title: 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.
authors.affiliation: Department of Nephrology, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Kerr
authors.forename: Anna
authors.initials: A
authors.lastname: Richards
mesh_terms: D065766:Atypical Hemolytic Uremic Syndrome; D003167:Complement Activation / Q000502:physiology*; D003179:Complement C3b / Q000276:immunology; D015936:Complement C5a / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000276:immunology*; D004727:Endothelium / Q000276:immunology*; D006463:Hemolytic-Uremic Syndrome / Q000276:immunology*; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology
chemical_list: D015938:Complement Membrane Attack Complex; C047610:SC5b-9 protein complex; D003179:Complement C3b; D015936:Complement C5a