Trends in Immunology
ReviewComplement activation and inhibition: a delicate balance
Introduction
The complement system (Box 1) was initially recognized as a defence system against infections, and this is certainly one of its main functions. However, it is now clear that complement also functions as an important humoral system to sense danger, which in addition to conserved molecular patterns on pathogens, also includes damaged or altered self tissues. After sensing these danger signals, complement is able to respond to them directly but also indirectly by activating cellular innate and adaptive immune responses via several complement receptors [1]. These complement receptors can interact directly with danger sensors such as C1q (Box 2), but they can also interact with products that are generated via the proteolytic complement activation cascade, for example fragments of C3 and anaphylatoxins (C5a, C3a). This complex pattern of responses enables the body to react in a different manner according to the various types of danger. For some types of danger signal, the complement system initiates a strong inflammatory response, whereas for others it merely flags the target molecules and/or cells for enhanced phagocytosis. Furthermore, under physiological conditions, limited complement activation on host material can occur not just as a result of danger sensing to promote clearance, as exemplified by the restricted complement activation on acrosome-reacted spermatozoa [2]. Complement is an aggressive proteolytic cascade working under the tight control of inhibitors (Figure 1 and Box 3) and the final outcome in each case depends on a tipping of the balance between activation and inhibition [3]. We propose that one important mechanism determining the nature of the complement-mediated response relies on the fact that many endogenous targets that are recognized by C1q and initiate the classical pathway, also interact with the complement inhibitors factor H (FH) and C4b-binding protein (C4BP). Here, we focus on mechanisms of complement regulation by endogenous molecules and their implications in several human diseases. We provide several examples of such mechanisms to illustrate the importance of balanced complement regulation on endogenous ligands, the skewing of which in one direction or the other can result in deleterious effects.
Section snippets
Extracellular matrix proteins
The extracellular matrix (ECM) consists mainly of large molecules such as proteoglycans and collagens but it is structurally organized and stabilized by members of the family of small leucine-rich repeat proteins (SLRPs). Several of these proteins interact directly with C1q (Table 1). The SLRPs fibromodulin and osteoadherin bind C1q via its globular head domains (Box 2) and activate the classical pathway as efficiently as IgM at the level of C4 and C3 4, 5. Surprisingly, the terminal pathway is
Rheumatoid arthritis
Joint inflammation in rheumatoid arthritis (RA) is a very complex process, but evidence from both clinical studies measuring many different products resulting from complement activation [50] and experiments using animal models [51] show that complement contributes to the development of the disease (see Ref. [52]). Traditionally, complement is considered to be a serum component, but in fact all its components can also be found at high concentrations in the synovial fluid of joints. During
Concluding remarks
In contrast to most pathogens, endogenous ligands of C1q also bind fluid-phase complement inhibitors. The binding of these inhibitors does not completely block complement activation, but enables opsonisation and is sufficient to prevent massive complement activation and lysis, which could trigger inflammation. It is clear that disruption of the balance between complement activation and inhibition contributes to several diseases. More examples will certainly become apparent in the near future.
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