Elsevier

Immunobiology

Volume 217, Issue 2, February 2012, Pages 195-203
Immunobiology

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

https://doi.org/10.1016/j.imbio.2011.07.028Get rights and content

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.

Section snippets

The endothelium

Endothelial cells line the interior surface of all blood vessels in the body, occupying a strategic location between the blood vessel walls and the blood stream. The endothelium is able to detect and respond to mechanical stimuli, such as pressure and shear stress, and to hormonal stimuli such as vasoactive mediators. Endothelial cells have important roles in health and disease. Endothelial cell functions include the release of agents which regulate vasomotor function, trigger inflammatory

Haemolytic uraemic syndrome (HUS)

HUS is a type of thrombotic microangiopathy and is characterised by the formation of fibrin-platelet clots in arterial microcirculations. There is an apparent predilection for the renal glomerular capillaries and arterioles, resulting in kidney failure, although the simultaneous involvement of other microvascular beds in the heart, brain and pancreas to a greater or lesser extent, is recognised and reported in all subtypes of HUS. Endothelial cell injury (swelling, detachment, and

The complement cascade

A principal biological function of the complement system is the rapid recognition and elimination of pathogens. Key mechanisms include opsonisation by C3b, activation of the inflammatory cascade by the generation of the anaphylotoxins C3a and C5a and lysis by the membrane attack complex (MAC; C5b-9). The complement cascade is activated by the classical pathway (CP) (Kojouharova et al. 2010), the alternative pathway (Harboe and Mollnes, 2008, Wallis et al., 2010) or the MBL/MASP pathway (Wallis

Endothelial protection against complement-mediated injury

The complement system is tightly controlled by natural fluid phase and membrane bound inhibitors, to restrict propagation to invading pathogens or altered self cells.

Endothelial cell activation and injury in HUS

Specific insights into the pivotal role of endothelial activation and injury as a trigger and a determinant of outcome in HUS will aid in understanding pathogenic mechanisms. Unravelling the links between genetic predisposition, inflammatory triggers, complement and the coagulation cascade will potentially identify therapeutic pathways with wider relevance for other conditions in which thrombotic vascular injury is a key feature, for example, ischaemia–reperfusion injury (IRI), preeclampsia and

Complement inhibition in aHUS

Current treatment protocols for aHUS are based on plasma exchange/infusion. The rationale for this treatment, which has significantly improved morbidity and mortality in individual cases, but has not been formally evaluated in a clinical trial, is logical. It may beneficially supplement levels of deficient complement components contained in plasma, e.g. Factor H or Factor I, secondly, it removes mutated proteins which may exert a dominant negative effect on complement regulation and thirdly it

Conclusions

Consideration of the interactions between complement and the endothelium is critical for understanding the pathophysiology of conditions with prominent endothelial cell injury. Unanswered questions in aHUS relate to reasons for the renal endothelial susceptibility; the determinants of penetrance in those with a genetic predisposition and the balance between soluble and membrane bound complement regulation at endothelial and basement membrane surfaces. Many aspects of endothelial cell biology

Acknowledgements

The authors gratefully acknowledge the support of their funding bodies. HK is a Medical Research Council Clinical Training Fellow and AR is a Wellcome Trust Intermediate Clinical Fellow. We would also like to thank David Kavanagh, Anne Astier and Jeremy Hughes for their careful consideration and valuable comments on the manuscript.

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