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Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice

Authors :
Smith-Jackson, Kate
Yang, Yi
Denton, Harriet
Pappworth, Isabel Y.
Cooke, Katie
Barlow, Paul N.
Atkinson, John P.
Liszewski, M. Kathryn
Pickering, Matthew C.
Kavanagh, David
Cook, H. Terence
Marchbank, Kevin J.
Source :
Journal of Clinical Investigation. March 2019, Vol. 129 Issue 3, p1061, 15 p.
Publication Year :
2019

Abstract

Introduction Our understanding and treatment of complement-mediated diseases has grown exponentially over the last 20 years. We now understand that complement plays an integral role in many autoimmune-and inflammation-based diseases [...]<br />Atypical hemolytic uremic syndrome (aHUS) is frequently associated in humans with loss-of-function mutations in complement-regulating proteins or gain-of-function mutations in complement- activating proteins. Thus, aHUS provides an archetypal complement-mediated disease with which to model new therapeutic strategies and treatments. Herein, we show that, when transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the complementactivation protein C3 results in aHUS. Homozygous C3 p.D1115N (C3KI) mice developed spontaneous chronic thrombotic microangiopathy together with hematuria, thrombocytopenia, elevated creatinine, and evidence of hemolysis. Mice with active disease had reduced plasma C3 with C3 fragment and C9 deposition within the kidney. Therapeutic blockade or genetic deletion of C5, a protein downstream of C3 in the complement cascade, protected homozygous C3KI mice from thrombotic microangiopathy and aHUS. Thus, our data provide in vivo modeling evidence that gain-of-function changes in complement C3 drive aHUS. They also show that long-term C5 deficiency is not accompanied by development of other renal complications (such as C3 glomerulopathy) despite sustained dysregulation of C3. Our results suggest that this preclinical model will allow testing of novel complement inhibitors with the aim of developing precisely targeted therapeutics that could have application in many complement-mediated diseases.

Details

Language :
English
ISSN :
00219738
Volume :
129
Issue :
3
Database :
Gale General OneFile
Journal :
Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
edsgcl.577907794
Full Text :
https://doi.org/10.1172/JCI99296