Complement ntial activation of the s molecules.Like C ntains nd that (MAC). can attach covalently to surfaces via their hydroxyl or result of this antibody-mediated omp agregauo Alternative Pathway C2 a othe The alternative pathway is activated by a variety of orotease.C2 binds to C4b in a Mg -dependent manner and is cleaved by CIs to C2a and C2b. he association c bac ria,fungi and C2a(which ontas the catalyticsite)with C has been shown to enhance the activation process.The This enzy alternative pathway is kept in a low level of steady state which is then deposited in large amounts onto the target surface.I his depo nize the targe t of hydr nativ s of the itate its aing th al s C3continuously available and ready to react with potential (C4b.2a.3b).With the C2a fragr the pathogens.It is also necessary because the half-life of the catalytic subunit,C5 convertase cleaves C5 to Csb.which is then added to the complex. acoecoromoS5ho able to bind to rB. proteolytically activated and cleaved to Bb(66kDa)and Lectin Pathway Ba(33 kDa)fragments by a second serine protease acto also directly activate the complement system (including viruses.bacteria and fungi)via its metastable serine protease (MASPI and MASP2).Once MBL binds to thioester bond.Most of this resulting C3b,as well as the C3(H2O),is i ntaneously inactivated by or c MCP The Cih that is not inactivated (the Ci ho d to and ctiv SPng C3 activating surfaces)is involved in an amplification loop of ve pathway Bb Lytic Pathway 、urther din.Close another C3b molecule with the C3b.Bb complex form All three pathways of complement activation converge enzyme C5 onvertase (C3b.Bb.3b).which cleaves C5 into with the production ofa C5 convertase which cleaves C5 to C5a and C5b(Figure1 Activation of the pathway is very MAC CSC the self-assembly of the whether amplification (hinding of factor B to C3b)or the Components of the Complement System It has now become clear that the complement system arose Classical Pathway first in invertebrate species more than 600 million years Activation of the syste by the classical complement genes ha ave already b oned they ene In t出 ve even more primitive species.the complement sstem m complex via the Clqsubunit (Figure1).Binding ofantibody have emerged as a simple system comprising a small and factor B and Dand/o ons(perhaps onl ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group /www.els.net it can be covalently attached to target surfaces where it leads to either opsonization, or cytolysis through the sequential activation of the membrane attack complex (MAC). Alternative Pathway The alternative pathway is activated by a variety of microorganisms including viruses, bacteria, fungi and protozoans. Although the initiation of activation is essentially antibody-independent, aggregated antibody has been shown to enhance the activation process. The alternative pathway is kept in a low level of steady state activation as a result of hydrolysis of the thioester group of native C3, which forms C3(H2O) (hydrolysed C3). This low-level activation is essential since it makes ‘functional’ C3 continuously available and ready to react with potential pathogens. It is also necessary because the half-life of the active form of C3 is very short. Once formed, C3(H2O) is able to bind to factor B, the catalytic subunit of the alternative pathway. Factor B is proteolytically activated and cleaved to Bb (66 kDa) and Ba (33 kDa) fragments by a second serine protease, factor D, to generate the enzyme C3 convertase (C3b,Bb). C3 convertase is able to cleave native C3 to C3a and C3b; C3b can then covalently bind to the surface of nearby particles (including viruses, bacteria and fungi) via its metastable thioester bond. Most of this resulting C3b, as well as the C3(H2O), is instantaneously inactivated by factor I in the presence of cofactor regulatory molecules (CR1, factor H, MCP). The C3b that is not inactivated (the C3b bound to activating surfaces) is involved in an amplification loop of the activation process, an essential feature of the activation of the alternative pathway. Binding of factor B to the newly generated C3b forms a new C3 convertase (C3b,Bb), which is further stabilized by properdin. Close association of another C3b molecule with the C3b,Bb complex forms the enzyme C5 convertase (C3b,Bb,3b), which cleaves C5 into C5a and C5b (Figure 1). Activation of the pathway is very much dependent upon the microenvironment surrounding the C3b bound molecule; conditions therefore determine whether amplification (binding of factor B to C3b) or abrogation of the pathway (binding of a regulator molecule to C3b) will occur. Classical Pathway Activation of the system by the classical pathway is primarily dependent on the immunoglobulin M (IgM) or IgG present in immune complexes, which binds to the C1 complex via the C1q subunit (Figure1). Binding of antibody induces conformational changes in the C1 complex and leads to the activation of its C1r and C1s serine protease subunits. Once activated, the C1s can cleave C4 to C4a and C4b; one molecule of activated C1s can cleave many C4 molecules. Like C3b, C4b contains a thioester bond that can attach covalently to surfaces via their hydroxyl or amino groups. The result of this antibody-mediated activation of the C1 complex is an aggregation of C4 molecules surrounding the antibody–C1 site. The next protein to bind to the complex is C2, another serine protease. C2 binds to C4b in a Mg2+-dependent manner and is cleaved by C1s to C2a and C2b. The association of C2a (which contains the catalytic site) with C4b leads to the formation of the classical pathway C3 convertase (C4b,2a). This enzyme is capable of binding and cleaving C3 to C3b, which is then deposited in large amounts onto the target surface. This deposition of C3 serves to opsonize the target surface and facilitate its phagocytosis, while initiating the terminal reaction sequence by forming C5 convertase (C4b,2a,3b). With the C2a fragment again supplying the catalytic subunit, C5 convertase cleaves C5 to C5b, which is then added to the complex. Lectin Pathway Lectins can also directly activate the complement system, through the binding of mannans to the complex compound of mannose-binding lectin (MBL) and theMBL-associated serine protease (MASP1 andMASP2). OnceMBL binds to mannans on the surface of various microorganisms, MASP becomes capable of cleaving and activating C3, C4 and C2. The distinct roles ofMASP1 andMASP2 are as yet unclear. Lytic Pathway All three pathways of complement activation converge with the production of a C5 convertase which cleaves C5 to C5b and C5a. C5b then initiates the self-assembly of the MAC C5b–C9(see below). Components of the Complement System It has now become clear that the complement system arose first in invertebrate species more than 600 million years ago, since complement genes have already been cloned, and the molecules they encode have been purified, from echinoderms and tunicates. In these animals, or perhaps even more primitive species, the complement system may have emerged as a simple system comprising a small number of components (perhaps C3, factor B and D and/or C3, MASP and MBL) with limited functions (perhaps only Complement 2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net