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

Weckmann, M; Bahmer, T; Sand, JM; Rank Rønnow, S; Pech, M; Vermeulen, C; Faiz, A; Leeming, DJ; Karsdal, MA; Lunding, L; Oliver, BGG; Wegmann, M; Ulrich-Merzenich, G; Juergens, UR; Duhn, J; Laumonnier, Y; Danov, O; Sewald, K; Zissler, U; Jonker, M; König, I; Hansen, G; von Mutius, E; Fuchs, O; Dittrich, A-M; Schaub, B; Happle, C; Rabe, KF; van de Berge, M; Burgess, JK; Kopp, MV; ALLIANCE Study Group as part of the German Centre for Lung Research (DZL),

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

Weckmann, M Bahmer, T Sand, JM Rank Rønnow, S Pech, M Vermeulen, C Faiz, A

Leeming, DJ Karsdal, MA Lunding, L Oliver, BGG Wegmann, M Ulrich-Merzenich, G Juergens, UR Duhn, J Laumonnier, Y Danov, O Sewald, K Zissler, U Jonker, M König, I Hansen, G von Mutius, E Fuchs, O Dittrich, A-M Schaub, B Happle, C Rabe, KF van de Berge, M Burgess, JK Kopp, MV ALLIANCE Study Group as part of the German Centre for Lung Research (DZL),

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Publisher:: EUROPEAN RESPIRATORY SOC JOURNALS LTD
Publication Type:: Journal Article
Citation:: Eur Respir J, 2021, 58, (6)
Issue Date:: 2021-12

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Field	Value	Language
dc.contributor.author	Weckmann, M
dc.contributor.author	Bahmer, T
dc.contributor.author	Sand, JM
dc.contributor.author	Rank Rønnow, S
dc.contributor.author	Pech, M
dc.contributor.author	Vermeulen, C
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538
dc.contributor.author	Leeming, DJ
dc.contributor.author	Karsdal, MA
dc.contributor.author	Lunding, L
dc.contributor.author	Oliver, BGG
dc.contributor.author	Wegmann, M
dc.contributor.author	Ulrich-Merzenich, G
dc.contributor.author	Juergens, UR
dc.contributor.author	Duhn, J
dc.contributor.author	Laumonnier, Y
dc.contributor.author	Danov, O
dc.contributor.author	Sewald, K
dc.contributor.author	Zissler, U
dc.contributor.author	Jonker, M
dc.contributor.author	König, I
dc.contributor.author	Hansen, G
dc.contributor.author	von Mutius, E
dc.contributor.author	Fuchs, O
dc.contributor.author	Dittrich, A-M
dc.contributor.author	Schaub, B
dc.contributor.author	Happle, C
dc.contributor.author	Rabe, KF
dc.contributor.author	van de Berge, M
dc.contributor.author	Burgess, JK
dc.contributor.author	Kopp, MV
dc.contributor.author	ALLIANCE Study Group as part of the German Centre for Lung Research (DZL),
dc.date.accessioned	2022-03-25T05:04:57Z
dc.date.available	2021-04-28
dc.date.available	2022-03-25T05:04:57Z
dc.date.issued	2021-12
dc.identifier.citation	Eur Respir J, 2021, 58, (6)
dc.identifier.issn	0903-1936
dc.identifier.issn	1399-3003
dc.identifier.uri	http://hdl.handle.net/10453/155572
dc.description.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 (paediatric cases/controls: n=134/n=35; adult cases/controls: n=149/n=31). Exacerbation of allergic airway disease in mice was induced by sensitising to ovalbumin (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 (n=14) and cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA; n=9) as well as patients with severe allergic uncontrolled asthma (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed using 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 cystic fibrosis plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic OR 31.5). CONCLUSION: C4Ma3 levels 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.
dc.format	Electronic-Print
dc.language	eng
dc.publisher	EUROPEAN RESPIRATORY SOC JOURNALS LTD
dc.relation.ispartof	Eur Respir J
dc.relation.isbasedon	10.1183/13993003.03969-2020
dc.rights	info:eu-repo/semantics/embargoedAccess
dc.subject	11 Medical and Health Sciences, 1116 Medical Physiology
dc.subject.classification	Respiratory System
dc.subject.mesh	Adult
dc.subject.mesh	Animals
dc.subject.mesh	Antibodies, Anti-Idiotypic
dc.subject.mesh	Aspergillosis, Allergic Bronchopulmonary
dc.subject.mesh	Asthma
dc.subject.mesh	Autoantigens
dc.subject.mesh	Child
dc.subject.mesh	Collagen Type IV
dc.subject.mesh	Cystic Fibrosis
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Omalizumab
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Aspergillosis, Allergic Bronchopulmonary
dc.subject.mesh	Cystic Fibrosis
dc.subject.mesh	Asthma
dc.subject.mesh	Collagen Type IV
dc.subject.mesh	Antibodies, Anti-Idiotypic
dc.subject.mesh	Autoantigens
dc.subject.mesh	Adult
dc.subject.mesh	Child
dc.subject.mesh	Omalizumab
dc.title	COL4A3 is degraded in allergic asthma and degradation predicts response to anti-IgE therapy.
dc.type	Journal Article
utslib.citation.volume	58
utslib.location.activity	England
utslib.for	11 Medical and Health Sciences
utslib.for	1116 Medical Physiology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
utslib.copyright.embargo	2022-07-29T00:00:00+1000Z
dc.date.updated	2022-03-25T05:04:56Z
pubs.issue	6
pubs.publication-status	Published online
pubs.volume	58
utslib.citation.issue	6

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 (paediatric cases/controls: n=134/n=35; adult cases/controls: n=149/n=31). Exacerbation of allergic airway disease in mice was induced by sensitising to ovalbumin (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 (n=14) and cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA; n=9) as well as patients with severe allergic uncontrolled asthma (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed using 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 cystic fibrosis plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic OR 31.5). CONCLUSION: C4Ma3 levels 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.

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http://hdl.handle.net/10453/155572