 106/mL, were grouped into those with controlled airway eosinophilia (<3% sputum eosinophils, n = 5) or uncontrolled airway eosinophilia (>3% sputum eosinophils, n = 6). No differences were observed in blood ILC2 activation levels between these groups of patients with severe asthma. Journal of Allergy and Clinical Immunology 2016 137, 75-86.e8DOI: (10.1016/j.jaci.2015.05.037) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions