The membrane attack complex drives the thrombotic microangiopathy in complement mediated atypical haemolytic uraemic syndrome

Abstract

Complement mediated atypical haemolytic uraemic syndrome (c-aHUS), is an ultra-rare but important cause of kidney disease. The discovery of the role of the alternative pathway in disease has revolutionised the clinical management of this ultra-rare kidney disease, but also sparked a complement therapeutics revolution, that has led to the introduction of new complement inhibiting agents into clinical practice. The golden standard treatment of c-aHUS is life-long C5 inhibiting therapy, that said, our clinical practice is likely to evolve, becoming disease driven rather than continuous lifelong therapy. The seismic revolution in complement therapeutics will present to us alternative complement inhibiting agents. In tandem, with the real time advancement in complement therapeutics, we must advance our understanding of the pathogenesis of c-aHUS to see if therapy can be refined. In this thesis, I show a novel C3p.L1109V variant to be associated with the development of caHUS through an inability of FH to regulate the protein at the C terminus. Next, we engineered a mouse model of c-aHUS around a point mutation in C3p.D1115N associated with c-aHUS in man from a local Newcastle family. This mouse model fully recapitulates the clinical disease and is rescued through C5 genetic deletion or therapeutic inhibition. Backcrossing our model onto C7 deficient and C5aR1 deficient mice enabled us to determine the roles of the C5a-C5aR1 axis and C5b-9 (the membrane attack complex) on c-aHUS. C7 deficiency completely abolished both clinical and histological evidence of disease. We found that removing C5aR1 (CD88, and therefore C5a mediated signalling) significantly attenuated the risk of developing clinical disease, but 29% of mice could still develop a thrombotic microangiopathy. An oral C5aR1 antagonist when used before detectable clinical disease prevented hC5aR1.C3D1115N mice from succumbing to acute disease. Our data suggest that whilst C5aR1 inhibition can significantly attenuate disease penetrance, C5b-9 plays the dominant role in the development of the conditions required for sustenance of a TMA in the kidney. Consequently, as well as the requirement for AP dysregulation, membrane attack complex within the kidney is critical to drive disease pathology in c-aHUS.