REVIEWS                                   Complement regulators and inhibitory                                   proteins ...
REVIEWS                                     Alternative pathway          Classical pathway      Lectin pathway       to en...
REVIEWSTable 1 | Complement regulators and receptors for effector proteinsRegulator     Alternative          Point of     ...
REVIEWS Table 1 (cont.) | Complement regulators and receptors for effector proteins Regulator            Alternative      ...
REVIEWS                                                                                                   modified self ce...
REVIEWS Table 2 | Complement deficiencies and complement-mediated diseases Disease                              major defe...
REVIEWS                       a Complement regulators                                                      Alternative pat...
REVIEWS                          and CRIg, bind C3b or C4b deposited on the surface                a hemisphere with a rad...
REVIEWS                       multifunctional factor H protein. so, single mutations             (CFHR1, clusterin and vit...
REVIEWS Table 3 | Host and pathogen complement regulators Point of action          Host regulators                        ...
2  complemento receptores - segunda apresentação
2  complemento receptores - segunda apresentação
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2 complemento receptores - segunda apresentação

  1. 1. REVIEWS Complement regulators and inhibitory proteins Peter F. Zipfel*‡ and Christine Skerka* Abstract | The complement system is important for cellular integrity and tissue homeostasis. Complement activation mediates the removal of microorganisms and the clearance of modified self cells, such as apoptotic cells. Complement regulators control the spontaneously activated complement cascade and any disturbances in this delicate balance can result in damage to tissues and in autoimmune disease. Therefore, insights into the mechanisms of complement regulation are crucial for understanding disease pathology and for enabling the development of diagnostic tools and therapies for complement-associated diseases. Complement is one of the first lines of defence in innate The beneficial aspects of a moderately activated com- immunity and is important for cellular integrity, tis- plement system include immune surveillance, removal sue homeostasis and modifying the adaptive immune of cellular debris, organ regeneration and neuroprotec- response1–3. The activated complement system recog- tion. The two anaphylatoxins complement component 3a nizes and eliminates invading microorganisms and (C3a) and C5a have a role during organ regeneration17, thus is beneficial for the host 4,5. In addition, comple- in neuroprotection18 — including in migration of neu- ment facilitates the elimination of dead or modified self rons19 and synapse elimination20 — and in the release cells, such as apoptotic particles and cellular debris6,7. of progenitor haematopoietic stem cells21. In addition, The alternative pathway of complement forms a spon- crosstalk and cooperative effects between C3a receptor taneously and constantly activated immune surveillance (C3aR), C5aR, C5a receptor-like 2 (C5L2) and Toll-like system8,9. The individual complement reactions develop receptors have been reported22. These additional physi- in a sequential manner, allowing regulation that modu- ological functions highlight the role of complement lates the intensity of the response and adjusts the effector in physiology and homeostasis and demonstrate that functions for the specific immune response. appropriate regulation and balanced or targeted activa- Complement was identified more than 100 years tion are crucial to keep the complement system in its ago as a result of its ‘complementary’ bactericidal activ- proper physiological state. ity and its role in phagocytosis of cellular debris 10,11. This Review focuses on the complement regulators The activated complement system directs immune that modify and control the complement system. We effector functions and modulates the intensity of the highlight the mechanisms of complement control on dif- response in a self-controlling manner. This allows ferent biological surfaces, such as intact self cells, which for the appropriate innate immune response, which act as non-activator surfaces, and modified self cells and is needed for recognition and removal of infectious microbial cell surfaces, which act as activator surfaces. agents or modified self cells 6,12. Now, 110 years after*Department of InfectionBiology, Leibniz Institute for these initial reports, the central role of this system in The complement cascadeNatural Product Research immune defence is much better known: many of the Complement activation, amplification, progressionand Infection Biology, biological effects of complement action are under- and regulation. Complement activation occurs in aBeutenbergstrasse, 11a, stood in molecular terms and a role for complement sequential manner and can be divided into four main07745 Jena, Germany. in tissue homeostasis is emerging. Complement acti- steps: initiation of complement activation, C3 conver-‡ Friedrich Schiller University,Fürstengraben 1, 07743 vation in turn activates pro-inflammatory mediators, tase activation and amplification, C5 convertase activa-Jena, Germany. generates anaphylactic peptides, cytolytic compounds tion, and terminal pathway activity or the assembly ofCorrespondence to P.F.Z. and antimicrobial compounds, recruits effector cells and the terminal complement complex (TCC; also knowne-mail: induces effector responses13,14. These result in a moder- as MAC) (FIG. 1). Once activated, the complement cas-peter.zipfel@hki-jena.dedoi:10.1038/nri2620 ate and controlled outcome of complement activation, cade generates effector compounds that are deliveredPublished online which is beneficial for the host but detrimental for the to any surface in an indiscriminate manner. However,4 September 2009 invading microorganism15,16. progression of the cascade and the action of the effectorNATuRe RevIeWs | Immunology vOLuMe 9 | O CTObeR 2009 | 729 © 2009 Macmillan Publishers Limited. All rights reserved
  2. 2. REVIEWS Alternative pathway Classical pathway Lectin pathway to ensure that activation and generation of biologically active effector compounds occurs only at the appropri- a Initiation C3 C1 ate time and site. If the activation cascade progresses, MASP C3 the reactions are amplified and can result in potent and C4 and C2 powerful effector functions. The complement system has more than sixty components and activation fragments, b C3 convertase C3bBb C4bC2b which comprise the nine central components of the cas- cade (C1 to C9), multiple activation products with diverse biological activities (for example, C3a, C3b, iC3b, C3d and C3dg)12,23, regulators and inhibitors (such as factor H, fac- C3a C3b Opsonization tor H-like protein 1 (FHL1), complement factor H-related protein 1 (CFHR1), CR1 (also known as CD35), C4b- c C5 convertase Inflammation C3bBbC3b C4bC2bC3b binding protein (C4bP), C1q and vitronectin), proteases and newly assembled enzymes (for example, factor b, C5a C5 factor D, C3bbb and C4bC2b) or receptors for effector molecules (such as C3aR, C5aR, C5L2 and complement component C1q receptor (C1qR)) (TAble 1). The number C5b of known components of the network, particularly the d Terminal pathway C5b–C9 regulators and receptors, is continuously increasing and new functions for these proteins are being identified. Terminal complement complex (lysis)Figure 1 | Complement: a central immunosurveillance system. Complement is a Initiation of complement activation. Complement is acti-central defence mechanism of innate immunity and is activated in a tightly regulated vated by three major pathways. The alternative pathway ismanner. a | Complement is initiated by three major pathways. The alternative pathway is spontaneously and constantly activated on biological sur-spontaneously and continuously activated. The classical pathway is induced when faces in plasma and in most or all other body fluids24. Thisantibodies bind to their corresponding antigen. The lectin pathway is triggered by the spontaneous activation readily initiates amplification8.binding of mannan binding lectin (MBL; also known as MBP-C)Nature Reviews | Immunology to mannose residues on the The classical pathway is triggered by an antibody boundsurface of microorganisms. This activates the MBL-associated proteases mannan-bindinglectin serine protease 1 (MASP1) and MASP2, which then cleave C4 and C2. b | Complement to the target antigen25, but this pathway can also be acti-activation occurs in a sequential manner. The three pathways initiate the formation of vated in an antibody-independent manner by viruses andenzymes known as complement component 3 (C3) convertases (C3bBb for the alternative Gram-negative bacteria. The lectin pathway is initiatedpathway and C4bC2b for the classical and lectin pathways). These enzymes cleave the by carbohydrates on microbial surfaces26,27. Activationcentral complement component C3 and generate the anaphylactic and antimicrobial of each of these pathways results in assembly of the firstpeptide C3a and the opsonin C3b, which can be deposited onto any nearby surface. This enzyme of the cascade, which is termed C3 convertaseactivation is followed by an amplification reaction that generates additional C3 convertases (FIG. 1). Complement is also activated by an additionaland deposits more C3b at the local site. Subsequently, C3b is inactivated and sequentially bypass pathway that acts independently of C3 or bypassesdegraded and the various degradation products mediate important effector functions. the C3 convertase and is mediated by thrombin actingFor example, C3b deposition on a surface results in opsonization, which allows for the on the C5 convertase28.interaction of C3b with specific host C3 receptors expressed on the surface of immuneeffector cells. c | If activation progresses, a new enzyme, the C5 convertase (C3bBbC3b forthe alternative pathway and C4bC2bC3b for the classical and lectin pathways), is generated. C3 convertase and amplification. The convertase for theC5 convertase cleaves C5, releases the potent anaphylactic peptide C5a and generates C5b. alternative pathway (C3bbb) is formed by C3b and fac-d | C5b can initiate the terminal pathway , which recruits the components C6, C7, C8 and tor bb, whereas the convertase for the classical and lectinC9 to the surface of the target and inserts the C9 complex as a pore (termed the terminal pathways (C4bC2b) is composed of C4b and C2b. bothcomplement complex) into the membrane. The activated complement system generates convertases cleave C3 to C3a and C3b. C3a aids in themultiple effector compounds that drive and orchestrate further immune reactions. recruitment and activation of innate immune effector cells and also has antimicrobial and antifungal activity 29. If activation progresses, C3b is deposited close to the siteZymogen molecules are strictly controlled at each level by multiple of generation and, on formation of surface-bound con-An inactive pre-form of complement regulators and inhibitors. These regulators vertases, amplifies the cascade13,30. The C3b fragment alsoa protease that by itself lacks discriminate between self and non-self surfaces, such as coats microbial or apoptotic surfaces and marks the par-proteolytic activity. Uponprocessing or proteolytic cells — including modified self cells — tissues and infec- ticle for phagocytosis. On the surface membrane of intactcleavage the protein displays tious agents7–9,15. such regulators and inhibitory circuits self cells, C3b deposition is prevented by regulators andenzymatic activity. Using such operate at every level of the cascade and are therefore further progression is blocked; by contrast, on microbialinactive pre-forms allows central to understanding complement action. surfaces or on modified self cells activation can progress.targeting of protein activity to The complement system consists of a set of inactive However, pathogenic microorganisms and apoptoticthe right place at the right time.Most complement proteins, components that are linked and activated in a cascading cells acquire soluble regulators, which block progres-but also components of the manner. When they encounter a biological surface, the sion of the cascade beyond the level of C3 convertase.coagulation cascade and other inactive zymogens are structurally modified, assemble C3b opsonizes the biological surfaces, which are thenproteases, exist and circulate as with additional components and are converted to effector cleared by phagocytosis in a non-inflammatory manner.inactive pre-forms and requiremodification and proteolytic compounds or active enzymes that activate new substrates Interestingly, similar or related mechanisms are used forprocessing to be converted — and so the cascade progresses. The first enzymatic reac- the non-inflammatory removal of modified self particlesinto an active form. tions, which activate C3 convertase, are tightly controlled and for attack and removal of microorganisms.730 | O CTObeR 2009 | vOLuMe 9 © 2009 Macmillan Publishers Limited. All rights reserved
  3. 3. REVIEWSTable 1 | Complement regulators and receptors for effector proteinsRegulator Alternative Point of ligand Cell surface binding or Function Refs name action expressionSoluble regulators and effectorsFactor H None Alternative C3b and C3d Acquired to surface Cofactor for factor I and acceleration 53 pathway of alternative pathway C3 convertase decayFHL1 None Alternative C3b Acquired to surface Cofactor for factor I and acceleration 54 pathway of alternative pathway C3 convertase decayProperdin None Alternative C3 Binds to apoptotic surfaces Stabilization of alternative pathway 55,66 pathway convertasesCarboxy- Anaphylatoxin Classical C3a, C4a and NA Inactivation of anaphylatoxins C3a 56,57peptidase N inactivator pathway and C5a and C5a lectin pathwayC4BP None Classical C4 Acquired to surface Cofactor for factor I and acceleration 59 pathway and of classical pathway C3 convertase lectin pathway decayC1q None Classical IgG and IgM Binds to apoptotic surfaces Activation of the classical pathway 60 pathway immune complexesC1INH None Classical C1r, C1s and NA Blocks serine protease and is a 58 pathway and MASP2 suicide substrate for C1r, C1s, lectin pathway MASP2, coagulation factors and C3bCFHR1 None Terminal C5 convertase Acquired to surface Inhibition of C5 convertase and TCC 62 pathway and TCC assemblyClusterin SP-40,40 and Terminal C7, C8β, C9 NA Transport of cholesterol, HDL, 61,64 apolipoprotein J pathway and TCC APOA1 and lipidsVitronectin S-protein Terminal C5b-7 and TCC NA Adhesion protein, fibronectin- 63 pathway mediated cell attachment and Arg-Gly-Asp site coagulation in immune defence against Streptococcus spp.Surface bound regulators and effectorsCR1 CD35 and C3 C3b, iC3b, C4b Many nucleated cells Clearance of immune complexes, 68 immune and C1q and erythrocytes, B cells, enhancement of phagocytosis and adherence leukocytes, monocytes and regulation of C3 breakdown receptor follicular dendritic cellsCR2 CD21 and C3 C3dg, C3d and B cells, T cells and follicular Regulation of B cell function, B cell 69,70 Epstein–Barr iC3b dendritic cells co-receptor and retention of C3d virus receptor tagged immune complexesCR3 MAC1, C3 iC3b and factor Monocytes, macrophages, iC3b enhances the contact of 76 CD11b–CD18 H neutrophils, natural killer cells, opsonized targets, resulting in and αMβ2 eosinophils, myeloid cells, phagocytosis and adhesion by CR3 integrin follicular dendritic cells, CD4+ T cells and CD8+ T cellsCR4 CD11c–CD18 C3 iC3b Monocytes and macrophages iC3b-mediated phagocytosis 77 and αXβ2 integrinCRIg VSIG4 C3 C3b, iC3b and Macrophages iC3b-mediated phagocytosis and 74 C3c inhibition of alternative pathway activationCD46 MCP C3 C3b and C4b All cells except erythrocytes C3 degradation, cofactor for factor I 67,72 and factor H, and effector for T cell maturation CD55 DAF C3 C4b2b and GPI anchor expression by Acceleration of C3 convertase decay 67,72 C3bBb most cell types, including erythrocytes, epithelial cells and endothelial cellsCD59 Protectin TCC C8 and TCC GPI anchor expression by Inhibition of TCC assembly and 73 erythrocytes and most formation nucleated cells, including renal cellsNATuRe RevIeWs | Immunology vOLuMe 9 | O CTObeR 2009 | 731 © 2009 Macmillan Publishers Limited. All rights reserved
  4. 4. REVIEWS Table 1 (cont.) | Complement regulators and receptors for effector proteins Regulator Alternative Point of action ligand Cell surface binding or Function Refs name expression Receptors for complement effector proteins C3aR None C3 C3a Neutrophils, monocytes, Immune cell recruitment and 78 eosinophils, antigen-presenting inflammation cells, T cells, astrocytes, neurons and glial cells C5aR CD88 C5 C5a Myeloid cells, monocytes, Immune cell recruitment and 19,32, neutrophils, dendritic cells, inflammation 79,82 antigen-presenting cells, T cells, endothelial cells and renal tubular cells C5L2 None C5 C5a Macrophages and neutrophils Immune cell recruitment and 19,32, inflammation and possibly acts 80,82 as a decoy receptor C1qR CD93 Classical pathway C1q Monocytes and B cells Phagocytosis and cell adhesion 83,84 SIGNR1 CD209 Classical pathway C1q Dendritic cells and microglial Signalling, inflammation and 85 cells phagocytosis APOA1, apolipoprotein A-1; C, complement component; C1INH, C1 inhibitor; C4BP, C4b-binding protein; C5L2, C5a receptor-like 2; CFHR1, complement factor H-related protein 1; CR, complement receptor; CRIg, complement receptor of the immunoglobulin superfamily; DAF, complement decay-accelerating factor; FHL1, factor H-like protein 1; GPI, glycosylphosphatidylinositol; HDL, high-density lipoprotein; MASP2, mannan-binding lectin serine protease 2; MCP, membrane cofactor protein; NA, not applicable; SIGNR1, a mouse homologue of DC-SIGN, SIGN-related 1; TCC, terminal complement complex. C5 convertase. If the activation cascade is allowed to would otherwise eliminate the infectious agent and keep proceed beyond the cleaving of C3 into C3a and C3b, the host organism intact. However, a persisting pathogen an additional C3b molecule binds to the C3 convertases. triggers additional immune reactions. Thus, during an This generates C3bbbC3b, the C5 convertase for the infection by a pathogen, complement is induced locally alternative pathway, or C4bC2bC3b, the C5 convertase and this local complement activation also attacks host for the classical and lectin pathways31. both enzymes bystander cells at the site of infection. In this situation, an cleave C5 to C5a and C5b. C5a is a powerful anaphy- attacked host cell requires maximal protection and uses lactic peptide and the C5b fragment can initiate the numerous available regulators to ensure survival. so, the terminal pathway 32 (FIG. 1). The C5a-induced inflamma- human complement system maintains a delicate bal- tion and the C5b-initiated terminal pathway seem to be ance between activation and inhibition to allow activa- separately regulated33. tion on foreign or modified self surfaces and protection of self. This explains why the regulation of complement The terminal pathway. The C5b fragment bound to activation is crucial for homeostasis. the active convertase initiates the terminal pathway, which results in directed, non-enzymatic assembly of Protection of self cells. The action of complement effec- the terminal pathway components C5, C6, C7, C8 and tor molecules is blocked on the surface of intact host C9, which form the TCC. The assembly and confor- cells and biomembranes40,41 by a combination of integral mational changes of these soluble, hydrophilic proteins membrane, surface-attached and fluid-phase regulators. generate lipophilic, membrane-inserting complexes. The concerted action of regulators and inhibitors ensures ultimately, formation of a TCC leads to pore forma- cell and tissue integrity (FIG. 2). tion and cell lysis34–36. Additional functions for TCC Dysregulation of the complement cascade results in components have also been reported. These include immunopathology and autoimmune disease. Mutations stimulating activity in T helper cell polarization, a role in the genes encoding individual regulators can result in for membrane-bound C7 as a sink for the late comple- defective control and inappropriate delivery of comple- ment components to control excessive soluble TCC- ment activation products onto the surface of host cells. induced inflammation and a role for the soluble TCC This results in complement attack at self-cell surfaces and, in platelet-activating activity 37–39. depending on the intensity of complement activation, in pathology (see below and FIG. 2 and TAble 2).Opsonization Complement: a double-edged sword Mutations of a single complement gene can resultThe deposition of activation Complement is important for the clearance of infectious either in the absence of the protein in the circulation orproducts, for example the C3activation fragment C3b, on agents, but pathogens use a number of evasion strategies in the dysfunction of the inhibitor. Changes in a singlethe surface of a target to to modify and block complement activity. Most patho- component can disturb the whole regulatory network.mark the target and facilitate gens express surface proteins that bind to host comple- In a normal setting, when complement activationand enhance recognition and ment regulators or recruit complement inhibitors and occurs at low levels, the absence or dysfunction of auptake by phagocytic cells.Phagocytosis eliminates the thus block or interfere with complement effector func- single component can be tolerated or compensated forparticle from the circulation tions. such surface-bound host regulators delay or even by the presence and concerted action of multiple addi-and aids in its destruction. block protective host innate immune responses that tional regulators. However, when a local complement732 | O CTObeR 2009 | vOLuMe 9 © 2009 Macmillan Publishers Limited. All rights reserved
  5. 5. REVIEWS modified self cells such as apoptotic particles and a Protection of b Non-inflammatory c Complement activation host cells removal of modified and removal of infectious necrotic cells and allow non-inflammatory removal or host cells microorganisms clearance of immune complexes42–45. The membrane of an apoptotic cell undergoes dramatic morphologi- cal changes, resulting in the breakdown of membrane integrity and the ‘flip-flop’ of the membrane, which is accompanied by the loss of the membrane complement regulators at the cell surface. Consequently, such modi- Regulators Regulators No regulators fied self structures serve as activating surfaces for com- plement. To avoid complement-mediated attack andPhysiology adaptive immune responses to self antigens, modified Complement self surfaces acquire the soluble effector C1q in combi-Pathology nation with the regulator factor H. This initiates early steps of the classical pathway but blocks the formation No or defective No or defective Acquired regulators regulators regulators and amplification of the C5 convertase46–48. In this situation the initiation of the complement cascade by C1q allows C3b generation and deposi- tion, but progression beyond the C3 convertase stage is blocked by the complement regulators. This ulti- mately results in the C3b-mediated non-inflamma- d Inappropriate action e Inefficient removal f Pathogens acquire host tory removal of cell debris by phagocytosis48,49 (FIG. 2). of regulators leads to of modified host cells regulators and avoid Inappropriate tagging of modified self surfaces and host cell damage can lead to pathology complement attack inefficient clearance result in the accumulation of cellular debris, and self antigens can then serve as autoantigensFigure 2 | The benefits and risks of complement. Complement activation has in autoimmune diseases50 (FIG. 2). Nature Reviews | Immunologymultiple effects in a physiological setting, which can either benefit the host (a–c) orbe detrimental to the host and possibly lead to pathology (d–f). a | Owing to the Complement activation on the surface of micro­spontaneous nature of complement activation, intact host cells must protect their organisms. Most infectious agents are efficiently elimi-surfaces from the action of effector compounds. This protection is mediated by nated by a moderately activated complement system,multiple regulators. b | Complement is activated in a controlled manner on thesurface of damaged or modified host cells, such as apoptotic particles and necrotic even in the absence of inflammatory mediators. Newlycells. This allows complement activation to proceed until C3b surface deposition, released C3a recruits immune effector cells, and C3bbut further progression (generation of complement component 5 (C5) convertase or C3 activation fragments deposited on the foreignand terminal complement complex assembly) is blocked. This results in the surfaces promote phagocytosis through opsonization.non-inflammatory removal of modified self cells. c | Complement is activated and In addition, the activated terminal pathway forms theamplified on the surface of invading microorganisms. Activation results in TCC, which damages the microorganism. Most micro-recognition and damage of the invading microorganisms and in the removal of the organisms are eliminated at this stage8,9,51. However,cellular debris. d | Inappropriate action of complement regulators results in damage during millions of years of evolution, pathogenicto the surface of intact host cells. e | Inappropriate tagging of modified self cells, microorganisms have developed ways of avoiding com-which can lead to inefficient removal and accumulation of apoptotic particles, can plement recognition, evading host complement attackresult in secondary necrosis and pathology. This is thought to be a contributing factorto the initiation of autoimmune diseases. f | Some pathogenic microorganisms can and surviving in an immunocompetent host 51. A recentevade recognition and actively block immune attack by the activated complement study described the crystal structure of staphylococcalsystem. In this way, pathogens cross the first layer of immune defence, leading to the complement inhibitor (sCIN) from Staphylococcusestablishment of an infection. aureus bound to the alternative pathway C3 convertase C3bbb52. This provided insights into the action of C3 convertases as well as information on the mechanisms response is initiated and amplified at the site of an of inhibition by sCIN. infection the concerted action of membrane-bound and recruited regulators is required for the protection Distribution of complement regulators of bystander host cells from complement-mediated The importance of complement restriction is high- lysis. The absence or the defective function of a single lighted by the large number of regulators identified component results in incomplete local protection. This to date, which exceeds that of the components of the also demonstrates how complement acts as a power- complement cascade (C1 to C9) (TAble 1). ful weapon against a bacterial or viral infection. When Complement regulators operate at all levels and are complement activation is not properly controlled or categorized in three major classes: fluid phase, attached inhibited at the host surfaces it can progress and lead to to the surface of host cells and membrane-integral inflammation, pathology and ultimately autoimmune complement clearance receptors. surprisingly, several diseases (FIG. 2). regulators have additional activities beyond comple- ment, as they mediate cell adhesion and extracellular Role of complement in clearance of modified self cells. matrix interactions or link the complement cascade Complement serves an additional function in the with other important physiological networks such as human body as complement activation products tag the coagulation cascade.NATuRe RevIeWs | Immunology vOLuMe 9 | O CTObeR 2009 | 733 © 2009 Macmillan Publishers Limited. All rights reserved
  6. 6. REVIEWS Table 2 | Complement deficiencies and complement-mediated diseases Disease major defects Causes genes affected Refs Atypical haemolytic uraemic Defective C3 convertase, Mostly heterozygous Deficiency of CFHR1, 9,91, syndrome (aHUS) and possibly stabilization of the convertase, mutations, genetic defects and CFHR3, factor B, factor H 92,99 some cases of thrombotic defective regulation, and increased autoantibodies and factor I thrombocytopenic purpura (TTP) stability and turnover Membranoproliferative Defective C3 convertase Mostly homozygous mutations, Factor H and C3 93,99 glomerulonephritis, type genetic defects, autoantibodies II (MPGN II; also known as and C3 nephritic factor dense-deposit disease) Systemic lupus erythematosus Defective clearance of apoptotic Hereditary homozygous deficiency C1q, C1r, C1s, C2, C3 and 49,96, (SLE) cells and bodies and genetic defects C4 110,111 Pyogenic infections Inappropriate complement attack Infections with Neisseria C3, factor H, factor I, 99 meningitidis and Streptococcus properdin and TCC pneumoniae Deficiency of properdin Infections with Neisseria spp. Gene mutation 51 Deficiency of factor I Infections with N. meningitidis Gene mutation 5 and S. pneumoniae and other respiratory tract infection Deficiency of factor H Infection with N. meningitidis Gene mutation affecting 53 protein secretion Haemolysis and thrombosis Erythrocyte lysis and thrombus Unknown CD59, factor H and 9 formation deficiency of CFHR1 and CFHR3 Partial lipid dystrophy Loss of adipose tissue C3 nephritic factor Unknown 9 Hereditary angioedema Recurrent spontaneous non-allergic Mostly heterozygous mutations C1 inhibitor 9 oedema of the subcutaneous tissues and mucous membranes Paroxysmal nocturnal Failure of CD55 and CD59 Genetic deficiency of PIG-A, and PIGA 9 haemoglobinuria (PNH) expression failure to form GPI anchor Age-related macular Drusen formation and chronic Unknown Factor H, C3, C2, deficiency 94,99, degeneration (AMD) inflammation of CFHR1 and/or CFHR3, 107 factor B and factor I Tumour cells Overexpression of membrane and Unknown Unknown 97 secreted regulators, and enhanced binding of soluble regulators C, complement component; CFHR, complement factor H-related protein; GPI, glycosylphosphatidylinositol; PIGA, phosphatidylinositol glycan anchor biosynthesis, class A; TCC, terminal complement complex. Fluid phase complement regulators. Fluid phase com- fibronectin-like activity 64. Properdin can directly bind plement regulators are distributed in human plasma to and initiate complement activation on a microbial and in body fluids such as the synovial and vitreous surface and triggers local assembly and action of the fluids. These regulators are grouped according to their alternative pathway C3 convertases65,66. major activity and include the alternative pathway regulators factor H53, FHL1 (ReF. 54) and the activator Membrane­bound complement regulators. The mem- protein properdin55 (FIG. 3a). Carboxypeptidase N, which brane of host cells is also equipped with complement cleaves and partly inactivates the anaphylactic peptides regulators67, including CR1 (ReF. 68), CR2 (also known C3a and C5a, acts in all three major complement activa- as CD21)69,70, CD55 (also known as DAF)71, CD46 (also tion pathways56,57 (TAble 1). soluble classical and lectin known as MCP)72, CD59 (also known as protectin)73 and pathway regulators include C1 inhibitor (C1INH)58 and complement receptor of the immunoglobulin super- C4bP59. C1q has a crucial role in host defence and in family (CRIg; also known as vsIG4)74. CRIg is expressed clearance of immune complexes60. The known soluble in a long and a short form. The long proteins CRIg and inhibitors of the terminal pathway include the recently CR1 act further away from the cell membrane than identified CFHR1, clusterin and vitronectin61–63, which the short membrane proteins CD46, CD55 and CD59. have additional biological functions beyond complement. Membrane-bound regulators control the three major Clusterin, for example, is associated with high-density complement activation pathways and inactivate both lipoprotein particles and acts as an adhesion protein and C3 and C4 (CR1 and CD46). by contrast, fluid phase as a potent inducer of cell aggregation. vitronectin binds regulators are more specific and control either the alter- to the extracellular matrix, functions in cell attachment native, the classical or the lectin pathway and act almost or cell spreading and acts as an adhesion protein with exclusively on either C3 or C4 (FIG. 3a).734 | O CTObeR 2009 | vOLuMe 9 © 2009 Macmillan Publishers Limited. All rights reserved
  7. 7. REVIEWS a Complement regulators Alternative pathway Classical pathway Terminal phase C1q FHL1 Fluid phase Factor H C1INH Clusterin regulators Properdin Carboxypeptidase N Vitronectin CFHR1 C4BP CR1 CRIg Membrane CD55 CD59 zone regulators CD46 Cell membrane b Cell surface receptors for complement components CR1 CR3 CR4 CRIg CR2 C3aR C5aR C5L2 C1qR C1qRII CRIgs Figure 3 | Complement regulators and surface receptors. a | Complement regulators can exist either in the fluid phase or at the cell membrane. There are multiple fluid phase complement regulators, whichNature Reviews | Immunology control different steps of the cascade and are distributed in different compartments. Alternative pathway regulators distributed in the plasma and body fluids are factor H, factor H like protein 1 (FHL1) and the activator protein properdin. Carboxypeptidase N has regulatory activity in the alternative pathway, the classical pathway and the lectin pathway. The soluble classical and lectin pathway regulators include complement component 1q (C1q), C1 inhibitor (C1INH) and C4b-binding protein (C4BP). The soluble inhibitors of the terminal pathway include clusterin, vitronectin and complement factor H-related protein 1 (CFHR1). Membrane zone complement regulators include CR1 (also known as CD35), CD46 (also known as MCP), CD55 (also known as DAF), CD59 (also known as protectin) and complement receptor of the immunoglobulin superfamily (CRIg; also known as VSIG4). The complement regulators act in various ways. For example, C1INH induces the dissociation of the C1 components. CD35, CD55 and C4BP displace a component of the C3 convertase in the classical pathway. CD59 prevents final assembly of the membrane attack complex. b | The membrane of host cells is equipped with complement receptors, including CR1, which binds C3b, iC3b and C4b, and CR2 (also known as CD21), which binds C3d and C3dg, CD46, CD55, CD59 (not shown) and CRIg. However, the distribution and number of the individual membrane-bound receptors varies between different cell types and on different surfaces. On the membrane of B cells, both CR1 and CR2, which act as co-receptors for surface-bound immunoglobulin, regulate B cell differentiation and maturation and instruct B cells to respond to C3d-coupled foreign antigens. So, C3b attached to the antigen interacts with CR2 and acts as a molecular adjuvant74. CR3 (also known as MAC1, αMβ2 integrin and CD11b–CD18) and CR4 (also known as αXβ2 integrin and CD11c–CD18) are also integrin receptors. CR3 and CR4 bind iC3b, C3dg and C3d and mediate phagocytosis of C3b-opsonized cells or particles. In addition, these receptors bind multiple other ligands including the matrix protein fibrinogen75,76 (TAbleS 1,3). The recently identified receptor CRIg, and the shorter form CRIgs, has a major role in the clearance of C3d- and iC3b-tagged particles, including microorganisms and autologous cells77. C5L2, C5a receptor-like 2. Receptors for complement effector molecules. Complement There are many receptors for complement effec- activation products and effector compounds have tor molecules, which bind and respond to effector potent biological activity. They induce and modulate compounds such as C3a and C5a, C3b-opsonized sur- inflammation, control inflammatory responses, direct faces, modified self surfaces and tagged microorgan- multiple cellular responses and induce effector functions, isms, toxins or antigens. Five major membrane-bound such as tagging of cellular surfaces and induction or effector receptors, CR1, CR2, CR3 (also known as enhancement of phagocytosis46,48. CD11b–CD18), CR4 (also known as CD11c–CD18)NATuRe RevIeWs | Immunology vOLuMe 9 | O CTObeR 2009 | 735 © 2009 Macmillan Publishers Limited. All rights reserved
  8. 8. REVIEWS and CRIg, bind C3b or C4b deposited on the surface a hemisphere with a radius of approximately 70 nm. In of the target and drive effector functions correspond- addition, membrane-bound regulators such as CD46 ing to the specific form of the C3 and C4 activation and CD59 are released or shed from the membrane and compounds75–77 (FIG. 3b; TAble 1). thus contribute to the protective shield90. The action of the anaphylactic fragments C3a and C5a is mediated by members of the seven transmembrane Complement regulators in disease spanning receptor family, including C3aR and the two Diseases caused by defective complement functions surface receptors C5aR and C5L2. The biological role mirror the central surveillance roles of complement of the newly described C5L2 is still under discussion. in the human body. Defective complement regulation At present it is unclear whether C5L2 mediates effector and deficiency of particular components acting early functions in response to C5a or whether the receptor in the cascade can result in both host cell damage and acts as a decoy and attenuates C5a function12,32,78–82. In accumulation of immunological debris. These defects addition, C1q is recognized on the cell surface by two are associated with the renal disorder atypical haemo- receptors: C1qR and the dendritic cell-specific ICAM3- lytic uraemic syndrome (aHus)91,92. similarly, a defec- grabbing non-integrin (DC-sIGN) homologue sIGN- tive surface zone and accumulation of debris have been related 1 (sIGNR1; also known as CD209)83–85. reported to be a cause of dense-deposit disease (DDD; An important aspect of the role of membrane also termed membranoproliferative glomerulonephritis, receptors in regulation and the response to effector type II (MPGN II))93, the retinal disease age-related compounds is their expression and distribution on macular degeneration (AMD)94,95 and systemic lupus individual cell lineages or cell types. surface-attached erythematosus (sLe)96. by contrast, tumour cells and complement and effector receptors are not uniformly pathogenic microorganisms attach host complement expressed by nucleated host cells, erythrocytes or plate- regulators and mimic a self surface zone to escape com- lets. Consequently, the distribution and number of indi- plement surveillance, resulting in unrestricted growth vidual receptors and the complete receptor repertoire and infections, respectively 4,5,53,97,98. on a given cell membrane are important parameters The three distinct disorders aHus, DDD and AMD for defining the protective surface coat and the cellular manifest in different organs and have different pathol- response to complement. ogy. In aHus, thrombi form in the glomerulus, whereas DDD and AMD involve formation of deposits at renal Surface­attached complement regulators. It is now and retinal sites, respectively. However, these disorders clear that several fluid phase complement regulators are caused by mutations in the same genes, and the also attach to cell surfaces and to biomembranes such same set of genes is associated with each of the three as the glomerular basement membrane of the kidney disorders. each disease is clearly associated with sur- and the bruch’s membrane of the retina86–88. In addi- face damage occurring at platelets, renal endothelial tion, these regulators bind to modified self surfaces cells, the glomerular basement membrane of the kid- such as apoptotic particles, necrotic bodies and the ney or the bruch’s membrane in the retina. The affected extracellular matrix 48,59. Thus, factor H, FHL1, C4bP, genes encode C3 and factor b (the two components CFHR1, clusterin and vitronectin, which control of C3 convertase) or the regulators of C3 convertase complement in the fluid phase, also attach to lipid factor H, CD46 and factor I99–101. The absence of CFHR1 bilayers or to biomembranes and maintain complement- and CFHR3 in plasma as a result of a chromosomal regulatory activity. This surface attachment forms an deletion has opposite effects on the progression of the additional protective layer (known as the surface zone) disorders102–105: in aHus, the deletion seems to repre- for intact host cells that controls complement and lim- sent a risk factor and is associated with generation of its formation of complement activation products and autoantibodies to factor H92,102,103, whereas in AMD it effector compounds at the cell surface. This flexible is described as having a protective effect 104. Deletion and protective shield cooperates with the membrane of single components causes pathology and drives the zone, an inner shield that is formed by membrane- balanced complement regulatory network in opposing anchored regulators. At present, the ligands on the cell directions. The crystal structure of the first four domains surface and the biomembrane that anchor the fluid of factor H in complex with its target, C3b, was recently phase complement regulators have not been identi- identified, providing information on the mechanisms of fied at the molecular level but, as heparin modifies action of factor H and a structural basis for the effects and inhibits this interaction, it has been proposed of disease-associated mutations106. that glycosaminoglycans act as cell and biomembrane The fact that this set of genes can induce diseases surface receptors. that manifest in different organs suggests that the quan- The simultaneous attachment of multiple regula- tity of protein at local sites is relevant and that mutated tors creates an additional protective surface zone. The proteins attach to different surfaces in distinct organs. approximate dimension of the surface zone depends on For example, factor H gene mutations can be either the length and the density of the attached proteins. For homozygous or heterozygous and thus can result in example, the length of a fully extended complement fac- various concentrations of functional protein both in the tor H protein was calculated to be 73 nm and that of circulation and at the cell surface. In addition, mutations membrane bound CD46 to 14 nm89. A single, extended that result in amino acid exchanges occur within dis- factor H molecule can control an area corresponding to tinct sites and affect different functional domains of this736 | O CTObeR 2009 | vOLuMe 9 © 2009 Macmillan Publishers Limited. All rights reserved
  9. 9. REVIEWS multifunctional factor H protein. so, single mutations (CFHR1, clusterin and vitronectin, CFHR2 and CFHR5). as well as polymorphic exchanges translate into differ- This overlap highlights the similarity of AMD and DDD, ent effects, cause different conditions and can define shows that complement is associated with the pathology whether the defect manifests in renal or retinal sites. of both diseases and suggests that defective complement regulation results in chronic inflammation. Atypical haemolytic uraemic syndrome. In aHus, most patients have one defective allele and one intact allele Autoimmune diseases. Defective clearance of self anti- of factor H. This results, in general terms, in a ~50% gens or apoptotic particles and accumulation of cellular reduction in complement activity. This reduced level debris can occur in the absence of C1q or C4. This can of functional protein allows complement control in lead to exposure of self antigens to lymphocytes and the fluid phase. However, following an immunological can also lead to inappropriate activation of self-reactive insult, amplified local complement activation requires b and T cells47. This is considered a major susceptibil- maximal protection of bystander cells from lysis. In this ity factor for development of autoimmune diseases. situation, damage to host structures can occur. such a Defective complement action can result in the accumu- scenario may explain the incomplete penetrance of het- lation of cellular debris or the formation of pathological erozygous mutations and may explain why the disease deposits (FIG. 2). Mutations and homozygous deficiency frequently develops after an episode of infection. of genes of the classical pathway of complement activa- In aHus, most of the heterozygous factor H gene tion and the presence of autoantibodies are associated mutations cluster in the carboxy-terminal surface rec- with the pathogenesis of the systemic autoimmune dis- ognition region and leave the complement-regulatory ease sLe110,111. Most homozygous deficiencies for genes region, in the amino-terminus, intact. Reduced surface encoding components of the early classical pathway, binding of mutant factor H weakens the protective sur- including C1q, C1r and C1s as well as C2, C3 and C4, face zone. In DeAP (deficient for CFHR proteins and are strongly associated with the development of sLe. The factor H autoantibody positive)–Hus the deficiency strongest association is observed with C1q deficiencies for CFHR1 and CFHR3 is frequently associated with and over 90% of these cases develop rheumatic diseases. the development of autoantibodies, which bind to and In addition, deficiencies of C5, C8 and mannose bind- block the C-terminal recognition region of factor H92. ing lectin (MbL) are associated with sLe or lupus-like syndromes. similarly acquired factors, such as auto- Dense­deposit disease. In DDD, mutations in the gene antibodies — in particular autoantibodies to C1q, C3 and encoding factor H occur mostly in homozygous or com- CR1, but also C3 nephritic factor and autoantibodies to pound heterozygous conditions and result in defective C4b2a and C1INH — are reported in cases of sLe. These protein secretion and the absence of the protein in the defects or newly acquired factors probably result in the plasma93. This leads to unrestricted complement activa- failure to clear C3b-opsonized apoptotic cells or particles tion in the plasma. An additional aspect of DDD is the and lead to secondary necrosis and pathology. presence of autoantibodies (termed C3 nephritic factor) that bind to a neo-epitope of the C3 convertase, stabilize Tumour cells. Cancer cells are another type of modified the enzyme and enhance C3 cleaving 105. both predisposi- self cell that actively escape complement and immune tions result in C3 consumption in the fluid phase and local surveillance. The expression of membrane-bound C3 deposit formation at surfaces that lack endogenous complement inhibitors (CD46, CD55 and CD59) is regulators, such as the glomerular basement membrane upregulated in various primary tumours and tumour of the kidney and the bruch’s membrane of the retina. lines112. similarly, lung, ovarian, glial and colon cancer cells show enhanced expression and surface binding Age­related macular degeneration. The bruch’s mem- of soluble regulators, including factor H, FHL1, C4bP brane in the retina, similar to the glomerular basement and factor I. In addition, complement activation prod- membrane of the kidney, requires membrane-bound sol- ucts such as C5a suppress the antitumour response uble regulators for control. Thus, the absence or defec- mediated by CD8+ T cells and inhibition of comple- tive surface binding of factor H may lead to uncontrolled ment activation has been suggested as an option for complement activation at such unprotected sites. treatment of cancer 113,114. The AMD-associated factor H gene polymorphism The recent concept of the role of complement in (H402Y) is located in the heparin- and CRP-binding diseases has already been translated from the bench to domain 7 and affects surface attachments of factor H to the bedside, as defective complement regulators or the the bruch’s membrane and retinal epithelial cells as well absence of regulators is efficiently overcome by plasma as protein deposits known as drusen107. transfusion. similarly, the humanized monoclonal anti- Further evidence for a common disease mechanism body specific for C5 (eculizumab), which has been effi- for DDD and AMD is based on recent proteomic analy- ciently used as a treatment for aHus, provides an excellent ses of glomerular dense deposits and retinal drusen108,109. recent example of promising translational research115,116. The deposits formed in the two distinct organs comprise almost the same proteins, including complement acti- Infectious pathogens. The protective complement shield vation products and inflammatory components (such is also relevant in infectious diseases as pathogenic micro- as C3, C3d and iC3b), terminal pathway components organisms, by exploiting soluble host complement reg- (C5, C6, C7, and C8) and terminal pathway regulators ulators, generate a protective shield on their surfaces.NATuRe RevIeWs | Immunology vOLuMe 9 | O CTObeR 2009 | 737 © 2009 Macmillan Publishers Limited. All rights reserved
  10. 10. REVIEWS Table 3 | Host and pathogen complement regulators Point of action Host regulators Pathogen-encoded regulators and host Refs regulator binding proteins Fluid phase regulators membrane bound regulators C3 convertase Factor H, FHL1, C4BP, CR1, CD55, CD46 and CRIg CBPA, CRASP1–CRASP5, GPM, EFB, FBA, FHA, 4,5,52–55, properdin and C1INH GNA1870, HIC, IDES, LOS, M protein, OMP100, 58,59,68, PAAP, PAE, PLA, PLY, POR, PRA1, PREH, PRTH, 71,72,74,98 PSPA, PSPC, RCA, RCk, REC, SAk, SBI, SCIN, SPEB, STCE, SSCL, TUF and YADA C5 convertase CFHR1 None CHIPS, SCPA/SCPB and SSL-7 4,5,52,61,98 Terminal pathway CFHR1, clusterin and CD59 CD59-like, FHA, OMP A, SIC, TRAT, USPA1 and 4,5,52, vitronectin USPA2 61–63,73,98 C, complement component; C1INH, C1 inhibitor; C4BP, C4b-binding protein; C5L2, C5a receptor-like 2; CFHR1, complement factor H-related protein 1; CHIPS, chemotaxis inhibitory protein; CRASP, complement regulator-acquiring surface proteins; CRIg, complement receptor of the immunoglobulin superfamily; EFB, extracellular fibrinogen binding protein; FBA, fibronectin binding protein; FHL1, factor H-like protein 1; GMP, phosphogycerate mutase; GNA1870, genome-derived neisserial antigen 1870; HIC, factor H-binding inhibitor of complement, IDES, IgG-degrading enzyme of Streptococcus pyogenes; LOS, Lipooligosaccharide; M protein, membrane protein; OMP, outer membrane lipoprotein; PAAP, Pseudomonas aeruginosa protease; PAE, P. aeruginosa elastase; PLY, streptococcal pneumolysin; POR, outer membrane porins; PRA1, pH regulated antigen of Candida albicans; PRTH, Porphyromonas protease; PSPA/C, pneumococcal surface protein A/C; SAk, staphylokinase; SBI, Staphylococcus aureus IgG binding protein; SCIN, staphylococcal complement inhibitor; SIC, streptococcal inhibitor of complement; SPEB, streptococcal pyogenic exotoxin B; SSL7, staphylococcal superantigen like protein 7; STCE, streptococcal E protease; TUF, translation elongation factor of P. aeruginosa; USPA, universal stress protein A; YADA; Yersinia adhesion protein A. Acquisition of soluble host regulators converts the Concluding remarks and perspectives foreign, non-self surface of the pathogen to a ‘self-like’ Complement-mediated innate immune function not only surface. such a camouflaged pathogen remains invisible recognizes and eliminates infectious agents but also con- to the host innate immune system. Pathogens can also trols homeostatic processes such as organ and neuron mimic features of host cells by expressing endogenous development, clearance of cellular debris and elimination regulators that block complement activation. The ability of infectious particles. In the future new functions will of the conserved mechanism of complement to damage probably be identified for other cleavage products, such many different membrane types is illustrated by the fact as ba, C2a and C4a. that diverse human pathogens, including Gram-negative because of its central role in multiple physiological bacteria, Gram-positive bacteria, fungi, viruses, multicel- processes, dysregulation or imbalance of the comple- lular parasites and helminths, use similar, and even iden- ment system can result in pathology and diseases that tical, strategies to evade host complement attack4,5,51,98 manifest in different organs. Interestingly, disturbances (TAble 3). As complement forms one of the first barri- of the alternative pathway in particular, a master regu- ers of innate immunity any pathogenic microorganism lator of homeostasis, are associated with several auto- has to cross this important layer of immune defence in immune diseases. so, the mechanistic characterization of order to establish an infection. Interestingly, the innate complement-mediated clearance and the identification immune responses are constant and all human patho- of associated genes and gene products represent a major gens face the same complement attack. This may explain challenge for the future. why different classes of pathogens use similar strategies In addition, an important aspect of future work is to to evade human complement attack. precisely define the link between the complement system Many different mechanisms of action for individual and other important immune and homeostatic effector inhibitors have been defined; for example, Borrelia burg- circuits, such as the coagulation cascade, and the integra- dorferi expresses five different complement regulator- tion of complement receptor signalling with other path- acquiring surface proteins, termed CRAsP1–CRAsP5, ways, such as the Toll-like receptor signalling network. for immune evasion117. structural data explain the inter- The interplay between complement and coagulation sys- action in molecular terms; for example, the S. aureus tems is expected to provide new clues to the pathological extracellular fibrinogen binding protein (efb) blocks the mechanisms of various diseases, for example the various conformational activation of the C3b molecule118, and disorders that are associated with thrombus formation. the Neisseria meningitidis factor H-binding protein Additional new methods for targeting complement genome-derived neisserial antigen 1870 (GNA1870) are now being developed122. One of the great challenges mimics host surfaces by binding host factor H119. The suc- of future complement research is to specifically interfere cess of microbial complement regulator GNA1870 binding with, and block, the damaging inflammatory reactions proteins as vaccine candidates demonstrates the clinical that lead to pathology, but at the same time maintain the relevance of these types of proteins120–122 (TAble 3). protective effects that are benefical for the host.1. Walport, M. J. Complement. First of two parts. 4. Zipfel, P. F., Wurzner, R. & Skerka, C. Complement 6. Ogden, C. A. & Elkon, K. B. Role of complement and N. Engl. J. Med. 344, 1058–1066 (2001). evasion of pathogens: common strategies are shared other innate immune mechanisms in the removal of2. Walport, M. J. Complement. Second of two parts. by diverse organisms. Mol. Immunol. 44, 3850–3857 apoptotic cells. Curr. Dir. Autoimmun. 9, 120–142 N. Engl. J. Med. 344, 1140–1144 (2001). (2007). (2006).3. Volonakis, J. E. & Frank. M. M. The Human Complement 5. Rooijakkers, S. H. & van Strijp, J. A. Bacterial 7. Medzhitov, R. & Janeway, C. A. Jr. Decoding the System in Health and Disease (Dekker, New York, complement evasion. Mol. Immunol. 44, 23–32 patterns of self and nonself by the innate immune 1998). (2007). system. Science 296, 298–300 (2002).738 | O CTObeR 2009 | vOLuMe 9 © 2009 Macmillan Publishers Limited. All rights reserved