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Regulators and receptors of the complement system

Regulators and receptors of the complement system
Literature review current through: May 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)

The complement regulatory proteins, their location (in plasma or on cell membranes), function, miscellaneous comments, and associated diseases are summarized in the table (table 1).

Control of activation/initiation — In the classical pathway, C1 inhibitor (C1Inh) prevents excessive complement activation on a target, as well as in 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 C1r and C1s. 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 C1r 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'.)

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 (CSMD1).

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 [DAA]).

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 and a 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:

Age-related macular degeneration [20] (see "Age-related macular degeneration")

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")

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 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 of T 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 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].

Receptors for C5a and C3a — The complement system, which can be engaged in a few seconds, is likely the earliest response 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, C5aR1 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. C5aR1 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 of a 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 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.)

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".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

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