KRUK Postdoctoral Fellowship awarded to Danielle Paixão-Cavalcante
Dr Danielle Paixão-Cavalcante has received a 3 year Postdoctoral Fellowship funded by Kidney
Research UK to study the mechanisms by which C3 nephritic factors cause renal diseases.
- Date
- 2nd June 2010
Amplification of the complement cascade from a small trigger to a massive downstream effect is brought about by the central enzyme of the complement cascade, the alternative pathway C3 convertase (or C3-cleaving enzyme). This enzyme is responsible for successful targeting and destruction of pathogens and/or infected cells; its fast action and ability to amplify the cascade means it must be tightly regulated.
C3 nephritic factors (C3NeFs) are autoantibodies which stabilise and prevent the natural control of the C3 convertase, leading to uncontrolled amplification and consumption of complement in vivo. The presence of C3NeF is strongly associated with chronic renal pathologies although interestingly the outcomes vary enormously -individuals with NeF can be completely healthy, or they may develop devastating and often fatal pathologies such as membranoproliferative glomerulonephrites types I, II or III, aquired partial lipodysthrophy with or without glomerulonephritis, and other diseases. This suggests that different types of C3NeFs may trigger pathology in diverse and different ways, or that their action may be 'safe' and does not cause disease.
Over the last few years in the Complement Biology Group, we have been developing assays to detect and characterise these autoantibodies in the plasma of patients presenting with renal disease, and we are currently translating some of these screens to the Clinical Immunology Labs at UHW. We have developed functional assay to dissect at the molecular level how different NeFs cause disease -our data show that different NeF affect the half-life of the C3 convertase to different extents, they can affect enzyme activity such that is some cases the stabilised C3 convertase is "hyper-active", and they also prevent (in different ways) the natural control proteins found in blood and on cell membranes from controlling the enzyme.
In this fellowship, Danielle will build on these findings to understand at an intricate level the mechanisms behind these various modes of action. She will identify those NeF likely to be most informative and will use molecular methods to generate recombinant forms of these autoantibodies -her ultimate goal is to generate the first structure of a NeF-associated C3 convertase. This Fellowship will provide insights to better understand the pathological mechanisms behind C3NeFs and their relationship with disease, thereby
opening new avenues for development of therapies to improve the treatment of patients with C3NeF.