ReviewComplement: a unique innate immune sensor for danger signals
Section snippets
The C system in the context of an ancestral innate immune response involved in the recognition of pathogens and toxic cell debris
Innate immune systems use proteins encoded in the germ line to identify potentially noxious susbstances. These proteins whether they are cell surface receptors or soluble, seem usually able to recognise carbohydrate structures. From the concept originally presented by Medzhitov and Janeway (1997), it is now well established that soluble and membrane defense molecules of the innate immune system are expressed by cells at the site of infection and inflammation to recognize pathogen-associated
The C system and C-associated proteins: C biosynthesis and routes of activation against pathogens
C was initially recognized as the heat-labile factor in serum required along with heat-stable antibody, for bactericidal activity. Today, due to the events of molecular biology screening methods, the C system consists of some 30 fluid phase and cell-membrane proteins and is important in innate immunity to recognise and kill pathogens such as bacteria, virus infected cells and parasites but preserving normal ‘self’ cells (for review Frank and Fries, 1991). Recent studies have indicated a marked
The C system and C-associated proteins: clearance of apoptotic cells
More recently several lines of evidence suggested that C1q has an important role in the clearance of apoptotic cells. Three independent studies have shown that C1q can bind directly and specifically to surface blebs of UV-induced apoptotic cells (keratinocytes and T cells) leading to the activation of the CP of C (Korb and Ahearn, 1997, Mevorach et al., 1998, Ogden et al., 2001, Taylor et al., 2000). Moreover, it has been reported by Botto et al. that C1q knockout mice show a profound
C1q and other defense collagen receptors (CR1, cC1qR, CD91, gC1qR)
CR1 (CD35) is found on circulating monocytes and neutrophils but the major site of expression is B lymphocytes. CR1 is a multifunctional receptor both in its ligand specificity and in the C regulation activities (Krych-Goldberg and Atkinson, 2001). As a receptor, CR1 binds to C opsonins (C4b, C3b, iC3b, C1q) and MBL and as such, has been involved in phagocytic activities (Nicholson-Weller and Klickstein, 1999). Several studies support a role for cell surface collagen C1q receptor (cC1qR; also
The proposed C1q receptor (also known as CD93) involved in phagocytosis and/or signalling events
One cell-surface molecule was reported as yet another defence collagen receptor (for C1q, MBL and SPA). Monocytes that have adhered to surfaces coated with C1q (or MBL or SPA) display a 4–10-fold enhancement of ingestion of targets opsonized with IgG or C (Guan et al., 1994). Monoclonal antibodies, selected for their ability to inhibit the C1q-mediated enhancement of phagocytosis were used to clone the cell-surface transmembrane glycoprotein, designated the C1q receptor, that enhances
Receptors involved in phagocytosis (β2 integrins: CD11b/CD18 and CD11c/CD18)
C3, when activated on a cell surface becomes covalently bound (opsonised) as C3b which is subsequently cleaved to yield a very stable fragment iC3b. There is well documented evidence that CR3 (CD11b/CD18) and CR4 (CD11c/CD18 also known as the p150, 95 antigen) are involved in the phagocytosis of targets opsonised with C3b and iC3b fragments (for review Cabanas and Sanchez-Madrid, 1999, Ehlers, 2000). Perhaps the capacity of CR3 to recognise natural microbial surface components, such as
C anaphylatoxin receptors involved in chemotaxis (seven-transmembrane receptors)
Hence, one aspect of the C system that has received consistent attention is the functions and mechanisms of action of biologically active small fragments derived from C molecules. C anaphylatoxins (C3a and C5a) released in the fluid phase after enzymatic cleavage of C3 and C5, respectively, are important proinflammatory molecules involved in the stimulation and chemotaxis of myeloid cells bearing specific anaphylatoxin receptors (C3aR and C5aR/CD88) which belongs to the rhodopsin family of
CR2(CD21): the link between the innate and acquired immune response
Innate immunity has been considered only to provide rapid, incomplete antimicrobial host defense until the slower, more definitive acquired immune response develops (Fearon and Locksley, 1996). In this context, it is now established that C-derived fragments play an important role in shaping the antibody response of acquired immunity. This was shown first by Pepys, who demonstrated that the formation of antibodies against T-cell-dependent antigens was reduced in animals in which C3 had been
The opsonic ancestral element
From the foregoing sections, it is evident that C3 is central both to the activation of C and to its functions. Therefore, one must conclude that this component was the nucleus around which the C system has evolved. It was proposed that the original C system would have resembled a simplified AP consisting of a C3-like and a factor-B like component together with a receptor on a phagocytic cell (for review Dodds and Law, 1998). The major function of such a system would therefore have been opsonic
C and other innate immune signalling pathways: an ancestral innate immune signalling pathway
The application of Drosophila genetics to deciphering the mechanisms involved in host defense and development has generated insights into innate immunity and uncovered similarities with mammalian immune responses (Hoffmann and Reichhart, 2002). For instance, analysis of immunocompromised flies has demonstrated that the Toll signalling pathway, previously characterised as a regulator of dorsal–ventral polarity in developing embryos, also regulates antifungal defense. One role of Toll pathway is
Conclusion
The essence of innate immunity is the detection of molecules that are unique to infectious organisms and noxious substances, to induce clearance of the intruders and it also dictates the conduct of the acquired immune response in vertebrates. C is widely accepted to constitute this critical link between the innate immune response involved in the selective recognition and clearance of potentially noxious susbstances, whether they are derived from the host following injury (apoptotic cells, toxic
Acknowledgements
This work was supported by the Medical Research Council.
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