COL4A3 is degraded in allergic asthma and degradation predicts response to anti-IgE therapy

ALLIANCE Study Group as part of the German Centre for Lung Research (DZL), Markus Weckmann*, Thomas Bahmer, Jannie Marie Bülow Sand, Sarah Rank Rønnow, Martin Pech, Cornelis Vermeulen, Alen Faiz, Diana Julie Leeming, Morten Asser Karsdal, Lars Lunding, Brian George G Oliver, Michael Wegmann, Gudrun Ulrich-Merzenich, Uwe R Juergens, Jannis Duhn, Yves Laumonnier, Olga Danov, Katherina Sewald, Ulrich ZisslerMarnix Jonker, Inke König, Gesine Hansen, Erika von Mutius, Oliver Fuchs, Anna-Maria Dittrich, Bianca Schaub, Christine Happle, Klaus F Rabe, Maarten van de Berge, Janette Kay Burgess, Matthias Volkmar Kopp

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Article number2003969
Number of pages13
JournalEuropean Respiratory Journal
Volume58
Issue number6
Early online date29-Jul-2021
DOIs
Publication statusPublished - 1-Dec-2021

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