Imperial College London
Alternate

PROFESSOR H. TERENCE COOK

Faculty of Medicine, Department of Immunology and Inflammation

Emeritus Professor
 
 
 
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Contact

 

+44 (0)20 3313 2009t.h.cook

 
 
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Assistant

 

Miss Claudia Rocchi +44 (0)20 3313 2315

 
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Location

 

9N9Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Smith-Jackson:2019:10.1172/JCI99296,
author = {Smith-Jackson, K and Yang, Y and Denton, H and Pappworth, IY and Cooke, K and Barlow, PN and Atkinson, JP and Liszewski, MK and Pickering, MC and Kavanagh, D and Cook, HT and Marchbank, KJ},
doi = {10.1172/JCI99296},
journal = {Journal of Clinical Investigation},
pages = {1061--1075},
title = {Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice},
url = {http://dx.doi.org/10.1172/JCI99296},
volume = {129},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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 complement-activation 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.
AU  - Smith-Jackson,K
AU  - Yang,Y
AU  - Denton,H
AU  - Pappworth,IY
AU  - Cooke,K
AU  - Barlow,PN
AU  - Atkinson,JP
AU  - Liszewski,MK
AU  - Pickering,MC
AU  - Kavanagh,D
AU  - Cook,HT
AU  - Marchbank,KJ
DO  - 10.1172/JCI99296
EP  - 1075
PY  - 2019///
SN  - 0021-9738
SP  - 1061
TI  - Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice
T2  - Journal of Clinical Investigation
UR  - http://dx.doi.org/10.1172/JCI99296
UR  - https://www.ncbi.nlm.nih.gov/pubmed/30714990
UR  - https://www.jci.org/articles/view/99296
UR  - http://hdl.handle.net/10044/1/66841
VL  - 129
ER  -
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