Complement in health and disease

Advanced Drug Delivery Reviews 63 (2011) 965–975

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Advanced Drug Delivery Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r

Complement in health and disease☆ Maria V. Carroll, Robert B. Sim ⁎ Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK

a r t i c l e

i n f o

Article history: Received 17 May 2011 Accepted 9 June 2011 Available online 16 June 2011 Keywords: Complement Innate immunity Blood plasma Collectins Inflammation Phagocytosis Opsonisation Autoimmunity Infection Disease

a b s t r a c t The complement system consists of about 35–40 proteins and glycoproteins present in blood plasma or on cell surfaces. Its main biological function is to recognise “foreign” particles and macromolecules, and to promote their elimination either by opsonisation or lysis. Although historically complement has been studied as a system for immune defence against bacteria, it has an important homeostatic role in which it recognises damaged or altered “self” components. Thus complement has major roles in both immune defence against microorganisms, and in clearance of damaged or “used” host components. Since complement proteins opsonise or lyse cells, complement can damage healthy host cells and tissues. The system is regulated by many endogenous regulatory proteins. Regulation is sometimes imperfect and both too much and too little complement activation is associated with many diseases. Excessive or inappropriate activation can cause tissue damage in diseases such as rheumatoid arthritis, age-related macular degeneration (AMD), multiple sclerosis, ischemia–reperfusion injury (e.g. ischemic stroke). Insufficient complement activity is associated with susceptibility to infection (mainly bacterial) and development of autoimmune disease, like SLE (systemic lupus erythematosus). © 2011 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Roles of the complement system in immunity and homeostasis History of complement research . . . . . . . . . . . . . . . The complement pathways . . . . . . . . . . . . . . . . . . 3.1. Convertase activity . . . . . . . . . . . . . . . . . . 3.2. The classical pathway . . . . . . . . . . . . . . . . . 3.3. C1q . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. The alternative pathway . . . . . . . . . . . . . . . . 3.5. The lectin pathway . . . . . . . . . . . . . . . . . . 3.6. MBL and collectin 11 . . . . . . . . . . . . . . . . . 3.7. Ficolins . . . . . . . . . . . . . . . . . . . . . . . . 4. Regulation of the complement system . . . . . . . . . . . . 4.1. The FH family . . . . . . . . . . . . . . . . . . . . . 4.2. Membrane-bound regulatory proteins . . . . . . . . . 4.3. Other fluid-phase regulatory proteins . . . . . . . . . 5. Complement receptors: opsonisation and adjuvant activity . . . 6. Complement and disease . . . . . . . . . . . . . . . . . . . 6.1. Not enough complement. . . . . . . . . . . . . . . . 6.2. Too much complement . . . . . . . . . . . . . . . . 6.3. Subtly-altered complement . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Complement Monitoring of Nanomedicines and Implants”. ⁎ Corresponding author. Tel.: + 44 1865271595. E-mail addresses: [email protected] (M.V. Carroll), [email protected] (R.B. Sim). 0169-409X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2011.06.005

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1. Roles of the complement system in immunity and homeostasis The complement system consists of about 35–40 proteins and glycoproteins present in blood plasma or on cell surfaces. The soluble

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(plasma) proteins are nearly all made in the liver, but most are also made in other cell types, particularly those of monocyte/macrophage lineage and this multiple-site synthesis results in significant local concentrations of complement proteins in tissues (e.g. brain, kidney) and other body fluids (e.g. saliva, lymph). Its main biological function is to recognise “foreign” particles and macromolecules, and to promote their elimination either by opsonisation (enhancing their uptake by phagocytic cells) or, if they have a lipid bilayer membrane (e.g. bacteria) by lysing them. Although historically complement has been studied as a system for immune defence (mostly against bacteria), it has been recognised particularly in the last 30 years that it has a very important homeostatic role: that is, the “foreign” material it recognises may be invading microorganisms (bacteria, viruses, fungi), but it is also damaged or altered “self” components, such as apoptotic and necrotic cells, abnormal protein assemblies (e.g. amyloids, clots or antibody aggregates). Thus complement has major roles in both immune defence against microorganisms, and in clearance of damaged or “used” host components. Complement proteins recognise (bind to) a very wide range of biological targets, and so it is not surprising that they also recognise synthetic materials, including liposomes, carbon nanotubes and various polymers. Thus in the development of synthetic materials, for example as drug carrier particles, prosthetics, it is important to assess whether such materials activate the complement system. Since complement proteins opsonise or lyse cells, complement can damage healthy host cells and tissues. Activation of complement also releases biologically active small proteins (anaphylotoxins: C3a, C4a and C5a) which contribute to inflammation. The activity of the system is regulated by many endogenous regulatory proteins (both soluble in plasma or on host cell surfaces). However regulation is sometimes imperfect and both too much and too little complement activation is associated with many diseases. Excessive or inappropriate activation can cause tissue damage in diseases such as rheumatoid arthritis, agerelated macular degeneration (AMD), multiple sclerosis, ischemia– reperfusion injury (e.g. ischemic stroke). Insufficient complement activity is associated with susceptibility to infection (mainly bacterial) and development of autoimmune disease, like SLE (systemic lupus erythematosus). 2. History of complement research The first observations of complement system activity were described between 1884 and 1894. In 1888, Nuttal demonstrated that fresh plasma possessed bactericidal activity which was abolished when heated to 55 °C [1]. Bordet later showed that the bactericidal activity of heat-treated immune serum could be restored with fresh non-immune serum, which alone had no activity [2]. Ehrlich and Morgenroth proposed that there were two main antibacterial components in the blood. The first was a heat-stable component, which they called “amboreceptors” (antibody), and the second was a heat-labile component, which they called “complement” [2,3]. Further research into complement was almost completely halted during World War I and World War II, but substantial progress was made in the 1920s and 1930s, with recognition that there were at least 4 components, and investigation of the lytic mechanism [4–6]. In 1941 four proteinaceous components were partially purified and characterised [7]. In the 1950s and 1960s there was detailed investigation of immune adherence (the phenomenon by which complement-coated particles become attached to human red blood cells), standardisation of assays of complement activity (by measuring lysis of red blood cells), the separation of 9 distinct complement protein components from guinea-pig serum and the description of a second pathway of complement activation, then called the properdin pathway, but now known as the alternative pathway [8–10]. In the 1970s and 1980s, protein components were isolated and sequenced, and subsequently cDNA and genomic clones and sequences were obtained [11–13], great progress was made in

characterising cell-surface complement receptors, and both soluble and cell-surface regulatory proteins [14,15]. Another major role of complement as an adjuvant was observed [16,17]. This refers to the property of complement in recognising and binding to foreign materials, then promoting their interaction with complement receptors on dendritic cells and B lymphocytes, stimulating the adaptive immune response to the complement activator. A third activation pathway, the lectin pathway was discovered [18]. In the last 20 years, the homeostatic role of complement has been explored (i.e. its role in clearance of damaged self material) and is still the subject of very active research [19]. Another topic which has expanded greatly is the recognition that genetic variants of complement proteins have subtle functional differences, and can predispose to disease. An example of this is the association of polymorphism in the regulatory protein, factor H (FH) [20] which is associated with the disease AMD, and with some kidney disorders. Studies on AMD subsequently showed that polymorphism in other complement proteins, including factor I, factor B also is associated with alteration in function [21–23]. The complexity of the lectin pathway has increased, with the discovery of three new proteases (the MASPs) [24] and new target-recognition proteins (the ficolins and, in 2010, collectin-11) [25,26]. X-ray crystallography and NMR studies have provided the three-dimensional structure of many complement proteins, and will form a basis for a much more detailed understanding of how they interact [27,28]. Development of reagents aimed at therapeutic manipulation of complement activity has at last gained momentum [29,30] and a monoclonal antibody, eculizumab, which inhibits complement at the C5 activation stage is in clinical use. 3. The complement pathways Soluble complement proteins normally circulate as protease zymogens or as inactive but activatable forms. Upon activation the proteases can cleave specific downstream targets or interact with other proteins, initiating amplification cascades and releasing anaphylotoxins (Fig. 1). Activation can occur by any or all of three pathways: classical, alternative and lectin. All of these result in turnover of C3, the most abundant complement protein, and subsequently in activation of the terminal pathway, and formation of the membrane attack complex (MAC). Complement activation also results in the deposition of protein fragments onto the cell surface of targets, flagging them for phagocytosis by macrophages. Each of the three pathways is initiated by different complement recognition proteins. These are, for the classical pathway, C1q and for the lectin pathway, mannose-binding lectin (MBL), the ficolins, or collectin 11. For the alternative pathway, there is still some controversy about what constitutes the recognition mechanism and this will be discussed below. The pathways are all antibodyindependent (i.e. they can recognise targets in the absence of any antibodies) [31,32] but all can also be activated by antibody–antigen complexes. 3.1. Convertase activity Initiation of the three complement pathways results in the activation of complement component 3 (C3). Activation of C3 results from either very slow spontaneous hydrolysis of its internal thioester, important for the alternative pathway, or proteolytic cleavage by the activity of the C3 convertases: C4b2a, in the classical and lectin pathways, and both C3(H2O)Bb and C3bBb in the alternative pathway (Fig. 1). Activation of the classical and lectin pathways results in the cleavage of C4 to generate C4a, an anaphylatoxin and the C4b fragment (Fig. 2 top). C2 is also cleaved, releasing a C2b fragment to generate the C4bC2a complex. The C4b fragment contains a highly reactive thioester and C2a contains an active serine protease domain. In the presence of activating surfaces such as a microbial cell, C4b

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Fig. 1. The complement system. There are three activation pathways in the complement system: classical, lectin and alternative. These pathways lead to the activation of the terminal pathway. Complement activation can lead to inflammation, opsonisation and cell lysis.

binds covalently to the cell surface via its active thioester near to the site of initial recognition event. The bound C4b2a is a C3 convertase, i.e. a protease which activates C3. This convertase cleaves C3, releasing two products, the anaphylatoxin C3a, and the C3b fragment. Like C4b, after cleavage of C3, C3b also exposes a highly active thioester. Through this site, C3b can form ester or amide linkages to nearby surfaces. C3b deposited onto cell surfaces can act as an opsonin, and it can also form the basis of another C3 convertase, C3bBb via further interactions with factor B (FB) and factor D (FD), or become part of the C5 convertase, C4b2a3b (Fig. 2). To form the C5 convertase, one molecule of C3b binds covalently to C4b in the C4b2a complex. The C3b–C4b assembly forms a binding site for C5, which is cleaved by C2a. The formation of the C5 convertase and resultant cleavage of C5 marks the beginning of the terminal complement pathway (Fig. 2 bottom). C5 cleavage generates C5a, another anaphylatoxin and the C5b fragment. Of the three anaphylatoxins generated from complement activation, C5a is the most potent, mediating inflammation and uniquely, C5a is also a chemotactic factor, attracting neutrophils to the site of complement activation (i.e. to a wound or site of infection) [33]. C5b forms a complex with C6 and C7, inducing structural reorganisa-

tion in C7 and exposing a hydrophobic site. This hydrophobic moiety allows the binding of the C5b67 complex to plasma membranes. The complex binds C8 which undergoes a conformational change allowing the insertion of its alpha chain into the target membrane. The inserted C5b678 complex can then bind 1–18 C9 molecules to form a pore, C5b6789(1–18) within the membrane of the target cell. The C5b-9 assembly is called the membrane attack complex (MAC). Formation of the MAC disrupts the proton gradient across the membrane, and results in cell lysis and death [34,35]. 3.2. The classical pathway The classical pathway is activated by the C1 complex, which is composed of the recognition molecule C1q (Fig. 3), and two molecules each of the serine protease proenzymes C1r and C1s which associate in the presence of calcium ions [36]. C1q can bind to antigen-bound IgG and IgM antibodies and can also bind a very wide variety of nonimmunoglobulin activators [31]. Upon binding to the target surface, C1q undergoes a conformational change which autoactivates the C1r zymogen. The C1r molecules subsequently cleave and activate the two C1s molecules to form the active C1s serine protease [37,38]. Activated

Fig. 2. The classical and terminal pathways. Formation of the C3 convertase and C5 convertase via the classical pathway recognition complex C1. C1q binds to a target (e.g. cell surface), and C1r and C1s are activated. C4 and C2 get cleaved by C1s to form the C3 convertase C4b2a which activates C3. Generation of C3b by the C3 convertase leads to the formation of the C5 convertase (bottom). Activity of the C5 convertase results in the cleavage of C5. C5b generation leads to the formation of the membrane attack complex.

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chondrial membranes, mitochondrial proteins, cardiolipin, ligand-bound C-reactive protein (CRP) and amyloids [31,43]. It binds the capsular polysaccharides of the Gram-positive type 1a Group B streptococci and to M-family proteins in Group A streptococci [44–46] and interacts with lipid A, porins and various lipolysaccharide structures of Gram-negative bacteria such as Klebsiella pneumonia, Escherichia coli, Salmonella minnesota and S. typhimurium [31,47–49]. C1q also binds to many synthetic particles, e.g. carbon nanotubes, various polymers [50,51]. 3.4. The alternative pathway

Fig. 3. Structure of C1q. The 6 globular heads each contain three lobes (one each from the A, B and C chains). Each lobe has binding sites which have low affinity recognition for many charge-cluster or hydrophobic motifs on targets. Binding of several heads to repetitive motifs on a target surface results in cumulative high avidity binding and activation of the proteases C1r and C1s, which are bound to C1q where the straight collagenous “stalks” diverge from the cylindrical collagenous N-terminal segment [36].

C1s cleaves C4 and C2 to generate the C3 convertase, C4b2a (Fig. 2). Once C3 is activated, the major fragment C3b can bind covalently to the target surface, or to C4b in the C4b2a complex. As noted above, the latter reaction forms the C5 convertase C4b3b2a, and the terminal pathway (Figs. 1, 2) proceeds. Once C3b is deposited on a surface, the alternative pathway can be activated, by formation of a C3b-Factor B complex, which is then activated to form the C3 convertase C3bBb by the action of Factor D (see Section 3.4). The alternative pathway amplifies the turnover of C3, and can result in clusters of several hundred C3b molecules binding to the target surface. Large numbers of bound C3b are needed for opsonisation, to promote the adhesion of the target particle to phagocytic cells, via hundreds of C3 receptor molecules. 3.3. C1q Human C1q is a 460 kDa multimeric protein composed of 6 subunits each made up of 3 homologous polypeptide chains: A, B and C. The A, B and C chains all have a collagen-like region at the Nterminal and a globular domain (gHA, gHB, gHC) at the C-terminal The A and the B chains within the subunit are linked via a disulphide bond at the N-terminal. The C chain holds the subunits together through a disulphide linkage to a C chain from another ABC subunit to form a dimeric subunit, where the collagen-like regions of the six chains associate in a triple helical structure [39,40]. Three of these dimeric subunits are held together non-covalently to produce the complete hexameric structure consisting of a total number of 18 polypeptide chains (Fig. 3). The plasma concentration of human C1q is on average 115 ug/ml [41]. It circulates in the plasma entirely as a calcium ion-dependent complex with the C1r2–C1s2 tetramer. C1q binds to an activator via its globular C-terminal head (gC1q) regions. When two or more gC1q are bound, this induces a conformational change in the collagen-like region resulting in the autoactivation of C1r. C1q binds to clusters of charged and hydrophobic regions and has a wide range of activators. It binds specifically to the Fc regions of IgG and IgM in immune complexes. Binding of one C1q (by several heads) to one antigen-bound pentameric or hexameric IgM can result in C1 activation Only one head can bind to one IgG, so two or more antigen-bound IgG are required for activation. The binding of C1q to monomeric IgG is weak, but the binding of multiple gC1q to multiple, closely-spaced antigen-bound IgG is of high avidity [42]. C1q can also bind non-immunoglobulin activators such as nucleic acids, chromatin, cytoplasmic intermediate filaments, mito-

The alternative pathway can be activated directly by contact with many types of complex carbohydrate structures present on the surfaces of bacteria, yeasts and also multicellular parasites. It is also activated by antibody–antigen complexes containing IgG or polymeric IgA, and by many synthetic materials [31]. The alternative pathway was until recently not thought to be initiated by a specific recognition molecule equivalent to C1q or MBL/ ficolins as seen in the classical or lectin pathways. Instead the alternative pathway relies on the spontaneous low level hydrolysis of C3 in plasma to form C3(H2O) (Fig. 4). This process occurs when small nucleophiles such as water or ammonia attack the thioester of the unactivated C3 in plasma. The resultant C3(H2O) molecule is similar in conformation and function to C3b. It can form a Mg 2+-dependent complex with FB which is subsequently cleaved by FD, releasing Ba, and leaving the Bb fragment which is an active serine protease bound to C3(H2O). This fluid phase complex, C3(H2O)Bb acts as an alternative pathway C3 convertase, cleaving C3 to C3b which is then deposited covalently, and randomly, on neighbouring cell surfaces. FB can then bind surface-bound C3b in a Mg 2+-dependent manner to form C3bB which can be cleaved by FD to form the alternative pathway surface-bound C3 convertase, C3bBb (Fig. 4). This convertase can cleave more C3 completing the alternative pathway C3 amplification loop. C3bBb is homologous to the classical pathway convertase, C4b2a, as C4 is a homologue of C3, and C2 a homologue of FB. C3bBb is quite unstable, and the Bb dissociates from C3b with a half life of 2–3 min. Properdin, however, slows down dissociation of the complex [52,53] and so acts as an up-regulator of complement activity. It may be that properdin binds to surface-bound C3b first, and accelerates the binding of FB to C3b to form the C3bBP complex (Fig. 5). FB can then be cleaved by FD generating C3bBbP, a stabilised C3 convertase [34]. Further studies have however now suggested that properdin may be an initiating molecule for the alternative pathway, in that properdin can bind directly to the target surface and recruit binding of C3b, then FB to form the C3 convertase (Fig. 5). The C3b could be derived from the activity of C3(H2O)Bb or of C4b2a. Direct binding of properdin has been recently demonstrated to zymosan and rabbit erythrocytes (both well-known alternative pathway activators), and to Neisseria gonorrhoeae [55], late apoptotic cells and necrotic cells [56] suggesting that properdin may be a recognition molecule for initiating the alternative pathway as was first implied by Pillemer in the 1950s [10]. Covalent binding of another C3b to the C3bBbP, C3 convertase, will form C3bBbP3b, the C5 convertase of the alternative pathway. Although properdin is not similar in structure to C1q, it is multimeric, and has functional similarity in that it has multiple binding sites which appear to recognise charge clusters and perhaps other motifs. 3.5. The lectin pathway The lectin pathway can be initiated by mannan-binding lectin (MBL) or ficolins, and the recently-described collectin 11 [26]. These are much less abundant than C1q in blood (ranging from b1 to about 25 ug/ml), so the lectin pathway has a lower capacity for activation than the classical pathway. However it responds to different targets. These recognition

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Fig. 4. The alternative pathway. The C3 and C5 convertases of the alternative pathway are homologous to those of the classical pathway. Two different C3 convertases can be formed, the fluid phase C3 convertase and the surface-bound C3 convertase. Formation of the latter convertase, which can be stabilised by properdin (P), completes the C3b amplification loop and can lead to the formation of the C5 convertase.

molecules bind carbohydrate or other structures present in a wide range of invading microorganisms and on apoptotic/necrotic cells [25,57]. MBL and the ficolins circulate in the serum complexed with zymogen serine proteases called MBL-associated serine proteases (MASPs) [24,58]. MASP-1 and MASP-3 are alternatively spliced products from a single MASP-1/3 gene, with identical N-terminal domains but different serine protease domains. Two additional alternative-splicing products are also in circulation bound to MBL or ficolins. These are MAp19, a truncated product of the MASP-2 gene, consisting of the first two Nterminal domains of MASP-2, and MAP-1, from the MASP1/3 gene, which like MAp19 lacks a serine protease domain [24,59]. The MASPs (−1, −2, and −3) are structurally and functionally similar to C1r and C1s. However C1q binds a tetramer of proteases (2 C1r, 2 C1s) but MBL and the ficolins appear to bind only one protease at a time (a dimer of MASP-1, or of MASP-2, or MASP-3, or MAp19, or MAP-1) [38]. Binding of these complexes to an activating surface results in a conformation change, inducing autoactivation of the MASPs[60]. MASP-1 and MASP-2 have been reported to autoactivate but MASP-3 does not [61]. Activated MASP-2 can cleave both C4 and C2, to form the classical and lectin pathway C3 convertase C4b2a. The function of MASP-1 and MASP-3 is still not clearly established. Unlike C1r and C1s, the MASPs do not seem to be involved in activation of each other, although there is some uncertainty. MASP-1 and -2 also activate some proteins of the coagulation pathway, so may be involved for example in release of chemotactic fibrinopeptides or small-scale clot formation. [62]. MASP 1 and/or 3, together with collectin 11, has been implicated in processes in growth and development [63].

Interactions of MBL with the activator occur at the CRDs. MBL is a C-type Ca 2+-dependent lectin and binds to terminal mannose, glucosamine, fucose sugar structures (containing vicinal, equatorial – OH groups) via its CRDs. The specificity of the CRD head groups and their oligomerisation enables MBL to form multiple weak interactions in order to build up to high-avidity binding. This allows MBL to discriminate between foreign and host surfaces, as foreign surfaces tend to have repetitive arrays of sugars (e.g. bacterial and fungal surfaces) [66]. These structures are abundant on the surfaces of bacteria, and their arrangement on the cell surface allows for multivalent binding of MBL. MBL has been shown to bind many bacteria, fungi, viruses and parasites, including Staphylococcus aureus, group-A Streptococci, Klebsiella aerogenes, Mycobacterium avium, M. tuberculosis, E. coli, Cryptococcus neoformans, Listeria monocytogenes and Neisseria meningitides [67–72]. As well as acting as a recognition molecule to activate the lectin pathway, MBL was shown to bind Salmonella montevideo in serum-free conditions and mediate attachment and uptake in polymorphonuclear leukocytes [73] and therefore has a role as an opsonin [64], as do C1q and the ficolins. Collectin 11 has recently been detected in plasma, and is likely to interact with MASPs [26]. Like MBL, it is a multimeric protein with multiple CRDs, which bind to fucose and mannose. Although the lectin pathway does not require antibodies, MBL does bind to the glycans on some immunoglobulins, such as IgG-G0, a glycosylation variant of human IgG [74], and mouse IgM but not human IgM [32].

3.7. Ficolins 3.6. MBL and collectin 11 MBL is part of the collectin (collagenous lectin) family [64]. It is made up of identical polypeptides, each about 25 kDa. Each polypeptide chain is composed of an N-terminal cysteine-rich domain, a collagen-like domain, an α-helical coiled-coil neck and a C-terminal carbohydrate recognition domain (CRD) (Fig. 6). Three of these polypeptide chains associate together to form a subunit, and two to six of these subunits (most commonly four) then associate together to form a structure similar to that seen under an electron microscope for C1q [65].

As well as MBL, ficolins are also involved in the recognition and initiation of the lectin pathway. Humans produce three types of ficolin, M-, L- and H-ficolin. An alternative nomenclature designates these as ficolin (FCN) -1, -2 and -3, respectively. They are all similar in structure to MBL (Fig. 6) and are made up of polypeptides which have an N-terminal cysteine-rich domain and a collagen-like domain. However, their C-terminal globular domain differs from MBL as the ficolins have fibrinogen domain-like C-terminals instead of C-type CRDs. These chains form homotrimeric subunits which associate together to form a structure consisting of three or four homotrimeric subunits [25].

Fig. 5. Functional roles of properdin. Properdin (P) has been suggested to act by three different mechanisms:—(i) stabilising the C3 convertase C3bBb by binding C3bBb to prevent complex dissociation; (ii) binding to surface-bound C3b and accelerating the formation of C3bBbP, and (iii) binding directly to complement-activating surfaces, recruiting C3b with subsequent formation of the C3 convertase C3bBbP.

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Fig. 6. Structural arrangements of the polypeptide chains of MBL. Three polypeptide chains of MBL assemble to form a trimeric subunit. Several subunits then oligomerise to form structures which resemble that of C1q. A trimer of subunits consisting of nine polypeptide chains is depicted here. MBL, and each of the ficolins, form trimeric subunits and larger oligomers, as depicted here. Each has only one type of polypeptide chain. C1q assembles similarly, but has three types of polypeptide chain.

H-ficolin (FCN-3) was the first ficolin to be identified and is the most abundant at a plasma concentration of 7–23 ug/ml in Japanese and 11–33 ug/ml in Caucasians [75]. L-ficolin (FCN-2) and M-ficolin (FCN-1) share 79% amino acid sequence identity and are believed to arise from a recent gene duplication [76,77]. However, H-ficolin does not share the same level of identity and its gene is found on a separate chromosome. Few binding ligands for H-ficolin are known, but it has been shown to bind N-acetylated monosaccharides, ligands present at the surface of Aerococcus viridans, lipopolysaccharides of Salmonella typhimurium, Salmonella minnesota, Escherichia coli, and the surface of the parasite Trypanosoma cruzi [75,78–80] and to apoptotic cells [81]. L-ficolin is the most widely studied of the human ficolins and has an estimated plasma concentration of 4–5 ug/ml in Caucasians and 14 ug/ ml in Japanese [25]. It has affinity for acetylated species, including Nacetyl sugars such as N-acetyl glucosamine, N-acetyl galactosamine and N-acetyl neuraminic acid [82,83] and has recently been shown to bind Creactive protein (CRP) [76,84–86]. Bacterial cell wall components such as lipoteichoic acid and peptidoglycan have been identified as L-ficolin ligands [87,88]. L-ficolin binds Salmonella typhimurium TV119, group B streptococci, Staphylococcus aureus, and Mycobacterium bovis [75,76,89,90] and to apoptotic cells [81]. Both L- and H-ficolin are found in complex with MASP-1, -2, -3 in serum. M-ficolin is found at a low level in serum, but is also reported to be present on the surface of monocytes, and in secretory granules. M-ficolin can activating MASP-2 to initiate the formation of the C4b2a, C3 convertase [91]. It has also a role in the binding and uptake of material in phagocytosis. Studies have located M-ficolin, bound to microorganisms, to phagosomes and shown that once the pH in the phagosome falls below physiological, M-ficolin undergoes a conformational change releasing the bound microorganism, and potentially gets recycled to the cell surface [92]. Binding studies so far have shown that M-ficolin can bind E. coli and S. aureus [93,94]. 4. Regulation of the complement system The three activation pathways of the complement system involve a high degree of amplification and therefore require an efficient system of regulatory proteins to ensure that complement is not exhausted and to prevent damage to host cells. There are regulatory proteins both in solution and on host cell membranes.

4.1. The FH family Factor H (FH) is a major soluble regulatory protein of the complement system, which prevents excessive turnover of C3. FH is a 155 kDa elongated glycoprotein [95]. It consists of 20 complement control protein (CCP) domains each consisting of 60 amino acids [96]. Along this length, the protein contains three different binding sites for C3b or C3d; the major site at CCP 1–4, and two others at CCP 19–20 and possibly at CCP 12–14 [97,98]. CCP 7 [22,99], CCP 9 [100] and CCP 19–20 [101,102] have also been identified as binding sites for negative charge clusters such as those on (highly-sulfated) heparin. In addition to binding C3b and possibly C3d and polyanions, FH also binds directly to pathogenic bacterial cell surfaces such as N. meningitidis, through the CCP 6–7 domain [103,104] and can bind other bacteria such as Borrelia burgdorferi, Streptococcus pneumonia, Streptococcus pyogenes, Yersinia enterocolitica, Haemophilus influenzae, Neisseria gonorrhoea, M. tuberculosis and the parasite Echinococcus granulosus [91,105–111]. Since FH is a complement down-regulator binding of FH to bacteria helps them to resist complement attack. FH is found in plasma, reportedly at widely varying concentration from about 150–750 ug/ml [41]. Its main function is to regulate the activation and activity of the alternative pathway. It discriminates between activators and non-activators, and limits the activation of C3 in the alternative pathway. It has been shown to have a higher binding avidity for C3b bound to non-activators compared to C3b bound to activators, due to the presence of sialic acids or other negative charge clusters which are present on non-activators, such as human cells. If C3b is deposited on such surfaces, FH can bind to both the polyanionic structure and to C3b, enhancing its apparent binding to C3b [112]. FH binding to C3b prevents formation of C3bBb and so stops further complement activation. Alternative pathway activating surfaces are regarded as lacking such negative charge clusters, so FH does not bind to them, and if C3b is deposited on them, FB will bind preferentially to it, forming the C3 convertase, C3bBb [31]. FH regulates the alternative pathway in two main ways (Fig. 7) [31,113]. Firstly, it possesses “decay-accelerating activity”, dissociating Bb from the C3 convertase, C3bBb. Cell-bound molecules, complement receptor 1 (CR1) and decay accelerating factor (DAF) also posses this activity (see Section 4.1). Secondly, once FH is bound to C3b, the C3b is cleaved by the regulatory protease Factor I (FI), forming iC3b. This is called “factor I-cofactor activity”. Cell-bound

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Fig. 7. FH activity. FH has two main regulatory functions. “Decay acceleration” refers to its capacity to dissociate the subunits C3b and Bb in the C3 convertase. “Factor I-cofactor activity” refers to the capacity of FH to bind to C3b, such that C3b in the complex can be cleaved by FI. CR1 and DAF possess the former function and CR1 and MCP possess the latter function.

regulators CR1 and membrane cofactor protein (MCP) also possess FI cofactor activity. Recent evidence suggests that FH has an additional major complement regulatory role of down-regulating classical pathway activation in response to certain targets. This is distinct from its role as an alternative pathway downregulator. FH and C1q, although not structurally similar, compete for binding to several types of chargecluster target [41,114–116], and so FH downregulates C1q binding to such targets. A number of proteins closely related in sequence to FH also circulate in plasma. This FH family is composed of seven structurally related proteins namely FH, FH-like protein-1 (FHL-1) and FH-related proteins 1–5 (FHR1–5) [117]. FHL-1, also known as reconectin consists only of 7 CCP domains and is a result of alternative splicing of the FH gene. Its CCP 1–7 are identical to these of FH [96]. It exhibits similar complement regulatory activity to FH, demonstrating both decay-accelerating, and cofactor activities [118], but is present at much lower concentration in plasma. FHRs 1–5 are each products of separate genes. They have no clearly assigned functions, but FHR-3 and FHR-5 both bind C3b and FHR-3 also binds heparin [117,119,120]. A gene cluster, called the regulation of complement activation (RCA) cluster on human chromosome 1q32 contains the FH family genes, and also the genes for other structurally-related complement regulatory proteins and receptors. These include CR1, CR2, MCP, DAF, C4 binding protein (C4bp) [121]. These are discussed further below Like FH, the other RCA cluster proteins are made up entirely or mainly of CCP domains. 4.2. Membrane-bound regulatory proteins Membrane-bound human complement regulatory proteins include the membrane cofactor protein (MCP: CD46), decay-accelerating factor (DAF: CD55), the membrane cofactor protein (MCP: CD55), decay-accelerating factor (DAF: CD46), complement receptor 1 (CR1: CD35) and CD59 [122]. MCP is present on most cells and binds C3b or C4b to facilitate degradation by factor I (as shown for FH in Fig. 7). DAF is also expressed on most cells and binds C3b to displace the Bb fragment from the alternative pathway membrane-bound C3 convertase, C3bBb. It can also dissociate C2a from the classical and lectin pathway C3 convertase, C4b2a. CR1, expressed on polymorphonuclear leukocytes, cells of monocyte lineage, erythrocytes, B-lymphocytes, kidney podocytes and follicular dendritic cells can behave similarly to MCP and DAF by helping to dissociate the C3 convertase and acting as a cofactor for factor I in the degradation of both C3b and C4b. CR1 is also the main receptor for C3b. CD59, also present on most human cells, plays a role later in the complement cascade, in the terminal pathway. It regulates the formation of MAC by binding to the C5b678 complex to prevent recruitment of C9 and pore-formation [122]. It protects host cells from complement-mediated lysis.

4.3. Other fluid-phase regulatory proteins Fluid-phase complement regulators include C1-inhibitor (C1-inh), FH, FI, C4bp, S-protein/vitronectin and clusterin. C1-inh is a serpin (serine protease inhibitor) that inactivates C1r, C1s and MASP-1 and MASP-2. C1-inh acts as a pseudo-substrate, reacting with the protease active site, and forming a stable protease–inhibitor complex. [123–125]. C1-inh activity prevents the formation of the C3 convertase C4b2a by inhibiting the classical and lectin pathway serine proteases. MASP-1 and -2, but not C1r and C1s, are also inhibited by the serpin antithrombin III, and by the major protease inhibitor, alpha-2 Macroglobulin [125]. FH as discussed above, and C4bp, act on the convertases. FH possesses decay-acceleration activity, accelerating the dissociation of Bb from C3b. C4bp acts in the same way for C4b2a. FH also acts as cofactor for the cleavage of C3b by FI, by which C3b is converted to iC3b. C4bp has the equivalent activity for C4, which is cleaved by FI into C4c plus C4d [23]. FI is a serine protease which circulates in active form and has no endogenous inhibitors. Its only known substrates, C3b in complex with a cofactor, or C4b in complex with a cofactor, are transiently formed so that its activity is controlled by substrate supply, not by inhibition [23]. As well as down-regulators of complement activation, there is one up-regulator, properdin, which acts as a positive regulatory protein only for the alternative pathway. It up-regulates C3 activation by stabilising the membrane-bound C3 and C5 convertases and has also been implicated as the initiating or recognition molecule for the alternative pathway (Fig. 4) [54,56]. S-protein (vitronectin), and clusterin (SP40, 40), are also involved later in complement activation and inhibit the terminal pathway by preventing the insertion of the forming MAC into a cell membrane. S-protein and clusterin achieve this by binding to the C5b67 complex preventing access to the binding site needed for binding to a phospholipid bilayer [126,127]. This activity is essential to prevent C5b67 complexes, which form close to the surface of a complementactivating target, from diffusing away and attacking nearby host cells. 5. Complement receptors: opsonisation and adjuvant activity When a particle has been recognised by the complement system, it will activate complement and will have molecules of C1q (or MBL or ficolins) and many molecules of C3b bound to it. Once C3b has bound, it is gradually broken down by FI, in the presence of cofactors (FH, CR1 or MCP) to form iC3b and eventually a smaller fragment called C3d or C3dg. Each of these interacts with cellular receptors. A C3b-coated particle in the blood will bind mainly to red blood cells, which have the receptor CR1 which binds C3b [128]. As the particle circulates, bound to red blood cells, the C3b will gradually be converted to iC3b, since CR1 is a cofactor for the cleavage of C3b by FI. iC3b binds only weakly to CR1, but binds strongly to CR3 and CR4 (complement

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receptors 3 and 4) which are found on phagocytic cells. When the red blood cells pass through the liver and spleen, where there are many macrophages, the particles, now coated mainly with iC3b, will transfer to phagocytic cells and be ingested and destroyed [129]. iC3b is therefore the most effective opsonin of the complement system. CR3 and CR4 are integrins, and they bind many other ligands in addition to iC3b. Another C3b and iC3b receptor on tissue macrophages has been described, and is named CRIg (Ig indicating that it is a member of the immunoglobulin superfamily) [130]. If the iC3b-coated particle is in circulation for longer, iC3b will eventually be broken down to the smaller C3d or C3dg fragment, which binds to a receptor called CR2 (complement receptor 2: CD21) . CR2 is not present on phagocytic cells, but is most abundant on B lymphocytes and on follicular dendritic cells (FDC). It is mostly through CR2 that the complement system acts as an adjuvant (stimulates the adaptive immune response) [131–133]. Binding to CR2 on FDC causes C3d-bearing particles (“antigens”) to adhere to the FDC, and promotes the germinal centre reaction and B cell memory. If B-cells bearing surface immunoglobulin which can bind the “antigen” are already formed, the particle can bind the B cell via surface immunoglobulin, and the secondary C3d–CR2 interaction causes B-cell proliferation. Peripheral dendritic cells (antigen presenting cells) can bind particles that have reacted with complement via other receptors, e.g. CR3, CR4 and C1q receptor [134,135] (see below), so that complement enhances antigen presentation and/or transport to the lymph nodes. Receptors also exist for C1q, MBL, the ficolins and the lung collectins, SP-A and SP-D, which are similar in structure and binding specificity to MBL. These proteins, when bound to a target, may also promote adhesion of the target to phagocytic or antigen-presenting cells. Generally however, this effect would be weaker than for C3b or iC3b, because fewer molecules of C1q, MBL or ficolins are bound to targets. Adhesion requires interactions between hundreds of receptor–ligand pairs, so C3b or iC3b, which can be fixed to the target in clusters of hundreds of molecules [136], are more effective. A receptor which will bind all of these collagenous proteins, C1q, MBL, ficolins, SP-A and SP-D has been identified. It is calreticulin, bound to cell surfaces via CD91 or other surface proteins [137–139]. 6. Complement and disease The roles of complement in killing invading microorganisms have been studied for many decades. Since the system can opsonise and lyse foreign particles and cells, and generate inflammatory peptides (C3a, C4a, C5a), it has the capacity, if inappropriately activated, to damage host tissues. From the 1970s onwards, its unwanted activities in damaging host tissue were explored, in association with diseases such as rheumatoid arthritis, glomerulonephritis, ischemic stroke, myasthenia gravis, multiple sclerosis, drug-induced lupus. More recently, genetic, genomic and gene-targeting studies have led to new findings on complement heterozygous deficiencies or common polymorphisms, which lead to subtle alterations in activation and regulation, and are associated with diseases such as age-related macular degeneration (AMD), hemolytic uremic syndrome (HUS) and pre-eclampsia. Knockout studies in mice also highlighted the contributions of complement and related proteins to homeostasis (apoptotic and necrotic cell clearance). Deficiencies in apoptotic cell clearance, which can arise from diminished complement activity are associated with autoimmune responses, as occur in systemic lupus erythematosus. 6.1. Not enough complement Insufficient complement system activity can arise from rare genetic deficiencies of complement proteins [140], and also, temporarily, from consumption of complement proteins because of infections, wounds or

surgery. Lack of complement activity can predispose to susceptibility to infection (mainly bacterial or fungal) and also to SLE-like autoimmune disease because of perturbation of clearance of “altered-self” materials e.g. apoptotic cells [141]. Deficiency of the early components of the classical pathway is associated with SLE. Deficiency of the central component, C3 leads to susceptibility to bacterial infection. Deficiency of FI or FH produces the same effect as C3 deficiency, since in the absence of FI or FH, C3b breakdown to iC3b is impaired, and the C3 convertase, C3bBb can form continually until all the C3 or FB in circulation is consumed. FH deficiency, or other perturbations of the control of C3 turnover are additionally associated with kidney disease including type II membranoproliferative glomerulonephritis and atypical hemolytic– uremic syndrome (aHUS) [142,143]. Lack of C5–C9 is associated only with susceptibility to Neisserial infections [140], emphasising the relative unimportance of lysis, versus opsonisation, in the antibacterial activities of complement. The association with development of SLE is reinforced by observations on “drug-induced SLE” [144], a condition which develops when certain nucleophilic drugs (e.g. hydralazine, isoniazid) are administered over long periods. A side-effect of these drugs is complement inhibition. They inhibit the reaction by which C4b (and C3b) bind covalently to complement activators. One complement protein which has a high incidence of deficiency is MBL. MW Turner and colleagues demonstrated that MBL deficiency was associated with recurrent bacterial infection in infants [145]. Subsequent genetic studies showed a high incidence (gene frequency 20–45%) in all human populations of mutations which cause diminished secretion or assembly of MBL. Subtle effects of MBL deficiency on many diseases and infections have been reported [146,147]. 6.2. Too much complement Excessive or prolonged complement activation can arise from persistent presence (or large dose) of complement activators (e.g. immune complexes, bacteria, yeasts, damaged self tissue) or from diminished expression of complement downregulators. Tissue damage in many conditions, such as rheumatoid arthritis, multiple sclerosis, myasthenia gravis and ischemia reperfusion (IR) is mediated by complement attack on host tissue [148]. In IR, blood supply to tissue is interrupted (e.g. in myocardial infarction, ischemic stroke) and when blood supply is restored, complement recognises the surface of the anoxic blood vessel endothelium as altered-self, and is activated, causing much greater cell death than would occur from brief anoxia alone. This type of injury can also occur in transplanted organs, and there is increasing pharmaceutical research aimed at finding suitable complement inhibitors to prevent such damage (see e.g. a development of an inhibitory antibody against the protease MASP2 which shows promise in animal models of ischemia–reperfusion injury [30]). A monoclonal antibody therapy (eculizumab) which inhibits complement activity by stopping activation of C5 is currently licenced for therapy of a rare hemolytic disease, paroxysmal nocturnal hemoglobinuria (PNH), but its use in other complement-related diseases in being explored, as are other targets for inhibition of complement [149–151]. PNH is an example of a disease involving loss of complement downregulators. Spontaneous mutation in the bone marrow produces red blood cells in which the regulator CD59 is not attached to the cell surface. These cells are very susceptible to lysis by C5b-9. 6.3. Subtly-altered complement Only in the last few years has it become possible to explore subtle variation in complement proteins, i.e. polymorphic variation. In the 1980s and 90s, many complement proteins were known to have sequence variants, but it was assumed that these variants all had similar activity (since there were not suitable experimental systems

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to determine otherwise). More recently, with faster DNA sequencing and improved protein expression, the genotype of many individuals can be determined and the variant proteins expressed and tested in vitro. A striking finding in 2005 was that a known Tyr–His interchange in FH was associated with greatly altered susceptibility to the eye disease, AMD. This gave a clue that the disease was associated with complement activation, and could arise from subtle functional alteration in FH, leading to variation in the level of regulation of complement (and so of complement-mediated tissue damage) in the macula [152]. In the disease aHUS progress has been made along similar lines, from the initial findings of FH heterozygous deficiency which showed the involvement of complement dysregulation in the disease. Subsequently, mutations and polymorphisms in FB, FI and MCP have also been found in association with aHUS [23]. A relatively new theme in complement research is based on the knowledge that complement proteins are abundantly synthesised in the brain. It has been recognised that complement abnormalities may be associated with neurological (developmental) disorders (e.g. schizophrenia); such an association could arise from altered clearance of apoptotic neurons, or synapse remodelling during brain development [153–155]. Interests in therapeutic manipulation of complement activity are mainly directed towards ischemia/reperfusion injury and acute transplant rejection. The rapid advances in determination of the three-dimensional structures of whole complement proteins and their complexes [27,28] are opening new opportunities for design of therapeutic control. References [1] C.A. Alper, A history of complement genetics, Exp Clin Immunogenet 15 (1998) 203–212. [2] B.J. Morley, M.J. Walport, The Complement Facts Book, Academic Press, London, 2000. [3] J.E. Figueroa, P. Densen, Infectious diseases associated with complement deficiencies, Clin Microbiol Rev 4 (1991) 359–395. [4] H.R. Whitehead, J. Gordon, A. Wormall, The “third component” or heat-stable factor of complement, Biochem J 19 (1925) 618–625. [5] J. Gordon, H.R. Whitehead, A. Wormall, The action of ammonia on complement. The fourth component, Biochem J 20 (1926) 1028–1035. [6] J. Gordon, A. Wormall, The relationship between haemolytic complement of guinea-pig serum and lipase, Biochem J 23 (1929) 730–737. [7] L. Pillemer, E.E. Ecker, J.L. Oncley, E.J. Cohn, The preparation and physicochemical characterization of the serum protein components of complement, J Exp Med 74 (1941) 297–308. [8] D.S. Nelson, R.A. Nelson, On the mechanism of immune-adherence. I. Differentiation from acid-adhesion of bacteria to erythrocytes, Yale J Biol Med 31 (1959) 185–200. [9] R.A. Nelson Jr., J. Jensen, I. Gigli, N. Tamura, Methods for the separation, purification and measurement of nine components of hemolytic complement in guinea-pig serum, Immunochemistry 3 (1966) 111–135. [10] R.J. Wedgewood, L. Pillemer, The nature and interactions of the properdin system, Acta Haematol 20 (1958) 253–259. [11] H.J. Müller-Eberhard, Complement, Annu Rev Biochem 44 (1975) 697–724. [12] H.J. Müller-Eberhard, Molecular organization and function of the complement system, Annu Rev Biochem 57 (1988) 321–347. [13] R.D. Campbell, S.K.A. Law, K.B.M. Reid, R.B. Sim, Structure, organization, and regulation of the complement genes, Annu Rev Immunol 6 (1988) 161–195. [14] J.G. Wilson, N.A. Andriopoulos, D.T. Fearon, CR1 and the cell membrane proteins that bind C3 and C4. A basic and clinical review, Immunol Res 6 (1987) 192–209. [15] D. Hourcade, V.M. Holers, J.P. Atkinson, The regulators of complement activation (RCA) gene cluster, Adv Immunol 45 (1989) 381–416. [16] M.B. Pepys Role, of complement in induction of antibody production in vivo. Effect of cobra factor and other C3-reactive agents on thymus-dependent and thymus-independent antibody responses, J Exp Med 140 (1974) 126–145. [17] D.T. Fearon, The complement system and adaptive immunity, Semin Immunol 10 (1998) 355–361. [18] K. Ikeda, T. Sannoh, N. Kawasaki, T. Kawasaki, I. Yamashina, Serum lectin with known structure activates complement through the classical pathway, J Biol Chem 262 (1987) 7451–7454. [19] M.J. Walport, K.A. Davies, M. Botto, C1q and systemic lupus erythematosus, Immunobiology 199 (1998) 265–285. [20] A.J. Day, A.C. Willis, J. Ripoche, R.B. Sim, Sequence polymorphism of human complement factor H, Immunogenetics 27 (1988) 211–214. [21] S. Rodriguez de Córdoba, E.G. de Jorge, Genetics and disease associations of human complement factor H, Clin Exp Immunol 151 (2008) 1–13. [22] S.J. Clark, V.A. Higman, B. Mulloy, S.J. Perkins, S.M. Lea, R.B. Sim, A.J. Day, His-384 allotypic variant of factor H associated with age-related macular degeneration

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Sim, Target pattern recognition by complement proteins of the classical and alternative pathways, Adv Exp Med Biol 653 (2009) 117–128. J.N. Arnold, M.R. Wormald, R.B. Sim, P.M. Rudd, R.A. Dwek, The impact of glycosylation on the biological function and structure of human immunoglobulins, Annu Rev Immunol 25 (2007) 21–50. M.M. Frank, L.F. Fries, The role of complement in inflammation and phagocytosis, Immunol Today 12 (1991) 322–326. S. Bhakdi, J. Tranum-Jensen, Complement lysis: a hole is a hole, Immunol Today 12 (1991) 318–320 discussion 321. A.F. Esser, Big MAC attack: complement proteins cause leaky patches, Immunol Today 12 (1991) 316–318 discussion 321. G.J. Arlaud, C. Gaboriaud, N.M. Thielens, V. Rossi, Structural biology of C1, Biochem Soc Trans 30 (2002) 1001–1006. A.W. Dodds, R.B. Sim, R.R. Porter, M.A. Kerr, Activation of the first component of human complement (C1) by antibody–antigen aggregates, Biochem J 175 (1978) 383–390. R. Wallis, D.A. Mitchell, R. Schmid, W.J. 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N.J. Levy, D.L. Kasper, Surface-bound capsular polysaccharide of type Ia group B Streptococcus mediates C1 binding and activation of the classic complement pathway, J Immunol 136 (1986) 4157–4162. I.V. Koroleva, A.G. Sjoholm, C. Schalen, Binding of complement subcomponent C1q to Streptococcus pyogenes: evidence for interactions with the M5 and FcRA76 proteins, FEMS Immunol Med Microbiol 20 (1998) 11–20. F. Clas, M. Loos, Antibody-independent binding of the first component of complement (C1) and its subcomponent C1q to the S and R forms of Salmonella minnesota, Infect Immun 31 (1981) 1138–1144. A.J. Tenner, R.J. Ziccardi, N.R. Cooper, Antibody-independent C1 activation by E. coli, J Immunol 133 (1984) 886–891. M. Latsch, J. Mollerfeld, H. Ringsdorf, M. Loos, Studies on the interaction of C1q, a subcomponent of the first component of complement, with porins from Salmonella minnesota incorporated into artificial membranes, FEBS Lett 276 (1990) 201–204. C. Salvador-Morales, E. Flahaut, E. 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