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

Abstract

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.

Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties

“…12,13 It also carries a unique high incidence (30%-60%) [12][13][14] of documented genetic or constitutional dysregulation of the complement alternative pathway (CAP). Furthermore, C5 blockade prevents the development of aHUS in disease-prone animal 15,16 and completely or at least substantially reverses aHUS in clinical studies. 17,18 These characteristics do not necessarily apply to other complement-mediated nephropathies starting with C3G and Ig-mediated MPGN (Ig-MPGN).…”

Terminal complement effectors in atypical hemolytic uremic syndrome: C5a, C5b-9, or a bit of both?

“…In spite of these limitations, the studies in FH R/R mice may provide some interesting insights into the role of the terminal complement effectors in renal TMA, as well as in large vessel thrombosis, at least in rodents. Replication studies in other mouse TMA models, such as the recently published study in C3 p.D1115N mice that develop spontaneous renal TMA 9 and most importantly ex vivo studies in patients with aHUS are needed to establish what role C5aR1, C6, and C9 play in complement-mediated TMA and to clarify the relevance of these findings to the human condition.…”

Pathologies of the complement system

“…При этом имеются в виду несколько дефицитов внутри функ-циональных блоков или дефициты отдельных компонентов. Как правило, под дефицитами понимают такие дефекты белков (как отражение генетического полиморфизма), которые ведут к снижению их функциональных возможностей (хотя описаны и обратные ситуации [3]).…”