Complement in disease: a defence system turning offensive

Abstract

Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists. The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris — such as sensing molecular danger patterns, generating immediate effectors, and extensively coordinating with other defence pathways — can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases. These host-offensive actions become more pronounced with age and are exacerbated by a variety of genetic factors and autoimmune responses. Complement can also be activated inappropriately, for example in response to biomaterials or transplants. A wealth of research over the past two decades has led to an increasingly finely tuned understanding of complement activation, identified tipping points between physiological and pathological behaviour, and revealed avenues for therapeutic intervention. This Review summarizes our current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and, with an emphasis on kidney disease and transplantation, discusses the involvement of complement in clinical conditions and promising therapeutic approaches.

Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development

“…Both systems control infection by pathogens, are connected in their activation mechanisms, and influence innate immune cell function following tissue injury. 1 Genetic dispositions leading to hyperactive complement are increasingly recognized as contributors to vascular and thromboembolic diseases, including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, 2 and antiphospholipid syndrome. 3 The central role for complement is highlighted by the clinical efficacy of complement factor 5 (C5) inhibitors in preventing thrombotic complications in these diseases, 4 but the connections between complement and hemostatic systems in other settings of thrombosis remain incompletely understood.…”

“…69 Specifically, ultra-large VWF multimers, as observed after tissue injury, can provide a binding platform for C3b to trigger complement activation. 1,70,71 Although direct reciprocal activation of complement and coagulation was indicated by several studies, 7 complement activation is also known to alter cell surface activity of PDI that is increasingly recognized for its role in vascular thrombosis. 29 Platelet activation and VWF are regulated by thiol-disulfide exchange reactions [49][50][51] and C3-dependent activation of C5 is known to modify the redox state of cell surface PDI.…”

The role of the alternative pathway of complement activation in glomerular diseases

“…This seems to be supported by the reports on the growing role of properdin (FP) as a recognition pattern molecule, which can activate AP by binding to C3b. Also, C3 and C5 can be directly activated by 'extrinsic' proteases that are not traditionally associated with the complement system, for example, thrombin and plasmin [16,17]. The CP is triggered by IgG and or IgM-containing immune complexes, viruses and acute-phase proteins, binding to C1q.…”

“…However, C3a alone also acts as an anti-inflammatory agent in an acute phase of inflammation by suppressing neutrophil migration and degradation. [16,20,23,26].…”

Le système du complément

“…À l'inverse, la suractivation du système du complément peut avoir des conséquences délétères et être responsable de dommages tissulaires. C'est notamment le cas dans les C3 glomérulo-pathies [9], le syndrome urémique hémolytique atypique, ou dans la dégénérescence maculaire liée à l'âge [2,10]. Récemment, des études ont suggéré un rôle du système du complé-ment dans le cancer.…”