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

Abstract

BackgroundAsthma 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).ObjectiveTo delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response.MethodsThe 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.ResultsSerum 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).ConclusionC4Ma3 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.

Long noncoding RNA antisense noncoding RNA in the INK4 locus inhibition alleviates airway remodeling in asthma through the regulation of the microRNA‐7‐5p/early growth response factor 3 axis

“…Using readily available biomarkers, people with T2 high asthma can be identified at all ages, and different phenotypes can be depicted 42 . The level of C4Ma3 is elevated in the phenotype of severe and aggravating allergic asthma, and C4Ma3 can be used as a new biomarker to predict the response to anti IgE treatment 43 . IgA positive memory B cells are significantly increased in patients with asthma and small airway dysfunction, which indicates the direction for future selection of asthma prevention and treatment strategies guided by B cells 44 …”

Role of clinical biomarkers in predicting the effectiveness of omalizumab

“…In addition to pretreatment clinical biomarkers, studies have also reported that some molecules, such as CXCL10, IL12, Galectin-3, CD3E andC4Ma3, can be used as markers to predict omalizumab responsiveness. 13 , 14 , 16 , 32 , 36 Baseline molecular biomarkers may be the future of clinical biomarkers that predict the effectiveness of omalizumab.…”

Association of blood total immunoglobulin E and eosinophils with radiological features of bronchiectasis

“…Airway in ammation in bronchiectasis has been historically recognized as neutrophilic in nature, however, recent studies also revealed a T2 endotype of the disease, as manifested by higher blood and/or sputum eosinophil counts, increased serum total IgE, higher FeNO, and allergy to various antigens (4,11,12). In recent years, novel biomarkers, such as those related to IL-5, IL-33 (24) and COL4A3 (25) are emerging, but their expressions and potential roles in bronchiectasis still await investigation.…”