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

Weckmann, Markus; Bahmer, Thomas; Bülow Sand, Jannie Marie; Rank Rønnow, Sarah; Pech, Martin; Vermeulen, Cornelis; Faiz, Alen; Leeming, Diana Julie; Karsdal, Morten Asser; Lunding, Lars; Oliver, Brian George G; Wegmann, Michael; Ulrich-Merzenich, Gudrun; Juergens, Uwe R; Duhn, Jannis; Laumonnier, Yves; Danov, Olga; Sewald, Katherina; Zissler, Ulrich; Jonker, Marnix; ... (2021). COL4A3 is degraded in allergic asthma and degradation predicts response to anti-IgE therapy. European respiratory journal, 58(6) European Respiratory Society 10.1183/13993003.03969-2020

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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.

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