regulators and receptors of the complement system

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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)

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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’.)

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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")

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¢ 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

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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

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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].

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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

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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.)

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° 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.

Use of UpToDate is subject to the Terms of Use.

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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.

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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

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function most
pathway and initiates of the lytic membrane attack complex (MAC). The
system is designed to efficiently on a biologic membrane.

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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

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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.

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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.

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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.

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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.

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