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. 2022 Nov 3;60(5):2102130.
doi: 10.1183/13993003.02130-2021. Print 2022 Nov.

IgA+ memory B-cells are significantly increased in patients with asthma and small airway dysfunction

Anika Habener  1   2   3 , Ruth Grychtol  1   2   3 , Svenja Gaedcke  2 , David DeLuca  2 , Anna-Maria Dittrich  1   2 , Christine Happle  1   2 , Mustafa Abdo  4   5 , Henrik Watz  4   6 , Frauke Pedersen  4   5   6 , Inke Regina König  4   7 , Dominik Thiele  4   7 , Matthias Volkmar Kopp  4   8   9 , Erika von Mutius  10   11   12 , Thomas Bahmer  4   5   13 , Klaus Friedrich Rabe  4   5 , Almut Meyer-Bahlburg  14 , Gesine Hansen  15   2   16 ; ALLIANCE Study Group as part of the German Center for Lung Research (DZL); Oliver Fuchs, Barbara Roesler, Nils Welchering, Naschla Kohistani-Greif, Johanna Kurz, Katja Landgraf-Rauf, Kristina Laubhahn, Nicole Maison, Claudia Liebl, Bianca Schaub, Markus Ege, Sabina Illi, Alexander Hose, Esther Zeitlmann, Mira Berbig, Carola Marzi, Christina Schauberger, Ulrich Zissler, Carsten Schmidt-Weber, Isabell Ricklefs, Gesa Diekmann, Lena Liboschik, Gesche Voigt, Laila Sultansei, Markus Weckmann, Gyde Nissen, Anne-Marie Kirsten, Benjamin Waschki, Christian Herzmann, Heike Biller, Karoline I Gaede, Xenia Bovermann, Alena Steinmetz, Berrit Liselotte Husstedt, Catharina Nitsche, Vera Veith, Marlen Szewczyk, Folke Brinkmann, Aydin Malik, Nicolaus Schwerk, Christian Dopfer, Mareike Price, Adan Chari Jirmo, Bin Liu, Mifflin-Rae Calveron, Stefanie Weber, Svenja Foth, Chrysanthi Skevaki, Harald Renz, Meike Meyer, Tom Schildberg, Ernst Rietschel, Silke van Koningsbruggen-Rietschel, Miguel Alcazar
Affiliations

IgA+ memory B-cells are significantly increased in patients with asthma and small airway dysfunction

Anika Habener et al. Eur Respir J. .

Abstract

Background: Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma.

Methods: In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models.

Results: Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgA+ memory B-cells were associated with impaired lung function and specifically with parameters indicative for augmented resistance in the peripheral airways. Accordingly, asthma patients with small airway dysfunction (SAD) defined by impulse oscillometry showed increased frequencies of IgA+ memory B-cells, particularly in patients with mild-moderate asthma. Additionally, IgA+ memory B-cells significantly correlated with clinical features of SAD such as exacerbations.

Conclusions: With this study we demonstrate for the first time a significant association of increased IgA+ memory B-cells with asthma and SAD, pointing towards future options for B-cell-directed strategies in preventing and treating asthma.

Trial registration: ClinicalTrials.gov NCT02419274.

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Conflict of interest statement

Conflict of interest: C. Happle reports grants from Novartis and Pari, outside the submitted work. M.V. Kopp reports grants from Allergopharma GmbH and Vertex GmbH; honoraria for lectures from Allergopharma GmbH, Sanofi GmbH, Infectopharm GmbH, Vertex GmbH and Leti GmbH; advisory board membership at Allergopharma GmbH and Sanofi GmbH; outside the submitted work. E. von Mutius reports royalties from Elsevier GmbH, Georg Thieme Verlag, Springer-Verlag GmbH and Elsevier Ltd; consulting fees from the Chinese University of Hong Kong, European Commission, HiPP GmbH & Co KG and AstraZeneca; lecture honoraria from Massachusetts Medical Society, Springer-Verlag GmbH, Elsevier Ltd, Boehringer Ingelheim International GmbH, European Respiratory Society, Universiteit Utrecht – Faculteit Diergeneeskunde, Universität Salzburg, Springer Medizin Verlag GmbH, Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), Klinikum Rechts der Isar, University of Colorado, Paul-Martini-Stiftung and Imperial College London; travel support from Verein zur Förderung der Pneumologie am Krankenhaus Großhansdorf eV, Pneumologie Développement, Mondial Congress & Events GmbH & Co. KG, American Academy of Allergy, Asthma & Immunology, Imperial College London, Margaux Orange, Volkswagen Stiftung, Boehringer Ingelheim International GmbH, European Respiratory Society, Universiteit Utrecht – Faculteit Diergeneeskunde, Österreichische Gesellschaft für Allergologie und Immunologie, Massachusetts Medical Society, OM Pharma SA, Hanson Wade Ltd, iKOMM GmbH, DSI Dansk Borneastma Center, American Thoracic Society, HiPP GmbH & Co. KG and Universiteit Utrecht – Faculteit Bètawetenschappen; outside the submitted work. In addition, E. von Mutius has patent LU101064 (Barn dust extract for the prevention and treatment of diseases) pending, royalties paid to ProtectImmun for patent EP2361632 (Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders, granted on 19 March 2014), and patents EP1411977 (Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases, granted on 18 April 2007), EP1637147 (Stable dust extract for allergy protection, granted on 10 December 2008) and EP1964570 (Pharmaceutical compound to protect against allergies and inflammatory diseases, granted on 21 November 2012) licensed to ProtectImmun. In addition, E. von Mutius is a member of the EXPANSE (funded by European Commission) Scientific Advisory Board, member of the BEAMS External Scientific Advisory Board (ESAB), member of the Editorial Board of the Journal of Allergy and Clinical Immunology: In Practice, member of the Scientific Advisory Board of the Children's Respiratory and Environmental Workgroup (CREW), member of the International Scientific and Societal Advisory Board (ISSAB) of Utrecht Life Sciences (ULS), University of Utrecht, member of the External Review Panel of the Faculty of Veterinary Science, University of Utrecht, member of the Selection Committee for the Gottfried Wilhelm Leibniz Programme (DFG), member of the International Advisory Board of the Asthma UK Centre for Applied Research (AUKCAR), member of the International Advisory Board of The Lancet Respiratory Medicine, and member of the Scientific Advisory Board of the CHILD (Canadian Healthy Infant Longitudinal Development) study, McMaster University, Hamilton, Canada. T. Bahmer reports grants from Network University Medicine (NUM): National Pandemic Cohort Network (NAPKON); consulting fees and lecture honoraria from AstraZeneca, Novartis, GlaxoSmithKline, Roche and Chiesi; travel support from Chiesi and AstraZeneca; outside the submitted work. K.F. Rabe reports lecture honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, Novartis, Sanofi Regeneron, GlaxoSmithKline, Berlin-Chemie and Roche; advisory board membership at AstraZeneca and Sanofi Regeneron; leadership roles with the German Center for Lung Research (DZL), German Chest Society (DGP) and American Thoracic Society; outside the submitted work. A. Meyer-Bahlburg reports lecture honoraria from Pfizer; travel support from CSL Behring; advisory board membership with Pfizer; outside the submitted work. G. Hansen reports consulting fees from Sanofi GmbH; lecture honoraria from MedUpdate and AbbVie; outside the submitted work. All other authors have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Pairwise a) comparisons and b) correlations between B-cell populations and clinical parameters of asthma patients and healthy controls. Colour code shows a) significant p-values and b) estimate for significant correlations analysed by Kruskal–Wallis or Spearman's correlation, respectively, with adjustment for multiple testing (padjusted). B-cell subsets are presented as percentage of total CD19+ B-cells. BMI: body mass index; GINA: Global Initiative for Asthma; BDR: bronchodilator response; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; FEF25–75%: forced expiratory flow at 25–75% of FVC; AX: reactance area; R5–R20: resistance at 5 Hz−resistance at 20 Hz; OCS: oral corticosteroids; T1: transitional 1; T2: transitional 2. ns: nonsignificant.
FIGURE 2
FIGURE 2
Associations between B-cell subsets and clinical parameters of asthma patients and healthy controls. Associations with a) asthma severity, b) oral corticosteroid (OCS) intake, c) asthma control and sputum inflammation, and d) forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), forced expiratory flow at 25–75% of FVC (FEF25–75%), reactance area (AX) and resistance at 5 Hz−resistance at 20 Hz (R5−R20) are shown for asthma patients and healthy controls. Overall adjusted p-values after multiple test corrections and p-values from categorical group comparisons are shown as well as R and adjusted p-values from Spearman correlations. Further significant associations are shown in supplementary figure S2. T1: transitional 1; mod: moderate; T2: transitional 2; OCS: oral corticosteroids; C: controlled; PC: partly controlled; UC: uncontrolled; P: paucigranulocytic; E: eosinophilic; N: neutrophilic; M: mixed granulocytic. ns: nonsignificant; *: p<0.05; **: p<0.01; ***: p<0.001; ****: p<0.0001.
FIGURE 3
FIGURE 3
IgA+ memory B-cells and small airway dysfunction (SAD). a) CD27+IgA+ memory B-cells in patients with or without SAD. b) CD27+IgA+ B-cells in patients with or without SAD in mild–moderate (mild-mod) asthma and severe asthma. c) CD27+IgA+ B-cells in patients with or without central airway obstruction (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)<lower limit of normal (LLN; z-score −1.64)) and with or without SAD. **: p<0.01; ***: p<0.001.
FIGURE 4
FIGURE 4
Correlations of number of exacerbations with clinical and B-cell parameters. Dark red defines the highest positive correlation between the parameters and dark blue shows the lowest negative correlation between the variables. Adjusted p-values after multiple test corrections are shown next to the bars. AX: reactance area; ICS: inhaled corticosteroids; R5–R20: resistance at 5 Hz−resistance at 20 Hz; BMI: body mass index; FENO: exhaled nitric oxide fraction; OCS: oral corticosteroids; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; FEF25–75%: forced expiratory flow at 25–75% of FVC. ns: nonsignificant; *: p<0.05; **: p<0.01; ***: p<0.001.
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References

    1. Chronic Respiratory Disease Collaborators . Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med 2020; 8: 585–596. doi:10.1016/S2213-2600(20)30105-3 - DOI - PMC - PubMed
    1. Pavord ID, Beasley R, Agusti A, et al. . After asthma: redefining airways diseases. Lancet 2018; 391: 350–400. doi:10.1016/S0140-6736(17)30879-6 - DOI - PubMed
    1. McGregor MC, Krings JG, Nair P, et al. . Role of biologics in asthma. Am J Respir Crit Care Med 2019; 199: 433–445. doi:10.1164/rccm.201810-1944CI - DOI - PMC - PubMed
    1. Akdis CA, Arkwright PD, Bruggen MC, et al. . Type 2 immunity in the skin and lungs. Allergy 2020; 75: 1582–1605. doi:10.1111/all.14318 - DOI - PubMed
    1. Happle C, Jirmo AC, Meyer-Bahlburg A, et al. . B cells control maternofetal priming of allergy and tolerance in a murine model of allergic airway inflammation. J Allergy Clin Immunol 2018; 141: 685–696. doi:10.1016/j.jaci.2017.03.051 - DOI - PubMed

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