Complement fragments are biomarkers of antibody-mediated endothelial injury

•Complement activation on endothelial cells generates complement fragments.•Complement activation on endothelial cells generates microvesicles.•Complement fragments are increased in antibody-mediated rejection.•Plasma endothelial microparticles decreased in antibody-mediated rejection. Antibody-medi...

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Bibliographic Details
Published in:Molecular immunology 2020-02, Vol.118, p.142-152
Main Authors: Stites, Erik, Renner, Brandon, Laskowski, Jennifer, Le Quintrec, Moglie, You, Zhiying, Freed, Brian, Cooper, James, Jalal, Diana, Thurman, Joshua M.
Format: Article
Language:English
Subjects:
Adult
Allografts
Allografts - immunology
Antibodies
Antibodies - immunology
Antibody mediated rejection
Biomarker
Biomarkers
Biomarkers - blood
Biopsy
Cells, Cultured
Complement
Complement Activation
Complement Activation - immunology
Complement System Proteins
Complement System Proteins - immunology
Donor specific antibody
Endothelial Cells
Endothelial Cells - immunology
Female
Graft Rejection
Graft Rejection - immunology
Hematology
Human health and pathology
Humans
Immunology
Kidney
Kidney - immunology
Kidney Transplantation
Kidney Transplantation - methods
Life Sciences
Male
Middle Aged
Transplantation, Homologous
Transplantation, Homologous - methods
Urology and Nephrology
Vascular System Injuries
Vascular System Injuries - immunology
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Summary:•Complement activation on endothelial cells generates complement fragments.•Complement activation on endothelial cells generates microvesicles.•Complement fragments are increased in antibody-mediated rejection.•Plasma endothelial microparticles decreased in antibody-mediated rejection. Antibody-mediated rejection (AbMR) adversely affects long-term graft survival in kidney transplantation. Currently, the diagnosis of AbMR requires a kidney biopsy, and detection of complement C4d deposition in the allograft is one of the diagnostic criteria. Complement activation also generates several soluble fragments which could potentially provide non-invasive biomarkers of the process. Furthermore, microvesicles released into the plasma from injured cells can serve as biomarkers of vascular injury. To explore whether soluble complement fragments or complement fragments bound to endothelial microvesicles can be used to non-invasively detect AbMR, we developed an in vitro model in which human endothelial cells were exposed to anti-HLA antibodies and complement sufficient serum. We found that complement fragments C4a and sC5b-9 were increased in the supernatants of cells exposed to complement-sufficient serum compared to cells treated complement-deficient serum. Furthermore, complement activation on the cell surface was associated with the release of microvesicles bearing C4 and C3 fragments. We next measured these analytes in plasma from kidney transplant recipients with biopsy-proven acute AbMR (n = 9) and compared the results with those from transplant recipients who also had impaired allograft function but who did not have AbMR (n = 30). Consistent with the in vitro results, complement fragments C4a and Ba were increased in plasma from patients with AbMR compared to control subjects (P 
ISSN:0161-5890
1872-9142
DOI:10.1016/j.molimm.2019.12.011