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gC1qR Antibody Can Modulate Endothelial Cell Permeability in Angioedema

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Abstract—

Angioedema is characterized by swelling of the skin or mucous membranes. Overproduction of the vasodilator bradykinin (BK) is an important contributor to the disease pathology, which causes rapid increase in vascular permeability. BK formation on endothelial cells results from high molecular weight kininogen (HK) interacting with gC1qR, the receptor for the globular heads of C1q, the first component of the classical pathway of complement. Endothelial cells are sensitive to blood-flow-induced shear stress and it has been shown that shear stress can modulate gC1qR expression. This study aimed to determine the following: (1) how BK or angioedema patients’ (HAE) plasma affected endothelial cell permeability and gC1qR expression under shear stress, and (2) if monoclonal antibody (mAb) 74.5.2, which recognizes the HK binding site on gC1qR, had an inhibitory effect in HK binding to endothelial cells. Human dermal microvascular endothelial cells (HDMECs) grown on Transwell inserts were exposed to shear stress in the presence of HAE patients’ plasma. Endothelial cell permeability was measured using FITC-conjugated bovine serum albumin. gC1qR expression and HK binding to endothelial cell surface was measured using solid-phase ELISA. Cell morphology was quantified using immunofluorescence microscopy. The results demonstrated that BK at 1 µg/mL, but not HAE patients’ plasma and/or shear stress, caused significant increases in HDMEC permeability. The mAb 74.5.2 could effectively inhibit HK binding to recombinant gC1qR, and reduce HAE patients’ plasma-induced HDMEC permeability change. These results suggested that monoclonal antibody to gC1qR, i.e., 74.5.2, could be potentially used as an effective therapeutic reagent to prevent angioedema.

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Acknowledgements

The authors would like to thank Ms. Chloe Leigh Ong for her technical support in cell morphology analysis. The authors would like to thank Dr. Anette Bygum (University of Odense, Denmark) for providing HAE patient plasma.

Funding

This work was supported in part by the National Institutes of Health (1 R56 AI122376-01A1, Ghebrehiwet).

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Authors and Affiliations

  1. Department of Biomedical Engineering, Stony Brook University, NY, Stony Brook, USA

    Marina Fandaros, David A. Rubenstein & Wei Yin

  2. Department of Medicine, Medical University of South Carolina, Charleston, SC, USA

    Kusumam Joseph & Allen P. Kaplan

  3. Department of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA

    Berhane Ghebrehiwet

  4. BioCryst Pharmaceuticals Inc., Durham, NC, 27703, USA

    Kusumam Joseph

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  1. Marina Fandaros
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  2. Kusumam Joseph
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Contributions

Marina Fandaros: investigation, formal analysis, validation, writing—original draft, visualization, Kusumam Joseph: resources, validation, writing—review and editing, Allen P. Kaplan: resources, conceptualization, writing—review and editing, David A. Rubenstein: conceptualization, methodology, resources, writing—review and editing, Berhane Ghebrehiwet: conceptualization, methodology, resources, writing—original draft, supervision, funding acquisition, and Wei Yin: conceptualization, methodology, validation, formal analysis, resources, writing—original draft, visualization, supervision, project administration.

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Correspondence to Wei Yin.

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Fandaros, M., Joseph, K., Kaplan, A.P. et al. gC1qR Antibody Can Modulate Endothelial Cell Permeability in Angioedema. Inflammation 45, 116–128 (2022). https://doi.org/10.1007/s10753-021-01532-w

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