Complement-mediated injury and protection of endothelium: lessons from atypical haemolytic uraemic syndrome

Abstract

The complement system provides a vital defence against invading pathogens. As an intrinsic system it is always 'on', in a state of constant, low level activation. This activation is principally mediated through the deposition of C3b on to pathogenic surfaces and host tissues. C3b is generated by spontaneous 'tick over' and formal activation of the alternative pathway, and by activation of the classical and lectin pathways. If the deposited C3b is not appropriately regulated, there is progression to terminal pathway complement activation via the C5 convertases, generating the potent anaphylotoxin C5a and the membrane attack complex C5b-9. Unsurprisingly, these highly active components have the potential to cause injury to bystander host tissue, including the vascular endothelium. As such, complement activation on endothelium is normally tightly controlled by a large number of fluid-phase and membrane bound inhibitors, in an attempt to ensure that propagation of complement activation is appropriately restricted to invading pathogens and altered 'self', e.g. apoptotic and necrotic cells. The kidney is increasingly recognised as a site at particular risk from complement-mediated endothelial injury. Both genetic and acquired defects which impact on complement regulation predispose to this susceptibility. The thrombotic microangiopathy, haemolytic uraemic syndrome (HUS), will be used to illustrate the mechanisms by which the endothelial cell injury occurs. Finally, the underlying rationale for current and future potential therapeutic interventions in HUS and also the opportunities for enhancing endothelial defence to prevent relapsing disease through increased complement cytoprotective strategies will be summarised.

Fig. 1. Activation of the complement cascade by the classical, lectin or alternative pathway leads to the generation of biologically active complement components.

C3a and C5a are potent anaphylotoxins which recruit leucocytes and platelets to the endothelial cell surface following upregulation of adhesion molecules, e.g. ICAM-1 and P-selectin. C5a also promotes endothelial cell retraction, exposing underlying basement membrane, and upregulates the expression of procoagulant tissue factor. C5b participates in the formation of the membrane attack complex C5b-9. Downstream effects of sublytic MAC on endothelium additionally include secretion of multimers of endothelial von Willebrand factor and release of heparan sulphate proteoglycans from endothelial glycocalyx. These changes favour a switch from an anti-inflammatory, anti-coagulant endothelial phenotype to a highly active, pro-coagulant phenotype. In atypical HUS, the downstream effects of excessive complement activation in the vicinity of the glomerular endothelium leads to thrombotic microangiopathy within capillaries and arterioles, causing renal failure.