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Blood Adv. 2019 Feb 26;3(4):621-632. doi: 10.1182/bloodadvances.2018025692.

Potentiation of complement regulator factor H protects human endothelial cells from complement attack in aHUS sera.

Author information

1
Department of Immunopathology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
2
Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands.
3
Laboratory of Pediatric Nephrology, Department of Development and Regeneration, Katholieke Universiteit Leuven, Leuven, Belgium.
4
Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
5
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany.
6
Department of Medical Microbiology, Netherlands Reference Laboratory for Bacterial Meningitis, Center for Infection and Immunity Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
7
Complement Research Group, Hospital La Paz Institute for Health Research, La Paz University Hospital, and Centre for Biomedical Network Research on Rare Diseases, Madrid, Spain; and.
8
Department of Blood Cell Research, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

Mutations in the gene encoding for complement regulator factor H (FH) severely disrupt its normal function to protect human cells from unwanted complement activation, resulting in diseases such as atypical hemolytic uremic syndrome (aHUS). aHUS presents with severe hemolytic anemia, thrombocytopenia, and renal disease, leading to end-stage renal failure. Treatment of severe complement-mediated disease, such as aHUS, by inhibiting the terminal complement pathway, has proven to be successful but at the same time fails to preserve the protective role of complement against pathogens. To improve complement regulation on human cells without interfering with antimicrobial activity, we identified an anti-FH monoclonal antibody (mAb) that induced increased FH-mediated protection of primary human endothelial cells from complement, while preserving the complement-mediated killing of bacteria. Moreover, this FH-activating mAb restored complement regulation in sera from aHUS patients carrying various heterozygous mutations in FH known to impair FH function and dysregulate complement activation. Our data suggest that FH normally circulates in a less active conformation and can become more active, allowing enhanced complement regulation on human cells. Antibody-mediated potentiation of FH may serve as a highly effective approach to inhibit unwanted complement activation on human cells in a wide range of hematological diseases while preserving the protective role of complement against pathogens.

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