Elsevier

Molecular Immunology

Volume 41, Issue 11, November 2004, Pages 1089-1098
Molecular Immunology

Review
Complement: a unique innate immune sensor for danger signals

https://doi.org/10.1016/j.molimm.2004.06.011Get rights and content

Abstract

The complement (C) inflammatory cascade is part of the phylogenetically ancient innate immune response and is crucial to our natural ability to ward off infection. It has three critical physiologic activities: (i) defending against microbial infections by triggering the generation of a membranolytic complex (C5b9 complex) at the surface of the pathogen and C fragments (named opsonins, i.e., C1q, C3b and iC3b) which interact with C cell surface receptors (CR1, CR3 and CR4) to promote phagocytosis. Soluble C anaphylatoxins (C4a, C3a and C5a) greatly control the local pro-inflammatory response through the chemotaxis and activation of leukocytes; (ii) bridging innate and adaptive immunity (essentially through C receptor type 2, CR2, expressed by B cells) and (iii) disposing of immune complexes and the products of the inflammatory injury (i.e., other danger signals, e.g., toxic cell debris and apoptotic corpses) to ensure the protection and healing of the host. The regulatory mechanisms of C are finely balanced so that, on the one hand, the deposition of C is focused on the surface of invading microorganisms and, on the other hand, the deposition of C on normal cells is limited by several key C inhibitors (e.g., CD46, CD55 and CD59). Knowledge of the unique molecular and cellular innate immunological interactions that occur in the development and resolution of pathology should facilitate the design of effective therapeutic strategies to fight selectively against intruders.

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.

References (82)

  • C.E. Hack et al.

    Elevated plasma levels of the anaphylatoxins C3a and C4a are associated with a fatal outcome in sepsis

    Am. J. Med.

    (1989)
  • S. Johnson et al.

    The ins and outs of calreticulin: from the ER lumen to the extracellular space

    Trends Cell Biol.

    (2001)
  • E.A. Levashina et al.

    Conserved role of a complement-like protein in phagocytosis revealed by dsRNA knockout in cultured cells of the mosquito, Anopheles gambiae

    Cell

    (2001)
  • R. Medzhitov et al.

    Innate immunity: the virtues of a nonclonal system of recognition

    Cell

    (1997)
  • B.P. Morgan

    Complement regulatory molecules—application to therapy and transplantation

    Immunol. Today

    (1995)
  • B.P. Morgan et al.

    Expression of complement in the brain: role in health and disease

    Immunol. Today

    (1996)
  • R.R. Nepomuceno et al.

    cDNA cloning and primary structure analysis of C1qR(p), the human C1q/Mbl/Spa receptor that mediates enhanced phagocytosis in vitro

    Immunity

    (1997)
  • A. Nicholson-Weller et al.

    C1q-binding proteins and C1q receptors

    Curr. Opin. Immunol.

    (1999)
  • O. Petrenko et al.

    The molecular characterization of the fetal stem cell marker AA4

    Immunity

    (1999)
  • N. Platt et al.

    Recognizing death: the phagocytosis of apoptotic cells

    Trends Cell Biol.

    (1998)
  • V. Rossi et al.

    Substrate specificities of recombinant mannan-binding lectin-associated serine proteases-1 and -2

    J. Biol. Chem.

    (2001)
  • C. Speth et al.

    Neuroinvasion by pathogens: a key role of the complement system

    Mol. Immunol.

    (2002)
  • H.A. Tharia et al.

    Complete cDNA sequence of SAP-like pentraxin from Limulus polyphemus: implications for pentraxin evolution

    J. Mol. Biol.

    (2002)
  • A. Aderem et al.

    Mechanisms of phagocytosis in macrophages

    Annu. Rev. Immunol.

    (1999)
  • D. Bharadwaj et al.

    The major receptor for C-reactive protein on leukocytes is fcgamma receptor II

    J. Exp. Med.

    (1999)
  • M. Botto et al.

    Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies

    Nat. Genet.

    (1998)
  • C. Cabanas et al.

    CD11c (leukocyte integrin CR4 alpha subunit)

    J. Biol. Regul. Homeost. Agents

    (1999)
  • T. Crass et al.

    Expression cloning of the human C3a anaphylatoxin receptor (C3aR) from differentiated U-937 cells

    Eur. J. Immunol.

    (1996)
  • P.J. Daffern et al.

    C3a is a chemotaxin for human eosinophils but not for neutrophils. I. C3a stimulation of neutrophils is secondary to eosinophil activation

    J. Exp. Med.

    (1995)
  • Y.D. Dean et al.

    Endothelial cells, megakaryoblasts, platelets and alveolar epithelial cells express abundant levels of the mouse AA4 antigen, a C-type lectin-like receptor involved in homing activities and innate immune host defense

    Eur. J. Immunol.

    (2001)
  • P.W. Dempsey et al.

    C3d of complement as a molecular adjuvant: bridging innate and acquired immunity

    Science

    (1996)
  • M.S. Diamond et al.

    The I domain is a major recognition site on the leukocyte integrin Mac-1 (CD11b/CD18) for four distinct adhesion ligands

    J. Cell Biol.

    (1993)
  • A.W. Dodds et al.

    The phylogeny and evolution of the thioester bond-containing proteins C3, C4 and alpha 2-macroglobulin

    Immunol. Rev.

    (1998)
  • J.A. Ember et al.
  • T.C. Farries et al.

    Analysis of the interactions between properdin, the third component of complement (C3), and its physiological activation products

    Biochem. J.

    (1988)
  • D.T. Fearon et al.

    The instructive role of innate immunity in the acquired immune response

    Science

    (1996)
  • W.H. Fischer et al.

    Regulation of IL-6 synthesis in human peripheral blood mononuclear cells by C3a and C3a(desArg)

    J. Immunol.

    (1999)
  • M.I. Fonseca et al.

    C1qR(P), a myeloid cell receptor in blood, is predominantly expressed on endothelial cells in human tissue

    J. Leuk. Biol.

    (2001)
  • K. Francis et al.

    Complement C3a receptors in the pituitary gland: a novel pathway by which an innate immune molecule releases hormones involved in the control of inflammation

    FASEB J.

    (2003)
  • P. Gasque et al.

    The receptor for complement anaphylatoxin C3a is expressed by myeloid cells and nonmyeloid cells in inflamed human central nervous system: analysis in multiple sclerosis and bacterial meningitis

    J. Immunol.

    (1998)
  • H. Gewurz et al.

    Nonimmune activation of the classical complement pathway

    Behring Inst. Mitt.

    (1993)
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