α1-Antichymotrypsin Present in Therapeutic C1-Inhibitor Products Competes with Selectin-Sialyl LewisX Interaction.

Engel, Ruchira; Delvasto-Nuñez, Laura; Roem, Dorina; van Mierlo, Gerard; Holst, Stephanie; Hipgrave Ederveen, Agnes L; van Buul, Jaap D; Wuhrer, Manfred; Wouters, Diana; Zeerleder, Sacha Sergio (2018). α1-Antichymotrypsin Present in Therapeutic C1-Inhibitor Products Competes with Selectin-Sialyl LewisX Interaction. Thrombosis and haemostasis, 118(12), pp. 2134-2144. Thieme 10.1055/s-0038-1675601

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BACKGROUND  C1-inhibitor (C1-inh) therapeutics can reduce neutrophil activity in various inflammatory conditions. This 'novel' anti-inflammatory effect of C1-inh is attributed to the tetrasaccharide sialyl Lewis (SLe) present on its glycans. Via SLe, C1-inh is suggested to interact with selectins on inflamed endothelium and prevent neutrophil rolling. However, C1-inh products contain plasma glycoprotein α1-antichymotrypsin (ACT) as a co-purified protein impurity. OBJECTIVE  This article investigates the contribution of ACT to the effects observed with C1-inh. MATERIALS AND METHODS  We have separated C1-inh and ACT from a therapeutic C1-inh preparation and investigated the influence of these proteins on SLe-selectin interactions in a specific in vitro model, which makes use of rolling of SLe-coated beads on immobilized E-selectin. RESULTS  We find that ACT and not C1-inh, shows a clear sialic acid-dependent interference in SLe-selectin interactions, at concentrations present in C1-inh therapeutics. Furthermore, we do not find any evidence of SLe on C1-inh using either Western blotting with anti-SLe antibodies (CSLEX1 and KM93) or by mass spectrometric analysis of glycans. C1-inh reacts weakly to antibody HECA-452, which detects a broad range of selectin ligands, but ACT gives a much stronger signal, suggesting the presence of a selectin ligand on ACT. CONCLUSION  The 'novel' anti-inflammatory effects of C1-inh are unlikely due to SLe on C1-inh and can in fact be due to SLe-like glycans on ACT, present in C1-inh products. In view of our results, it is important to assess the role of ACT in vivo and revisit past studies performed with commercial C1-inh.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Hämatologie (Erwachsene)

UniBE Contributor:

Zeerleder, Sacha Sergio

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2567-689X

Publisher:

Thieme

Language:

English

Submitter:

Pierrette Durand Lüthi

Date Deposited:

01 Apr 2019 09:36

Last Modified:

24 Oct 2019 21:27

Publisher DOI:

10.1055/s-0038-1675601

PubMed ID:

30453343

BORIS DOI:

10.7892/boris.123625

URI:

https://boris.unibe.ch/id/eprint/123625

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