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

Pouw, Richard B. and Brouwer, Mieke C. and de Gast, Marlon and van Beek, Anna E. and van den Heuvel, Lambertus P. and Schmidt, Christoph Q. and van der Ende, Arie and Sánchez-Corral, Pilar and Kuijpers, Taco W. and Wouters, Diana. (2019) Potentiation of complement regulator factor H protects human endothelial cells from complement attack in aHUS sera. Blood advances, 3 (4). pp. 621-632.

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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.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ricklin)
UniBasel Contributors:Pouw, Richard Benjamin
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society of Hematology
ISSN:2473-9537
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:07 May 2019 14:41
Deposited On:07 May 2019 14:40

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