regulators and receptors of the complement system

5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate | U pTo ® Official reprint from UpToDate® =) Date www.uptodate.com © 2024 UpToDate, Inc and/or its affiliates All Rights Reserved ® Regulators and receptors of the complement system AUTHORS: M Kathryn Liszewski, PhD, John P Atkinson, MD SECTION EDITOR: Jordan S Orange, MD, PhD DEPUTY EDITOR: Anna M Feldweg, MD All topics are updated as new evidence becomes available and our peer review process is complete Literature review current through: Apr 2024 This topic last updated: Mar 30, 2022 INTRODUCTION Precise control of the complement system is necessary because of its potent proinflammatory and cellular destructive capabilities The regulation of the complement system is reviewed here In order to comprehend the functions of the various regulatory proteins more fully, it is helpful to be familiar with the complement pathways, which are reviewed in greater detail separately ( figure 1) (See "Complement pathways".) COMPLEMENT REGULATION Nearly one-half of all complement proteins serve a regulatory function [1-4] The goal of regulation is to prevent complement damage to normal host tissue (inappropriate or wrong target) and fluid-phase activation (no target) [5] Deficiencies of control proteins lead to excessive complement activation and significant morbidity and mortality (See "Inherited disorders of the complement system", section on ‘Abnormalities in regulatory proteins'’.) Regulatory proteins inhibit the system by destabilizing activation complexes and by mediating specific proteolysis of activation-derived fragments The complement pathways are regulated at the following critical steps: ° Activation (initiation) ¢ Amplification (convertase formation) ¢ Membrane attack (lysis) https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complements 1/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate The complement regulatory proteins, their location (in plasma or on cell membranes), function, miscellaneous comments, and associated diseases are Summarized inthe table( table 1) Control of activation/initiation — In the classical pathway, C1 inhibitor (C1Inh) prevents excessive complement activation on a target, as well asin plasma(_— figure 1) C1 inhibitor, a member of the "serpin" superfamily of serine protease inhibitors, binds to each C1r and C1s subcomponent of the C1 complex(_‘ figure 2) This causes their dissociation and release from C1q, which is commonly attached to the Fc portion of immunoglobulin G (IgG) and immunoglobulin M (IgM) in an immune complex [6,7] C1 inhibitor performs a similar function in the lectin pathway This pathway has an activation scheme comparable to that of the classical complement pathway, but lectins (ie, proteins that bind to sugars) substitute for antibodies and lectin-associated proteases replace Cir and C's The lectins (specifically ficolins and collectins) bind sugar residues on microbial surfaces Mannose-binding lectin-associated serine proteases (MASPs) subsequently cleave C4 and C2 ( figure 1) (See "Complement pathways".) Activation/initiation is controlled by C1 inhibitor that blocks the active sites of these MASPs, analogous to the classical pathway where it inhibits Cir and C1s [6,7] (See "Inherited disorders of the complement system", section on ‘Lectin pathway deficiencies’.) C1 inhibitor has other biologic functions, in addition to control of the early steps in complement activation: ¢ C1 inhibitor regulates three other interrelated pathways: the coagulation (contact), fibrinolytic, and kinin-generating systems The role of C1 inhibitor in limiting the generation of kinins is central to the pathogenesis of hereditary angioedema, a condition caused by a deficit or dysfunction of C1 inhibitor Hereditary angioedema is reviewed in detail elsewhere (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis".) ¢ In animals, treatment with purified C1 inhibitor improves survival in experimental models of bacterial- and endotoxin-induced septic shock [8,9] The effect was also demonstrated with "inactivated" C1 inhibitor, suggesting that inhibition of the complement system was not the primary mechanism [8] The use of C1 inhibitor therapy in human sepsis has been studied primarily in lab-based studies, anecdotal reports, and small, randomized trials in humans [10] A possible role of complement in the pathophysiology of sepsis is discussed separately (See "Pathophysiology of sepsis", section on 'Complement activation’.) https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complements 2/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate Control of amplification — The C3 convertases are powerful amplifiers of the complement system The convertase steps are regulated by a family of complement-binding proteins ( table 1) [1,11-16]: ¢ Membrane proteins - Decay-accelerating factor (DAF; CD55), membrane cofactor protein (MCP; CD46), and CUB and sushi multiple domains protein 1 (CSMD‘1) ¢ Plasma proteins - C4b binding protein (C4BP) regulates C4b and C4b-containing classical and lectin pathway convertases Factor H regulates C3b, C3b-containing alternative pathway convertases, and C5 convertases that contain either one C3b (from the classical pathway/lectin pathway) or two C3bs (alternative pathway) These proteins function in three ways (_ figure 3): ¢ By preventing formation of the convertases ¢ By disassembling or disassociating the convertases (known as decay-accelerating activity [DAAI) ¢ By limited proteolytic cleavage of C4b and/or C3b This process, called cofactor activity, requires collaboration between the plasma-serine protease known as factor I anda cofactor protein, such as MCP or factor H These widely expressed membrane regulators inhibit complement on host tissue, while the plasma inhibitors primarily prevent activation in the fluid phase However, at sites of injury, the plasma inhibitors can interact with structures, such as the exposed basement membrane For example, anionic or heparin-binding sites in factor H and C4BP allow those plasma regulators, in essence, to act like a membrane protein at inflammatory sites and in areas of cellular injury (eg, apoptotic and necrotic cells) [17] Regulatory proteins are a target of pathogen inactivation or highjacking [18] Indeed, CD46 has been called a pathogen magnet [19] Deficiencies in regulators — Regulator deficiencies are associated with the following disorders: e Age-related macular degeneration [20] (see "Age-related macular degeneration") e Atypical hemolytic uremic syndrome [21,22] (see "Overview of hemolytic uremic syndrome in children") ¢ C3 glomerulopathy (C3G; formerly dense deposit disease) [23] (see "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis") https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complements 3/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate ¢ CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) syndrome [24] (see "Inherited disorders of the complement system") Control of membrane attack — The membrane attack complex (MAC) is also regulated both in the fluid phase and on cells [25,26] Control in plasma prevents diffusion from the activation site S protein (also known as vitronectin) controls fluid-phase MAC by binding to a site on the C5b-7 complex, thereby preventing its attachment to cell membranes MACs that deposit on self-tissue are inhibited by CD59 (also called protectin, membrane inhibitor of reactive lysis, or MAC inhibitory factor) This widely expressed glycolipid-anchored membrane protein has binding sites for both C8 and C9 and thereby inhibits the final steps of MAC assembly A deficiency of CD59 and DAF is the pathophysiologic basis of paroxysmal nocturnal hemoglobinuria (PNH) The deficiency is caused by a mutation in the PIGA gene (phosphatidylinositol glycan anchor biosynthesis, class A) that prevents the formation of a glycosylphosphatidylinositol anchor, such that CD59 and DAF are not expressed on the cell surface This results in an increased sensitivity to lysis Additionally, several cases with only loss- of-function CD59 deficiency have been described with all such patients (12 of 12) demonstrating neurologic symptoms, 92 percent (11 of 12) recurrent peripheral neuropathy, 50 percent (6 of 12) with recurrent strokes, and 8 percent (1 of 12) with retinal involvement [27] (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria", section on 'PIGA gene mutation’.) Control of anaphylatoxins — When complement proteins C3, C4, and C5 are activated, small peptides of 74 to 77 amino acids in length (C3a, C4a, and C5a) are released from the amino- terminus of the alpha chain and bind to their cognate receptors or are inactivated by a plasma enzymes (carboxypeptidase-N and carboxypeptidase-R) that remove the carboxyl-terminal arginyl residue [28-30] COMPLEMENT RECEPTORS Many host cells, especially human peripheral blood cells, possess receptors for complement activation fragments that promote the adherence and ingestion of microorganisms and immune complexes(_ table 2) Upon engagement, these receptors, which are expressed on most inflammatory and immunocompetent cells, induce cellular responses that trigger inflammatory and immune responses [6,12,31] Complement receptor 1 — Most peripheral blood cells express complement receptor 1 (also called CR1, CD35, C3b/C4b receptor, and immune adherence receptor) [32] CR1 plays a critical https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complements 4/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate role in the clearance of C4b- and C3b-coated particles (eg, immune complexes) on which the complement system has been activated Deposition of C3b and C4b on a target is particularly efficacious in promoting attachment to cells bearing complement receptors This phenomenon is known as "immune adherence." Erythrocytes express approximately 500 copies of CR1 per cell This allows the erythrocyte to bind intravascular immune complexes and then serve as a vehicle (taxi) to transport immune complexes to the liver and spleen Hepatic and splenic macrophages then "clear" such immune complexes by "stripping" them from the erythrocyte, destroying the antigen (often viruses or bacteria), and facilitating an immune response (antigen presentation) The erythrocyte may then return to the circulation for another round of immune complex clearance The function of CR1 depends in part upon the type of cell on which it is expressed The primary function of CR1 on erythrocytes is to clear circulating immune complexes In comparison, CR1 on neutrophils and monocytes binds C3b- and C4b-bearing immune complexes, resulting in a cellular response that often includes internalization and digestion In addition, CR1 is expressed on B lymphocytes, a subset ofT lymphocytes, and on follicular dendritic cells where it facilitates the localization of complement-bearing antigens to lymphoid follicles On peripheral blood cells, CR1 is primarily an immune adherence receptor However, in a highly inflammatory milieu with engagement of C3aR and C5aR, CR1 becomes capable of ingesting/internalizing such coated particles It also serves a regulatory role by preventing further complement activation and by converting C3b to hemolytically inactive fragments (iC3b and C3dg), which then serve as ligands for additional complement receptors CR1 is a receptor for the malaria parasite [33,34] It also has been implicated as a risk factor for Alzheimer disease and schizophrenia [35-37] Levels of CR1 are reduced in diseases, such as systemic lupus erythematosus (SLE), glomerulonephritides, and human immunodeficiency virus (HIV) [32] These diseases feature immune complexes that may reduce levels of CR1, and in the case of SLE, such reductions parallel disease activity [32] Additionally, a study found that CR1 protein levels and genetic variants were associated with chronic Chagas disease in a Brazilian cohort [34] Complement receptor 2 — Complement receptor 2 (also called CR2, C3d or C3dg receptor, and CD21) is expressed on B lymphocytes, follicular dendritic cells, epithelial cells in the pharynx and upper airway, and in low amounts on peripheral blood T cells It is not found on monocytes, granulocytes, or erythrocytes CR2 serves to localize complement-bearing immune complexes to B lymphocyte-rich areas of the spleen and lymph nodes In this way, CR2, as well as CR1, promotes antigen-driven https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complements 5/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate activation of B cells This "adjuvant" function of the complement system is being exploited by attaching C3 fragments to vaccines in order to enhance their antigenicity CR2, through its association with other membrane proteins, is also an important coreceptor in the signaling of B cells [1,38] CR2 is also the receptor for the Epstein-Barr virus (EBV) (See "Virology of Epstein- Barr virus".) Patients with the rare heritable disorder X-linked agammaglobulinemia lack mature B lymphocytes Consequently, EBV cannot infect the B cells of these patients [39,40] (See "Agammaglobulinemia".) Complement receptor 3 — Complement receptor 3 (also called CR3, Mac-1, and CD11b/18) binds and promotes the opsonization of particles bearing fragments of C3, especially iC3b [41] CR3 is expressed by macrophages/monocytes and certain lymphocytes and is part of the integrin family of adherence-promoting proteins (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".) CR3 promotes ingestion of iC3b-coated targets Deficiency of CR3 is associated with delayed separation of the umbilical cord, omphalitis, and severe childhood infections This disorder is known as leukocyte-adhesion deficiency syndrome (See "Leukocyte-adhesion deficiency".) Since immune complexes possess variable quantities of C3-derived fragments (C3b, iC3b, C3dg, and C3d), multiple complement receptors usually cooperate to help clear immune complexes and facilitate adaptive immune responses to antigens For example, CR1 promotes initial adherence, CR3 facilitates internalization, and CR2 transmits cellular signals to facilitate the adaptive immune response [41] Complement receptor 4 — Complement receptor 4 (CR4, CD11c/18) has a similar function and tissue distribution as CR3 However, CR4 may also play an important role in neutrophil and monocyte adhesion to endothelium [41] (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".) Complement receptor of the immunoglobulin superfamily — Complement receptor of the immunoglobulin superfamily (CRIg) recognizes C3b and iC3b molecules covalently bound to particle (eg, pathogen) surfaces [12,13] Functions of CRIg include inhibition of the alternative pathway, clearance of systemic pathogens, and regulation of the adaptive immune response CRIg is widely expressed in lung, adipose tissue, spleen, adrenal gland, small intestine, bladder, colon, breast, and on macrophages associated with blood vessels CRIg is the only complement receptor described thus far with immunoglobulin domains No mutations in CRIg have been linked to disease [42] https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complements 6/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate Receptors for C5a and C3a — The complement system, which can be engaged in a few seconds, is likely the earliest resoonse system to microbes and to tissue damage Liberation of C3a and C5a and interaction with their respective receptors triggers the acute inflammatory reaction C5a is a major chemotactic factor for neutrophils Both C3a and C5a "activate" a wide variety of cell types C5a receptor — Two C5a receptors have been identified, ChaR1 and C5aR2 Both belong to the G protein-coupled receptor (GPCR) family [43] C5aR1 is better defined, while C5aR2 is less well- understood and may be a decoy receptor for C5a [44] C5aR1 is prominently expressed on neutrophils, macrophages, mast cells, and basophils Also, it is a chemotactic factor for neutrophils and monocytes and causes release of their granular constituents C5aR11 is expressed on a wide variety of epithelial and endothelial cells C5a has a spasmogenic effect upon various tissues by a direct action on smooth muscle cells bearing C5a receptors (C5aR) or secondarily by the release of mediators from mast cells [45] Receptor binding of C5a may play a role in end-organ damage during sepsis [46] This was illustrated in an animal model of intra-abdominal infection in which C5aR1 upregulation was found in lung, liver, kidney, and heart soon after onset of sepsis [47] Administration of antibodies that blocked activation of C5a receptor was associated with improved survival Another study comparing healthy volunteers to patients in septic shock suggested that septic shock in humans is associated with complement activation, C-reactive protein-dependent loss of C5aR on neutrophils, and appearance of a circulating C5aR in serum, which correlated with poor outcome [48] (See "Pathophysiology of sepsis", section on 'Complement activation’.) The binding of C5a to its receptor may also provide a mechanism by which the complement- and immunoglobulin-activated inflammatory systems interact In a mouse model, binding of C5a to its receptor resulted in upregulation of Fc-gamma receptors Binding of immune complexes to Fc-gamma receptors, in turn, leads to generation of more C5a, thus establishing a positive feedback loop [49] This type of interaction also may be important in the pathogenesis of autoimmune diseases mediated by autoantibodies and immune complexes [50] Note that in late 2021 the US Food and Drug Administration (FDA) approved the use ofa small molecule inhibitor, avacopan, an inhibitor of C5aR, for the treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on ‘Induction therapy’) C3a receptor — The C3a receptor's major role appears to be in activating cells at sites of inflammation [51] It is a member of the same G-coupled superfamily as the C5a receptor and has a broad tissue distribution Receptors for C3a are present on endothelial, epithelial, and https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complements 7/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate many types of peripheral blood cells, including neutrophils, monocytes, most lymphocytes, and basophils Mast cell and basophil degranulation (similar to the C5a receptor) is mediated by C3a engaging its receptor on these cell types Variations in this receptor may affect susceptibility to asthma [52,53] CSMD1 — CUB and sushi domains protein 1 (CSMD1) is a transmembrane protein expressed in multiple tissues that serves as a cofactor in the factor I-mediated cleavage of C3b [54] Four isoforms have been described Changes in CSMD1 expression have been associated with several types of cancers, infertility, and disorders of cognitive function [55,56] Other receptors — Receptors for C1q [57], factor H [58], ficolins [59], and others have been noted on such cells as neutrophils, monocytes, and B cells Their function is not as clearly defined as those described above However, a protein, such as C1q, may serve both as a lectin to identify foreign materials and altered self as well as the link to proteases of the complement pathway Additionally, protease-activated receptors 1 and 4 have been identified as receptors for the C4a anaphylatoxin [60] SUMMARY ¢ Importance of complement regulation - Nearly one-half of all complement proteins serve a regulatory function Complement pathways are regulated at each important step: activation, amplification (convertase formation), and membrane attack( table 1) Precise control of the complement system is necessary because of its potent proinflammatory and cellular destructive capabilities The goal of regulation is to minimize complement damage at sites of inflammation (inappropriate or wrong target) and fluid-phase activation (no target) (See 'Complement regulation’ above.) ¢ Complement receptors - Receptors for complement activation fragments are expressed on many host cells, including peripheral blood cells, endothelial cells, and epithelial cells ( table 2) Receptors for C4b and C3b are present on most cells of the immune system and promote pathogen destruction and generation of the adaptive immune response Receptors for C3a and C5a are widely distributed where they trigger the local inflammatory response (innate immunity) and also cell activation to prepare for the adaptive immune response Together, these receptors promote the adherence and ingestion of microorganisms and immune complexes (See 'Complement receptors' above.) https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complements 8/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate ° Deficiencies - Deficiencies of inhibitory proteins lead to excessive complement activation and significant morbidity and mortality (See 'Deficiencies in regulators' above.) Deficiencies of certain complement receptors, such as complement receptor 3 (CR3), result in severe infections in childhood (See "Inherited disorders of the complement system" and "Leukocyte-adhesion deficiency".) 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61:209 57 Ghebrehiwet B, Hosszu KK, Valentino A, et al Monocyte expressed macromolecular C1 and C1q receptors as molecular sensors of danger: Implications in SLE Front Immunol 2014; 5:278 https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complement 12/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate 58 Losse J, Zipfel PF, Jozsi M Factor H and factor H-related protein 1 bind to human neutrophils via complement receptor 3, mediate attachment to Candida albicans, and enhance neutrophil antimicrobial activity.J Immunol 2010; 184:912 59 Kuraya M, Ming Z, Liu X, et al Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation Immunobiology 2005; 209:689 60 Wang H, Ricklin D, LambrisJD Complement-activation fragment C4a mediates effector functions by binding as untethered agonist to protease-activated receptors 1 and 4 Proc Natl Acad Sci U S A 2017; 114:10948 Topic 3967 Version 21.0 https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complement 13/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate GRAPHICS Complement pathways Antibodies bind antigens Lectins bind sugars Pathogens or damaged tissue C3 convertase = C3a (inflammation) = C3b (opsonization) @—— C3b C5 convertase = C5a (inflammation) = C5b (initiates MAC) cs =—————> Terminal pathway Membrane attack complex C5b, C6, C7, C8, C9 There are three major independent yet overlapping pathways for complement activation In the classical pathway, immune complexes (Ag-Ab complexes) bind C1 via its C1q subcomponent, while its C1s protease subunit cleaves C4 and C2 The large C4b fragment binds to a target and subsequently captures the large fragment of C2 (C2b) This bimolecular complex forms an enzyme (the C3 convertase, C4bC2b) that cleaves C3 to C3b and releases the anaphylatoxin, C3a The binding of C3b to the convertase (C4bC2bC3b) generates the C5 convertase The lectin pathway is an analogous system, except that the initiating step is the binding by lectins to repetitive sugars on microbial surfaces Mannose-associated serine proteases (MASPs) take the place of the C1 proteases The alternative pathway (AP) continuously self-activates at a low level (a process called C3 tickover) to generate C3b that deposits on pathogens or debris C3b or C3(HO) engages the alternative pathway components, factors B (FB) and D (FD), to form a C3 convertase (C3bBb), which in turn cleaves more C3 to C3b The binding by another C3b to the C3 convertase generates the C5 convertase (C3bBbC3b) Properdin (P) is a positive regulator that stabilizes both the AP C3 and C5 convertases The latter subsequently cleaves C5 to release the potent anaphylatoxin C5a, while C5b engages the terminal https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complement 14/21 5/15/24, 10:36 AM the formation Regulators and receptors of the complement system - UpToDate complement function most pathway and initiates of the lytic membrane attack complex (MAC) The system is designed to efficiently on a biologic membrane Graphic 56374 Version 11.0 https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complement 15/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate Complement regulatory proteins Protein Location Function Comment Disease* HAE C1 inhibitor Plasma Inactivates C1 and Binds C1r/C1s, MASPSsS MASPs C4BP4 Plasma DAA and CA Binds C4b One case of aHUS Factor H (FH) Plasma DAA and CA Binds C3b DAF (CD55) aHUS, AMD, Membrane DAA Prevents formation of C3G MCP (CD46) and dissociates C3/C5 Membrane CA convertases CHAPLE CR1 (CD35) Binds C3b and C4b to syndrome; CRIg all factor I-mediated CSDM1 cleavage PNH“ Factor I (FI) Binds C3b, C4b, C1q, Primarily aHUS and MBL but also Binds C3b and iC3b pregnancy- related disorders and CVID Membrane DAA and CA Membrane Blocks alternative Binds C3b aHUS, AMD Membrane pathway Requires a cofactor, Plasma such as MCP or factor CA H Protease that cleaves C3b and C4b Anaphylatoxin Plasma Protease that Binds and Some inactivator cleaves C3a, C4a, and combination ot (carboxypeptidase N) inactivates C5a angioedema, chronic anaphylatoxins urticaria, or ha fever/allergy Vitronectin Plasma Blocks fluid-phase Binds C5b67 MAC CD59 Membrane Blocks MAC on host Binds C8, C9 PNH: rare cells deficiency resulted in Coombs- negative hemolysis and https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complement 16/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate Clusterin Plasma Putative MAC inhibitor Binds C7, C8, C9 relapsing inflammatory demyelinating polyneuropath - MASPs: mannose-binding lectin (MBL)-associated serine proteases; HAE: hereditary angioedema; C4BP: C4b binding protein; DAA: decay-accelerating activity; CA: cofactor activity; aHUS: atypical hemolytic uremic syndrome; AMD: age-related macular degeneration; C3G: C3 glomerulopathy; DAF: decay- accelerating factor or CD55; CHAPLE: complement hyperactivation, angiopathic thrombosis, and protein- losing enteropathy; PNH: paroxysmal nocturnal hemoglobinuria; MCP: membrane cofactor protein or CD46; CVID: common variable immunodeficiency; CR1: complement receptor 1 or CD35; MBL: mannose- binding lectin; CRIg: complement receptor of the immunoglobulin superfamily; CSDM1: CUB and sushi multiple domains protein 1; MAC: membrane attack complex * Most diseases result from rare heterozygous deficiencies although there are a few cases of homozygous deficiencies Specifically, there are about 25 cases each of complete C3, FH or FI deficiency As in C3 deficiency (secondary C3 deficiency occurs with either FH or FI total deficiency), the clinical presentation is that of recurrent bacterial infections, primarily with Streptococcus pneumoniae Refer to UpToDate content on inherited disorders of the complement system and acquired deficiencies of the complement system for details {| C4BP and factor H transfer from the plasma to damaged cells and exposed acellular tissue surfaces (basement membranes) to prevent undesirable complement activation This is particularly important in cases of extracellular debris accumulation, as in AMD A In PNH, both DAF and CD59 are lacking due to a defect in the glycolipid anchoring mechanism Graphic 71885 Version 8.0 https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complement 17/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate Function of the C1 inhibitor Ci complex Cig subcomponent Cir-Cis subcomponent Antigen- Ab aA A antibody + AA complex Ag C1 inhibitor xé C1 inhibitor binds tightly to each Cir and Cis, causing them to dissociate from the complex Dissociated Cir,- Remaining Cis, with four Ciq and bound C1 inhibitors > antigen- antibody complex — ~~ _ pe J C1 inhibitor (a serpin or serine protease inhibitor) regulates the activation of the classical complement pathway by binding to and inactivating the serine protease subcomponents of C1 (ie, the tetramer consisting of two C1r and two C1s proteins) In this process, the C1 inhibitor complex dissociates from the C1q subcomponent of C1, which remains bound to the immune complex Note that C1 inhibitor also regulates in the same manner the mannose-binding lectin-associated serine proteases (MASPs) that are the C1r/C1s equivalents in the lectin pathway of complement activation Ab: antibody; Ag: antigen Graphic 72648 Version 7.0 https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complement 18/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate Alternative pathway cofactor activity A cofactor, such as CD46 (shown) or factor H, binds to C3b attached to host cell membranes This allows serine protease factor I to cleave C3b to prevent further C3 activation In the classical and lectin pathways, C4b is inactivated by the same mechanism, with CD46 or C4b binding protein serving as the cofactor protein Graphic 99644 Version 4.0 https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complement 19/21 5/15/24, 10:36 AM Regulators and receptors of the complement system - UpToDate Complement receptors: Ligands and functions Receptor Major ligands Functions C3b/C4b, C1q, MBL, Immune adherence; immune complex clearance; regulation of CR1 C3b/C4b ficolins B cell coreceptor; immune complex localization; EBV receptor; CR2 presents complement-opsonized antigens to T cells iC3b, C3dg, C3d, IgE CR3 receptor, interferon Phagocytosis; neutrophil activation; apoptosis; cell activation alpha, DNA CR4 iC3b, clotting factor X Phagocytosis; cell activation C3aR and up to 50 other Cell type dependent; cell activation; histamine release C4aR ligands Cell activation; endothelial cell permeability C5aR1 iC3b/fibrinogen/ICAMs Cell activation; chemotaxis; development and regeneration C5aR2 C3a Possible functions include nonsignaling decoy receptor; C1qR* C4a modulator of C5aR1; G-protein independent signaling C5a Phagocytosis; a variety of C1q receptors have been identified CRIg C5a with varied functions* Phagocytosis; alternative pathway inhibitor C1q* C3b/iC3b CR: complement receptor; MBL: mannose-binding lectin; EBV: Epstein-Barr virus; ICAMs: intercellular cell adhesion molecules; CRIg: complement receptor of the immunoglobulin superfamily * Ten putative C1q receptors with diverse structures have been proposed!"!, All bind C1q as well as other ligands triggering distinct cellular responses However, these interactions do not lead to complement activation References: 1 Bohlson SS, O'Conner SD, Hulsebus Hj, et al Complement, C1q, and C1q-related molecules regulate macrophage polarization Front Immunol 2014; 5:402 Graphic 58974 Version 9.0 https://www.uptodate.com/contents/regulators-and-receptors-of-the-complement-system/print?search=Regulators and receptors of the complement 20/21