RT Journal Article
SR Electronic
T1 COL4A3 is degraded in allergic asthma and degradation predicts response to anti-IgE therapy
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 2003969
DO 10.1183/13993003.03969-2020
A1 Markus Weckmann
A1 Thomas Bahmer
A1 Jannie Marie Bülow Sand
A1 Sarah Rank Rønnow
A1 Martin Pech
A1 Cornelis Vermeulen
A1 Alen Faiz
A1 Diana Julie Leeming
A1 Morten Asser Karsdal
A1 Lars Lunding
A1 Brian George G. Oliver
A1 Michael Wegmann
A1 Gudrun Ulrich-Merzenich
A1 Uwe R. Juergens
A1 Jannis Duhn
A1 Yves Laumonnier
A1 Olga Danov
A1 Katherina Sewald
A1 Ulrich Zissler
A1 Marnix Jonker
A1 Inke König
A1 Gesine Hansen
A1 Erika von Mutius
A1 Oliver Fuchs
A1 Anna-Maria Dittrich
A1 Bianca Schaub
A1 Christine Happle
A1 Klaus F. Rabe
A1 Maarten van de Berge
A1 Janette Kay Burgess
A1 Matthias Volkmar Kopp
A1 ,
YR 2021
UL http://erj.ersjournals.com/content/early/2021/05/06/13993003.03969-2020.abstract
AB Background Asthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3).Objective To delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response.Methods The serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (pediatric cases/controls: 134/35; adult cases/controls: 149/31). Exacerbation of allergic airway disease in mice was induced by sensitising to OVA, challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor, Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (CF, n=14) and CF with allergic broncho-pulmonary aspergillosis (ABPA, n=9) as well as severe allergic, uncontrolled asthmatics (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed by the Asthma Control Test.Results Serum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in CF plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic odds ratio 31.5).Conclusion C4Ma3 level depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Schweitzer has nothing to disclose.Conflict of interest: Dr. Weckmann reports grants from Federal Ministry for Education and Research (BMBF), grants from University of Luebeck, grants from German Academic Exchange Service, during the conduct of the study.Conflict of interest: Dr. Bahmer has nothing to disclose.Conflict of interest: Dr. Buelow-Sand reports other from Nordic Bioscience, during the conduct of the study; .Conflict of interest: Dr. Rank Rønnow reports is employed by Nordic Bioscience , grants from Innovation foundation , during the conduct of the study.Conflict of interest: Dr. Pech has nothing to disclose.Conflict of interest: Dr. Vermeulen has nothing to disclose.Conflict of interest: Dr. Faiz has nothing to disclose.Conflict of interest: Diana Julie Leeming is a full-time employee and stockowner at Nordic Bioscience A/S.Conflict of interest: Dr. Karsdal has nothing to disclose.Conflict of interest: Dr. Lunding has nothing to disclose.Conflict of interest: Dr. Oliver has nothing to disclose.Conflict of interest: Dr. Wegmann has nothing to disclose.Conflict of interest: Dr. Ulrich-Merzenich reports grants from Novartis AG, during the conduct of the study; In addition, Dr. Ulrich-Merzenich has a patent EPC 18185472.0-1118 pending.Conflict of interest: Dr. Juergen has nothing to disclose.Conflict of interest: Mr. Duhn has nothing to disclose.Conflict of interest: Dr. Laumonnier has nothing to disclose.Conflict of interest: Olga Danov has nothing to disclose.Conflict of interest: Dr. Sewald has nothing to disclose.Conflict of interest: Dr. Zissler reports grants and personal fees from Federal ministery for education and reserarch of Germany, during the conduct of the study.Conflict of interest: Dr. Jonker has nothing to disclose.Conflict of interest: Dr. Koenig has nothing to disclose.Conflict of interest: Dr. Hansen reports personal fees from Novartis, personal fees from Sanofi, during the conduct of the study.Conflict of interest: Dr. von Mutius reports grants from German Federal Ministry of Education and Research, during the conduct of the study; personal fees from Pharmaventures, from OM Pharma S. A., from Springer-Verlag GmbH, from Elsevier GmbH and Elsevier Ltd., from Peptinnovate Ltd., from Turun Yliopisto, from Tampereen Yliopisto, from Helsingin Yliopisto, from European Respiratory Society, from Deutsche Pharmazeutische Gesellschaft e. V., from Massachusetts Medical Society, from Chinese University of Hongkong, from European Commission, from Böhringer Ingelheim International GmbH, from Universiteit Utrecht, Faculteit Diergeneeskunde, from Universität Salzburg, from Georg Thieme Verlag, from Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), outside the submitted work; In addition, Dr. von Mutius has a patent LU101064 - Barn dust extract for the prevention and treatment of diseases pending, a patent EP2361632: Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders with royalties paid to ProtectImmun GmbH, a patent Publication number EP 1411977: Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases. licensed to ProtectImmun GmbH, a patent Publication number EP1637147: Stable dust extract for allergy protection licensed to ProtectImmun GmbH, and a patent Publication number EP 1964570: Pharmaceutical compound to protect against allergies and inflammatory diseases licensed to ProtectImmun GmbH.Conflict of interest: Dr. Fuchs reports personal fees from Vertex Germany, personal fees from Menarini Switzerland, personal fees from Novartis Switzerland, personal fees from ALK Abello Switzerland, personal fees from Vifor Switzerland, personal fees from Milupa Nutricia Switzerland, personal fees from Stallergenes Greer Switzerland, personal fees from Bencard Switzerland, personal fees from Medical Tribune Switzerland, personal fees from aha! Swiss Allergy Centre, personal fees from German Society of Paediatric Allergology, outside the submitted work.Conflict of interest: Dr. Dittrich has nothing to disclose.Conflict of interest: Dr. Schaub reports grants from DFG, grants from BMBF, grants from EU, outside the submitted work.Conflict of interest: Dr. Happle has nothing to disclose.Conflict of interest: Prof. Dr. Klaus F. Rabe reports grants and personal fees from Boehringer and Astra Zeneca, personal fees from Novartis, Sanofi, Regeneron, Roche and Chiesi Pharmaceuticals outside the submitted work.Conflict of interest: Dr. van den Berge reports grants paid to UNiversity from GlaxoSmithKline, Astra Zeneca, Genentech, outside the submitted work.Conflict of interest: Dr. Burgess reports grants from National Health and Medical Research Council, Australia, grants from University of Groningen, grants from European Union, during the conduct of the study.Conflict of interest: Dr. Kopp reports grants from Federal Ministry of Research and Education (BMBF), during the conduct of the study; personal fees from ALK-Abello, personal fees from Allergopharma, personal fees from Boehringer-Ingelheim, personal fees from Chiesi, personal fees from Glaxo, personal fees from Infectopharm, personal fees from Meda, personal fees from Sanofi-Aventis, personal fees from Leti Pharma, personal fees from Novartis, personal fees from Vertex, outside the submitted work.