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Complement in Immune and Inflammatory Disorders: Pathophysiological Mechanisms Daniel Ricklin and John D. Lambris This information is current as J Immunol 2013; 190:3831-3838; ; of September 29, 2021. doi: 10.4049/jimmunol.1203487 http://www.jimmunol.org/content/190/8/3831 Downloaded from References This article cites 85 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/190/8/3831.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Complement in Immune and Inflammatory Disorders: Pathophysiological Mechanisms Daniel Ricklin and John D. Lambris Although acute or chronic inflammation is a common vation can tip the balance between health and disease and lead component of many clinical disorders, the underlying to self-attack of host cells (1–3). In the worst case, a vicious processes can be highly distinct. In recent years, the cycle between tissue damage, complement , and has been associated with a growing immune attack perpetually re-creates inflammatory stim- number of immunological and inflammatory condi- ulators rather than resolving them. In view of this upstream tions that include degenerative diseases, cancer, and trans- position in inflammatory homeostasis, there is growing in- plant rejection. It becomes evident that excessive activa- terest in understanding the role of complement in patholog- tion or insufficient control of complement activation ical processes and in exploiting complement targets for Downloaded from on host cells can cause an immune imbalance that may therapeutic modulation (3, 4). Fortunately, our knowledge fuel a vicious cycle between complement, inflammatory about the functions of complement in health and disease has cells, and tissue damage that exacerbates clinical com- much improved, and new discoveries have revealed a fasci- nating cross-talk network that ties complement closely into plications. Although the exact involvement of comple- the immune-inflammatory network (1, 5). In this review we ment needs to be carefully investigated for each dis- provide an update on complement and its dialog with asso- http://www.jimmunol.org/ ease, therapeutic modulation of complement activity ciated systems, discuss major disease areas, and indicate op- emerges as an attractive target for upstream inhibition portunities for therapeutic intervention (see the accompanying of inflammatory processes. This review provides an up- Brief Review in Ref. 6 for more). date about the functional and collaborative capabilities of complement, highlights major disease areas with known Complement beyond microbial defense complement contribution, and indicates the potential The past decade revealed a new perception of complement for complement as a focal point in immunomodulatory that reaches beyond the elimination of pathogens and in- cludes key functions in immune surveillance, homeostasis,

strategies for treating inflammatory diseases. The by guest on September 29, 2021 Journal of Immunology, 2013, 190: 3831–3838. and mediation of inflammatory responses (1, 2). The hublike organization of complement and its cell surface–directed ac- tion (Fig. 1), involving some 50 constituents such as pattern- nflammation is a recognized hallmark of disease, yet the recognition molecules (PRM), components, pro- knowledge about underlying mechanisms that shape the teases, regulators, and cell surface receptors, is essential for I inflammatory response and its resolution has been largely adjusting the complement response to different triggers (Fig. extended in recent years. Given the classic perception of 2A). When faced with foreign intruders, binding of PRM complement as defense system against microbial intruders, it to molecular surface patterns can trigger distinct initiation may appear surprising that this ancient pillar of innate im- pathways. In the classical pathway (CP), this is mainly me- munity was identified as a contributor in various inflamma- diated by binding of the , consisting of the PRM tory pathologies. Yet it has become evident that complement C1q and the C1r and C1s, to Ig patches on the not only acts as a sensor of pathogens but also recognizes dis- pathogen. In the pathway (LP), microbial carbohydrates eased and damaged host cells, and it closely collaborates with are recognized by mannose-binding lectin (MBL) or ficolins other immune and defense systems to eliminate potential danger in complex with MBL-associated serine proteases (MASP). (1, 2). This interplay serves as a vital triage system that tailors Through activation of C2 and C4, both pathways lead to the according to the threat level. However, theassemblyofC3convertasecomplexes, which cleave the insufficient, excessive, or poorly controlled complement acti- abundant plasma protein C3 into an fragment

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Phila- cytoplasmic Ab; AP, alternative pathway; C4BP, C4b-binding protein; CPB, cardiopul- delphia, PA 19104 monary bypass; CP, classical pathway; CR, ; FB, factor B; FD, ; FH, ; FI, factor I; FP, factor P (); IRI, ischemia/reperfusion Received for publication December 20, 2012. Accepted for publication February 12, injury; LP, ; MAC, membrane attack complex; MASP, mannose-binding 2013. lectin–associated serine ; MBL, mannose-binding lectin; PNH, paroxysmal noc- This work was supported by National Institutes of Health Grants AI003040, AI068730, turnal hemoglobinuria; PRM, pattern-recognition molecule; RCA, regulator of comple- AI072106, AI097805, EY020633, GM097747, and DE021685. ment activation; SIRS, systemic inflammatory response syndrome.

Address correspondence and reprint requests to Dr. Daniel Ricklin and Dr. John D. Ó Lambris, University of Pennsylvania, 401 Stellar Chance, Philadelphia, PA 19104. Copyright 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 E-mail addresses: [email protected] (D.R.) and [email protected] (J.D.L.) Abbreviations used in this article: AD, Alzheimer’s disease; aHUS, atypical hemolytic uremic syndrome; AMD, age-related ; ANCA, anti- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1203487 3832 BRIEF REVIEWS: COMPLEMENT IN IMMUNE AND INFLAMMATORY DISORDERS

FIGURE 1. Simplified scheme of the com- plement activation network. *Only part of the functional spectrum of factor P (FP) is visualized: FP may act as pattern-recognition molecule and recruit from plasma to the target surface (alternative pathway [AP] ini- tiation); additionally, it stabilizes both the AP C3 and C5 convertases. Only the AP C5 convertase (C3bBb3b) is shown; a CP/LP C5 convertase (C4b2b3b) is also formed. The enzymatic fragment of C2 is referred to as C2binthisreview;thesamefragmentis sometimes designated as C2a in literature. **The regulation of the CP/LP C3 convertase is depicted a one-step process but follows a two-step mechanism similar to C3b, includ- ing decay acceleration (C4BP, CD35) and factor I (FI)–mediated degradation to iC4b Downloaded from (C4BP, CD35, CD46). ***The function of -like 2 (C5L2) is not fully de- scribed and may be content-specific; C5a andC5a-desArgbindequallywelltoC5L2, whereas their binding and signaling profiles on C5aR are distinct. The binding of - desArg to C5L2 remains controversial. C1- http://www.jimmunol.org/ INH, C1 inhibitor; Clu, ; CPN, car- boxypeptidase-N; CR, complement receptor; FB, factor B; Fcn, ficolins; FD, factor D; FH, factor H; MAC, membrane attack complex; RCA, regulator of complement activation; Vn, vitronectin. by guest on September 29, 2021

(C3a) and the C3b. The alternative pathway (AP) is reduces the threshold of activation. Additional recep- induced by conversion of C3 to its hydrolyzed form C3 tors for C3b/iC3b (i.e., CR of the Ig superfamily, CRIg) and (H2O), either spontaneously at a low rate in solution or ac- for C1q (e.g., gC1qR) also participate in the recognition and celerated by contact of C3 with various surfaces (tick-over) elimination of opsonized cells. Although host cells are probed (7), which leads to the formation of initial AP C3 con- by a constant low level of AP activation (referred to as the vertases. Once C3b is deposited on target surfaces, it pro- tick-over mechanism), they express membrane-bound regu- motes amplification of the response via the AP by forming lators of complement activation (RCA) that either destabilize additional C3 convertases via a tiered mechanism that in- convertases (CD35, CD55) or act as cofactors for the FI- volves binding of factor B (FB) and proteolytic activation by mediated degradation of C3b to iC3b (CD35, CD46) and factor D (FD) to result in the C3bBb complex (8). Factor P C3dg (CD35) and of C4b to iC4b (CD35, CD46) (1, 9). (FP, or properdin) further supports AP-mediated amplifica- Additionally, the soluble RCAs C4b-binding protein (C4BP) tion by stabilizing the C3bBb convertase. Continuous depo- and factor H (FH) recognize host cell surface patterns and sition of C3b favors generation of C5 convertases that con- contribute to the regulation of the CP/LP and AP convertases, vert component C5 into C5b, which initiates formation of respectively. Finally, the membrane regulator CD59 and membrane attack complexes (MAC; C5b-9) that lyse sus- soluble vitronectin and clusterin prevent MAC formation on ceptible cells (e.g., Gram-negative ). Cleavage of C5 host cells. Apoptotic cells induce yet another response that lies releases the C5a that, together with C3a, attracts in between that observed for foreign and host cells; whereas immune cells to sites of activation via binding to the ana- the recognition of surface modifiers on apoptotic cells by phylatoxin receptors C5aR (CD88) and C3aR, respectively. PRM induces opsonization, the presence of RCA prevents Carboxypeptidases rapidly convert C3a and C5a into their excessive amplification and, consequently, the pronounced desarginated forms, resulting in a shift in their activity/specificity generation of C5a or MAC. In this manner, complement profiles. Phagocytic cells recognize C3b-opsonized surfaces facilitates the elimination of apoptotic cells, immune com- via complement receptor (CR)1 (CD35), which facilitates plexes, and cellular debris, at the same time limiting induction and mediates the degradation of C3b to iC3b, of inflammatory triggers (Fig. 2B) (1). C3c, and C3dg by factor I (FI). Whereas iC3b is the primary Although complement was first described decades ago, re- ligand for the integrin receptors CR3 (CD11b/CD18) and cent discoveries have challenged key concepts, revealed new CR4 (CD11c/CD18), both iC3b and C3dg also interact with players, and redefined roles for established ones. For example, CR2 (CD21) that is part of the B cell coreceptor complex and pentraxins were identified as mediators of complement acti- The Journal of Immunology 3833

Whereas some coagulation enzymes directly cleave and acti- vate C3 or C5 (19), thereby bypassing traditional initiation pathways, the products of such activation may themselves influence coagulation, as shown for the stimulation of tissue factor expression by C5a (20). The LP may also play a linking role, as MASP-2 can activate prothrombin and induce clot formation, whereas MBL and ficolins were described to bind fibrinogen and fibrin (21, 22). Furthermore, there are links between platelet activation and the activity of complement and contact systems through an interplay involving hydro- lyzed C3, RCAs, chondroitin sulfate, P-selectin, gC1qR, and other components (23). Although complement and the TLR have both been described as “first line of defense” systems, it is only recently that the extent of cooperation between these two pathways has been realized. The cross-talk between TLR, CD14, and MyD88 on the Toll side and complement com- ponents including C5aR, CR3, CD46, CD55, and gC1qR is

important for antimicrobial defense but also contributes to Downloaded from inflammatory disorders (24). Despite its classification as a part of humoral innate , complement strongly mediates adaptive and cellular immune responses. The role of com- plement in the stimulation and maturation of B cells via CD21 is well described and critically contributes to autoim-

mune and other diseases (25). Our knowledge about the http://www.jimmunol.org/ FIGURE 2. (A) Triggered directly by foreign and altered surfaces, the cross-talk between complement and T cells, however, is still complement network resides upstream of most defense and homeostatic unfolding (26). Complement appears to modulate systems, thereby acting as an important mediator in physiological and path- B immunity during induction, contraction, and effector phases ophysiological processes. ( ) Although complement-mediated immune sur- by acting directly on T cells or by affecting APC. The in- veillance and mediation usually provide adequate physiological response (green arrows) to distinct surfaces (gray), any excessive trigger or inadequate teraction between T cells and APC induces a concerted re- regulation (e.g., due to deficiencies or polymorphisms) may lead to patho- action (enhanced secretion of C3, FB, FD, and C5 with physiological reactions (red arrows) that require therapeutic intervention. downregulation of CD55) that favors complement activation In the case of foreign surfaces (i.e., transplants, materials), complement- on immune cells, local generation of C3a and C5a, enhanced by guest on September 29, 2021 targeted modulation (orange arrows) may improve tolerance and compati- T cell proliferation, and release on APC that pro- bility. DAMP, damage-associated molecular pattern; DDD, dense deposit vokes a shift toward Th1 immunity (26). Moreover, CD46 disease; PAMP, pathogen-associated molecular pattern; PMN, polymor- has been identified as a central element in the IL-2–dependent phonuclear cell; PNH, paroxysmal nocturnal hemoglobinuria; SLE, sys- temic erythematosus. transformation of Th1 cells into a regulatory state (26), and C5aR and CD46 signaling have been associated with the function of gdT cells (27, 28). New insight was also achieved vation (10), properdin was attributed PRM functionality concerning the cooperation between complement and FcgR (leading to AP initiation by recruiting C3b from the plasma in the removal of immune complexes. For example, a positive pool to the surface) (11), and C5L2 (GPR77) was classified as feedback loop has been reported in which C5aR stimulation an anaphylatoxin receptor, although its functional implication promotes the expression of activating FcgR; binding of auto- is still under investigation (12). The LP recently gained in- induces the local secretion of C5 by activated cells, terest owing to the discovery of new PRM (e.g., PTX3), thereby increasing the generation of C5a and, consequently, regulators, and bypass routes that contributed to our under- C5aR signaling (29). More recently, a negative feedback standing of this pathway and to the identification of thera- mechanism has been discovered in which high-galactose im- peutic targets and templates (13, 14). Additionally, LP com- mune complexes bridge inhibitory FcgRIIB and the lectin ponents have been associated with a role in AP modulation, receptor dectin-1 to induce signaling that counteracts C5aR- as MASP-1 was shown to mediate the maturation of FD mediated responses (30, 31). Finally, complement was shown from its inactive proform in mice and in vitro (15), yet this to modulate the activities of other key players of cellular involvement remains controversial (16). Finally, the contri- immunity such as NK and NKT cells (32), myeloid-derived bution of central (i.e., hepatic) versus peripheral complement suppressor cells (33), or mast cells (34). These observations production (e.g., by migratory and tissue-resident cells) in underscore the importance of complement in physiological complement-driven pathologies is increasingly investigated, processes but also explain why dysregulation of the comple- particularly in the context of transplantation (17). ment system may result in far-reaching clinical consequences. However, it is the discovery of the dialogue between complement and other physiological systems that has pro- A balancing act between health and disease foundly changed how we perceive complement as inflamma- Although complement is considered a “master of sensing” that tory mediator and therapeutic target (1). For example, it is discriminates between foreign, altered, and healthy self sur- evident that during injuries and certain disease conditions, faces, several triggers may lead to an ill-fated triage of potential complement and coagulation act in a concerted manner (18). danger (Fig. 2B). Dysfunctions, deficiencies, or polymorphisms 3834 BRIEF REVIEWS: COMPLEMENT IN IMMUNE AND INFLAMMATORY DISORDERS of complement components are often factors that tip the diseases show strong correlation with disturbed AP activity balance (3), but tissue damage or confrontation with non-self (42). In atypical hemolytic uremic syndrome (aHUS), a rare surfaces (e.g., biomaterials, transplants) can also lead to ex- disease characterized by , thrombocytope- cessive activation. Importantly, disruption of the complement nia, and renal impairment, complement polymorphisms (e.g., balance with increased production of effector molecules may FH, CD46, C3), deletions (e.g., FH-related ), or trickle down the and contribute to autoim- (e.g., against FH) can cause perpetual self- mune, inflammatory, degenerative, hematological, and ische- attack (42, 43). More recently, two other forms of thrombotic mic disorders. Despite the variety of disease manifestations, the microangiopathies, that is, HUS caused by Shiga toxin–pro- involvement of complement typically follows a common ducing Escherichia coli and thrombotic thrombocytopenic scheme that involves the recognition of potential (although purpura, have been more closely linked to AP activation via not always “real”) danger patterns, an insufficiently controlled mechanisms involving P-selectin and platelet thrombi, re- amplification loop, and the stimulation of downstream in- spectively (44). Whereas dysfunctional AP activity is a driving flammatory responses. The activated immune system, in ad- force of these diseases, activation of C5 appears to be fueling dition to complement attack itself, may exacerbate the problem the cycle by causing endothelial cell damage. Indeed, C5- by further disrupting tissue integrity and creating additional targeted inhibition has shown promising effects in these dis- danger patterns, thereby fueling a vicious cycle between com- orders, and the anti-C5 mAb has meanwhile been plement activation, immune stimulation, and inflammation. approved for the treatment of aHUS (45). Another series of

What varies between individual disorders, however, are the kidney disorders characterized by dense renal deposits of C3 Downloaded from triggers, dynamics, extent, and localization of complement in- in the absence of CP markers have recently been classified volvement. as “C3 glomerulopathy” and include dense deposit disease In the case of age-related and degenerative diseases, it is the and CFHR5 nephropathy, among other forms (42). slow but steady accumulation of debris that can act as a pro- Disruption or exhaustion of complement-mediated clear- moter. Although disease etiologies are often complex, the ance of immune complexes and apoptotic cells and of its

“fitness” of the complement system is considered a key de- bridging to adaptive immunity are contributing factors of http://www.jimmunol.org/ terminant in how fast a symptomatic threshold is reached. autoimmune diseases, including systemic , Age-related macular degeneration (AMD), a degenerative eye rheumatoid , or antiphospholipid Ab syndrome (46, disease and major cause of blindness in elderly people, has 47). Bidirectional cross-talk between complement and FcgR evolved into a focal point of complement drug discovery. appears to be of particular importance in this disease class as Initiated by the discovery of complement proteins in the they cooperate in shaping B cell responses (48). The partici- characteristic subretinal drusen deposits and strong disease pation of complement pathways and components may differ correlations with polymorphisms in FH, research has mean- considerably. In systemic lupus erythematosus, CP activation

while identified additional genetic associations (e.g., C3, FB) and complement consumption by autoimmune complexes by guest on September 29, 2021 and established an imbalanced complement system as a key can be influenced by autoantibodies against C1q or defi- contributor to the development of both geographic atrophy ciencies in CP components, whereas AP involvement appears (dry AMD) and choroidal neovascularization (wet AMD) to be more prominent in the case of rheumatoid arthritis. (35). Although questions about disease triggers and the role of Finally, certain forms of anti-neutrophil cytoplasmic Ab systemic versus locally produced complement remain con- (ANCA)–induced vasculitis, being inflammatory small-vessel troversial (36), a recent study suggested a contribution of the disorders caused by autoantibodies against neutrophil con- oxidative stress adduct malondialdehyde as initiator and stituents, were linked to complement. When affected vascular provided a functional explanation about the disease correla- endothelial surfaces trigger complement activation, the gen- tion of the FH Y402H polymorphism (37). Whereas com- erated C5a attracts and primes , which in turn plement inhibition at various levels has shown promise in adhere to the endothelium. Primed neutrophils express Ags models of AMD, the translation into a clinical application has that are recognized by ANCAs, which leads to their activation proven challenging. Another age-related disease that gained and release of factors that induce cell damage, thereby fueling interest is Alzheimer’s disease (AD), especially after genome- an amplification cycle that culminates in necrotizing inflam- wide association studies revealed disease correlations with mation (49). C5aR-directed therapy has shown success in CR1 and clusterin (38). Indeed, the importance of locally a glomerular ANCA vasculitis model (50), and drugs blocking synthesized complement in the brain becomes increasingly at the level of C5 or C5aR are being evaluated. evident and encompasses physiological functions such as Some autoimmune diseases also impose a higher risk for synapse formation but also inflammatory roles in trauma, developing pregnancy-related complications, and important stroke, and AD (39). For example, accumulation of amyloid roles have been revealed for complement in both healthy and proteins in AD was shown to trigger complement primarily pathological pregnancy (51). Whereas complement is im- via C1q-mediated CP activation; the role of the AP, as well portant for the protection of mother and fetus from patho- as the contribution of individual pathways, may vary in dif- gens, pregnancy also seems to be a state particularly vulnerable ferent models of AD and requires further examination (39, 40). to excessive complement activity (51). For example, comple- The C5a/C5aR axis seems to play an important role in this ment is suspected to be a major factor in both Ab-dependent neuropathology by modulating inflammatory responses, and (i.e., in women with antiphospholipid Ab syndrome) and Ab- C5aR antagonists have shown beneficial effects in AD models independent pregnancy loss via mechanisms that likely in- (39, 41). volve C5a-mediated impairment of placental angiogenesis. For reasons not fully resolved, the kidney appears to be par- Similar dysregulation of angiogenesis may also be involved in ticularly susceptible to complement attack, and several glomerular preeclampsia, a major pregnancy complication characterized The Journal of Immunology 3835 by sudden onset of hypertension and proteinuria. In contrast induction of IRI as described above (17). In addition to the to C5a signaling, which is considered a detrimental factor in chemotactic and inflammatory effects of C5a, deposition of the etiology of preeclampsia, C1q has recently been attributed sublytic MAC has also been shown to induce direct cell ac- a preventive role against abnormal placentation in a mouse tivation with release of mediators such as IL-6 or TNF. Im- model of the disease (52). Finally, complement activation was portantly, complement activation is a major culprit in allograft found significantly elevated in preterm birth, and comple- rejection via direct tissue damage or by shaping the allo- ment activation products such as Bb or C3a have been de- reactive T cell response. Peripheral synthesis of complement scribed as predictive markers of preterm delivery; however, it components by the donor organ has a strong impact in this is not yet clear whether and under which circumstances com- context. Both the production (via B cell costimulation) and plement activation is a contributor to or a consequence of effect of alloantibodies (via CP/LP activation) are complement- events leading to premature delivery (51). Although comple- driven events in Ab-mediated rejection (AMR) (17). In the ment therapeutics have shown encouraging effects in models case of Langerhans islet transplantation in diabetic patients, of pregnancy disorders (53–55), the translation into the clinic the occurrence of a thromboinflammatory response known as is often challenging when involving pregnant patients. “instant blood-mediated inflammatory reaction” is caused by Whereas the lytic power of complement on most eukary- rapid complement activation and limits transplantation effi- oticcellsisrestricted,erythrocytes are comparatively sus- ciency due to islet destruction (59). A particularly interesting, ceptible to MAC attack, and several hemolytic disorders have yet still incompletely understood, phenomenon in the context ties to complement (56). In paroxysmal nocturnal hemo- of transplantation is accommodation, in which transplant cells Downloaded from globinuria (PNH), an acquired somatic mutation disables become “resistant” to complement-mediated destruction; the the synthesis of glycosyl-phosphatidylinositol anchors and promise of therapeutic complement inhibition for inducing prevents the expression of CD55 and CD59 on clonal pop- accommodation of renal allografts was shown both for C5 ulations of blood cells. As erythrocytes naturally lack CD46, inhibition (60) and after C3 depletion via cobra venom factor PNH erythrocytes show a very low capacity for complement (61) in mice and nonhuman primates, respectively. However, regulation and are prone to intravascular lysis with severe transplants are not the only non-self surfaces that trigger de- http://www.jimmunol.org/ hemolytic and thrombotic consequences. Whereas treatment fense responses by complement and coagulation; products of of this orphan disease has long been limited to transfusion modern medicine such as biomedical devices and implants, and allogeneic stem cell transplantation, the introduction of drug delivery vehicles, extracorporeal circuits, and other arti- eculizumab to the clinic has drastically changed disease manage- ficial materials can all induce biomaterial-induced thrombo- ment; nevertheless, complement inhibition at the level of C5 inflammatory reactions (62). Such incompatibility responses appears not to be sufficient for all patients, and inhibitory are known to influence the outcome of CPB surgery, during strategies that act on the C3 level are currently considered which circuit materials, blood/air interfaces in the oxygenator,

(56). In addition to PNH, complement-mediated activated platelets, and protamine complexes (generated to by guest on September 29, 2021 is also observed in aHUS (see above), as well as in cold- neutralize soluble heparin at the end of the procedure) can agglutinin disease, in which IgM autoantibodies against cer- activate complement and contribute to systemic inflammatory tain erythrocyte Ags bind at low temperature (i.e., mainly in response syndrome (SIRS; see below) (62, 63). Despite mov- peripheral capillaries) and lead to CP activation and lysis (56). ing out of the spotlight of complement-targeted therapy after Ischemic diseases constitute another widespread pathologi- years of clinical evaluation with soluble CR1 and anti-C5 Abs cal area in which complement is integrally involved. Ischemia/ (64, 65), CPB surgery remains a clinical problem and a prom- reperfusion injury (IRI) occurs when blood flow to tissue is ising indication for complement therapeutics (63). Another restored after a prolonged time of occlusion and is relevant in emerging area is hemodialysis; even modern dialyzer mem- clinical conditions ranging from stroke and myocardial in- branes activate complement significantly and contribute to farction to trauma, sepsis, shock, and cardiopulmonary bypass perpetual inflammation in patients suffering from end-stage (CPB) surgery (57, 58). The pathological mechanisms behind renal disease; therapeutic C3 inhibition was shown to prevent IRI are multifactorial and complex, and current models sug- complement activation and reduced markers of immune cell gest that the ischemic phase leads to cellular changes, exposi- activation, inflammation, and coagulation (66, 67). Alongside tion of neoepitoes, adhesion of polymorphonuclear cells, re- soluble inhibitors, the coating of materials with passive (e.g., lease of , and production of reactive oxygen species polyethyleneglycol) or active (e.g., FH-binding peptides) moie- that can trigger apoptosis and ; the reperfusion phase ties is considered an attractive strategy (62, 68). is characterized by leukocyte adhesion and increased perme- Other inflammatory diseases with complement contribu- ability. Complement is considered to be involved in aspects of tion include allergic and periodontitis. The ties between both phases from the recognition of neoepitopes with subse- complement and asthma have long been recognized, but the quent opsonization and amplification to the C5a-mediated involvement appears to be complex. Under asthmatic con- modulation of cellular responses and upregulation of adhe- ditions, complement is not only activated through the CP via sion molecules. Although the exact contribution of individual /Ab complexes but C3 and C5 might also be cleaved complement pathways may vary depending on the model or by proteases derived from certain (e.g., house dust disorder, recent studies have re-emphasized the importance of mites). The resulting C3a and C5a act synergistically in cre- the LP, and in particular the MBL/MASP-2 complex, in ating a proallergenic immune environment, yet C5a may also complement-mediated effects of IRI (57, 58). protect from maladaptive Th2 immunity during allergen IRI is also a major and inevitable contributor to transplant- sensitization (69). An important yet complex role in asthma related complications, especially when organs are transplanted has also been attributed to C5L2 (70). Whereas previous after circulatory arrest of the donor, which can lead to the therapeutic attempts focused on C5aR, the scope has recently 3836 BRIEF REVIEWS: COMPLEMENT IN IMMUNE AND INFLAMMATORY DISORDERS been expanded to include inhibitors at the levels of C5 and originally anticipated, with several studies demonstrating that C3 (69). Relatedly, C5a has also been implicated in the ex- complement activation and release of C5a may actually create acerbation of chronic obstructive pulmonary disease (71). a more favorable environment for tumor growth by shaping Although an involvement of complement in periodontal immune cell populations and/or angiogenesis in certain can- disease was proposed before (72), the intricate mechanisms cer models (33, 84, 85). behind the pathogenesis of periodontitis have only recently been revealed. In this biofilm-driven chronic inflammatory Conclusions disease that leads to progressive bone loss of the teeth, an The progression in genome-wide association studies, the avail- intense dialogue between complement effectors and receptors ability of improved disease models, and the unprecedented (C5aR, CR3), the TLR system (TLR4, CD14), and the oral insight into molecular details of humoral and cellular im- microbiome with its keystone pathogen Porphyromonas gin- munology have changed our perception of the role of com- givalis shapes the disorder (73). As C5a signaling is at the plement in health and disease. Although complement-mediated center of immune evasion and inflammatory activities, C5aR- pathologies so far have often been looked at in an isolated directed therapies have been evaluated and show encouraging manner, a common pattern within a wide spectrum of disease results (74, 75). Finally, complement-mediated processes have formsbeginstoemerge.Inthiscontext, the importance of been recognized critical for bone-related disorders and injury the intense cross-talk between complement and other physi- (e.g., via anaphylatoxin effects on osteoclast formation), thereby ological systems and the interplay between complement, in- suggesting another potential indication area for complement fection, immunity, and inflammation have become particularly Downloaded from therapeutics (76). evident. In view of the upstream and mediating position of Perhaps the most severe effects of complement activation complement in inflammatory events, it is expected that the list are seen in acute-phase conditions, often associated with SIRS of diseases with association to imbalanced complement will (see above), in which the host is confronted with a dramatic continue to grow. Unquestionably, complement may not be increase of damage- and/or pathogen-associated molecular the main driving force in some of these disorders, but it may patterns (77). In trauma, for example, the initial traumatic still be a critical factor that can tip the balance between in- http://www.jimmunol.org/ impact combined with posttraumatic IRI can trigger a devas- duction and resolution of inflammation. Even in knowledge tating cascade of immunoinflammatory reactions with com- of strong complement involvement and with identified risk plement contribution, which may sustain SIRS (78). As a genes, the translation into disease mechanisms or even thera- complication of trauma, or as an independent incident, massive peutic strategies may remain challenging, as the case of AMD may overwhelm the protective functions of comple- has shown. Profound investigation of involved triggers and ment and other innate immunity components (e.g., TLR) and complement pathways in each disease, as well as a holistic provoke sepsis (79). The early pathogen-induced hyperinflam- interpretation in the context of inflammation and immunity,

matory response with complement and immune cell activa- will be required to rapidly achieve clinical benefit. Fortunately, by guest on September 29, 2021 tion, a cytokine storm, and coagulopathy may result in SIRS an impressive body of research in recent years has created a and persist even after the pathogen is cleared; C5a-dependent broad arsenal of complement inhibitors that can be used to signaling seems to be a major player in those devastating dissect molecular pathways but may also pave the way to events. Independent of the trigger, SIRS can induce secondary complement-targeted immunomodulatory therapies (see ac- tissue damage, multiorgan failure, and, ultimately, death (77– companying review in Ref. 6). 79). Despite the prevalence and severity of sepsis, treatment of this condition has proven to be difficult, although comple- Acknowledgments ment therapies at the level of initiation (e.g., C1-INH), am- We thank Dr. Robert A. DeAngelis and Dr. Edimara Reis for critically reading plification (targeting C3), or signaling (blocking the C5a/C5aR the manuscript and for valuable discussion. axis) have shown promising results. Complement plays a dual role in many diseases, but the Disclosures dilemma between beneficial and adverse effects is especially D.R. and J.D.L. are the inventors of patents and/or patent applications that pronounced in cancer (80). On the one hand, complement describe the use of complement inhibitors for therapeutic purposes. J.D.L. is may recognize altered surface patterns and attack cancer cells. the founder of Amyndas Biotherapeutics and Amyndas Pharmaceuticals, which Complement can also be therapeutically engaged for the are developing complement inhibitors for clinical applications. killing of tumor cells via complement-dependent cytotox- icity; for example, Abs directed against the surface Ag CD20 References that is statically expressed on mature and malignant B cells 1. Ricklin, D., G. Hajishengallis, K. Yang, and J. D. Lambris. 2010. Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11: 785– induce a CP-mediated complement attack and trigger FcgR 797. activation and other mechanisms that lead to cell death, thereby 2. Leslie, M. 2012. Immunology: the new view of complement. Science 337: 1034– 1037. making them valuable tools for the therapy of lymphoma or 3. de Cordoba, S. R., A. Tortajada, C. L. Harris, and B. P. Morgan. 2012. Com- certain autoimmune disorders when applied in a well-adjusted plement dysregulation and disease: from genes and proteins to diagnostics and dose regimen (81, 82). On the other hand, tumor cells may drugs. Immunobiology 217: 1034–1046. 4. Ricklin, D., and J. D. Lambris. 2013. Progress and trends in complement thera- increase the expression of complement regulators as evasion peutics. Adv. Exp. Med. Biol. 734: 1–22. mechanism, and strategies to increase the efficiency of com- 5. Markiewski, M. M., and J. D. Lambris. 2007. The role of complement in in- flammatory diseases from behind the scenes into the spotlight. Am. J. Pathol. 171: plement-dependent cytotoxicity via regulator-specific inhib- 715–727. itors or knockdown via small interfering RNA have been in- 6. Ricklin, D., and J. D. Lambris. 2013. Complement in immune and inflammatory disorders: therapeutic interventions. J. Immunol. 190: 3839–3847. vestigated (83). Importantly, however, complement appears 7. Nilsson, B., and K. Nilsson Ekdahl. 2012. The tick-over theory revisited: is C3 to be more intricately involved in tumor progression than a contact-activated protein? Immunobiology 217: 1106–1110. The Journal of Immunology 3837

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