The Complement System in Mammals

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Complement is a central component of the innate immune system which is involved in host defence against infectious agents. The complement system in mammals is well characterised (particularly in mice and humans) and consists of about 35-40 proteins, present in blood plasma and other body fluids, and also on cell surfaces. In human blood plasma, the combined concentration of complement proteins is about 3.0-3.5 mg/ml, or about 4-5% of the total plasma protein. The function of complement is to recognise and then opsonise or lyse particulate materials



Fig. 1 The recognition proteins of the classical and lectin pathways. C1q, MBL and the ficolins are oligomeric proteins with a "bunch of tulips" shape. The "stalks" are made up of collagen triple helices, and the "heads" are globular domains, each with three lobes. One head and one collagenous stalk is made up of three polypeptide chains. C1q has six heads. It associates with a dimer of the serine protease proenzyme C1r, which in turn binds the serine protease proenzyme C1s. When C1q binds to a target, C1r autoactivates, then activates C1s. MBL has variable polymerisation and is thought to circulate in plasma in forms with four to six heads. The ficolins are probably mainly four-headed structures. MBL and the ficolins associate with one homodimer of MASP-1, or MASP2,or MASP3, or of Map19, a truncated alternative splicing product of the MASP2 gene, which lacks a serine protease domain. When MBL or ficolins bind to a target, MASP1 or MASP2 autoactivate. The activation mechanism for MASP3 is not yet known. MASP1 and MASP3 are alternative splicing products from a single gene and have different serine protease domains. C1r, C1s and the MASPs are homologues, and have the same domain structure (Fig. 3)

including invading micro-organisms and "altered-self" cells (dying, infected or damaged host cells). Opsonisation of micro-organisms with complement components targets them for phagocytosis by cells expressing complement receptors. In the complement system, large polymeric pattern recognition molecules including C1q, MBL and the ficolins (Fig. 1) have the capability to recognise micro-organisms via their highly conserved surface features (or "pathogen-associated molecular patterns"; PAMPS) such as lipopolysaccharides, lipoproteins, peptidoglycan, oligosaccharides and other surface structures (Janeway and Medzhitov 2002). Recent data extends the role of these complement pattern recognition molecules to the recognition and binding to apoptotic and necrotic host cells, and thereby complement contributes to the efficient clearance of cellular debris and apoptotic cells (Mevorach et al. 1998; Nauta et al. 2003). The innate and adaptive immune systems are often regarded as distinct arms of immunity; however, there is increasing data to suggest that innate and adaptive arms of immunity "cross-talk", and that complement has an important role bridging between innate and adaptive immunity.

The complement system can be activated via three routes, the classical pathway, lectin pathway and alternative pathway (Fig. 2). These pathways all converge at the cleavage of C3, the most abundant complement protein. The different pathways produce complex proteases capable of cleaving C3. These C3 convertases (C4b2a, C3bBb; Fig. 2) cleave C3 into two products, C3a and C3b. The major fragment, C3b, can bind covalently onto the surface of the complement-activating "target" particle, and act as an opsonin. C3b can also bind covalently onto the C3 conver-tases to form C5 convertases (C4b2a3b, C3bBb3b; Fig. 2) and so initiate assembly of the membrane attack complex (MAC), made up of complement proteins C5b, C6, C7, C8 and C9. This MAC can insert into lipid bilayers and cause lysis of a target cell.

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How To Bolster Your Immune System

How To Bolster Your Immune System

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