INTRODUCTION — The complement system is an ancient host defense system that traces its biologic origins to more than one billion years ago . It is part of innate and adaptive immunity. A major function is to guard the host's intravascular space by opsonizing and lysing bacteria. In addition, it promotes the local acute inflammatory response, which in turn instructs and influences the adaptive immune response. It has been increasingly shown to play a major role in debris clearance. The complement system consists of plasma proteins of the activating cascades and membrane regulators and receptors. The plasma proteins interact via three major cascades: the classical, alternative, and lectin pathways [2-8].
A review of the complement pathways is presented here. Other discussions of the complement system and its associated diseases, as well as an overview of the innate immune system, are presented separately. (See "Overview and clinical assessment of the complement system" and "Inherited disorders of the complement system" and "Acquired disorders of the complement system" and "An overview of the innate immune system".)
Note that a 2019 publication provided an update on complement nomenclature to simplify and clarify descriptions of the players in this immunologic system . This review employs those recommendations.
PROTEINS OF THE COMPLEMENT SYSTEM — Participants in the complement activation pathways circulate in the plasma and are present at a lower concentration in other body fluids as well as in the intracellular and interstitial spaces. The components in plasma are predominantly synthesized in the liver, while the components at other sites represent a combination of local synthesis (many cell types) and filtrates from plasma (table 1). (See "Regulators and receptors of the complement system".)
BIOLOGIC FUNCTIONS OF COMPLEMENT — The primary goal of the complement system is the rapid destruction of microbes. This is commonly accomplished through the deposition of large quantities (ie, hundreds of thousands to millions) of C3b fragments on a target. This process, known as opsonization, refers to the coating of targets with complement ligands to promote their elimination through immune adherence and then phagocytosis by cells bearing complement receptors. Opsonization also facilitates the adaptive immune response including antigen presentation and retention as well as immunologic memory and costimulation of B lymphocytes through the antigen receptor . Covalently bound C3b on a target is partially degraded to iC3b and then C3d fragments. These subsequently can interact with their receptors on phagocytic and immune cells.
A second goal of the complement system is promotion of the inflammatory response, primarily through the liberation of peptides C3a and C5a, known as anaphylatoxins. These approximately 10 kDa peptides bind to their receptors to promote vasodilation, chemotaxis, and other cell activation phenomena. Note that per the updated nomenclature, the large cleaved fragments (designated with a "b") bind to the cell surface to continue the cascade, while the smaller fragments (designated with an "a") are released.
Through these functional activities, complement participates in an array of processes including clearance of immune complexes, detection and removal of apoptotic cells, angiogenesis, tissue regeneration, and mobilization of hematopoietic progenitor cells [11,12].
COMPLEMENT PATHWAYS — Each of the complement pathways is triggered in a distinct manner, yet all have the common goal of modifying the target membrane by depositing C3 activation products and then engaging a common terminal sequence or pathway called the "membrane attack complex" (MAC) (figure 1). Three concepts facilitate the understanding of the different complement pathways: attachment (the trigger), activation and amplification (convertase formation), and membrane attack (membrane perturbation).
Classical pathway — The classical pathway was discovered first (in 1892). A Nobel Prize was awarded to Jules Bordet in 1919 for this discovery. The alternative pathway was later identified in 1954. Although some criticized it as an artifact, it was finally validated in the 1960s and 1970s. (See below.)
Attachment — The classical pathway is most commonly triggered by antibodies binding to antigens. The C1 complex is composed of three subunits: C1q, C1r, and C1s. The C1q subcomponent has a hydra-like conformation in which two C1r and two C1s molecules (both serine proteases) are entwined (figure 2). The C1q subcomponent attaches to the Fc portion of antibody. Immunoglobulin M (IgM) and immunoglobulin G (IgG) subclasses 1 and 3 activate complement in this manner. Subclass IgG2 is a weak activator while IgG4 does not activate the classical pathway . Neither immunoglobulin (Ig)D nor IgE are able to activate complement.
Note that activation by IgA has been controversial. However, IgA-bearing immune complexes interact with both the alternative and lectin pathways as indicated most convincingly by their deposition in the kidney in IgA nephropathy . Thus, renal biopsy assessment has been particularly informative in this disease, and anti-complement therapy is promising . (See "IgA nephropathy: Treatment and prognosis".)
A common perception is that attachment of C1 to antibody of the classical pathway by the C1 complex requires two IgG molecules in close proximity or a single IgM. However, work published in 2014 suggested the efficiency of the interaction can be enhanced when the C1q component of C1 binds a hexameric IgG complex . (See "Regulators and receptors of the complement system".)
Activation and amplification — After C1q of the C1 complex binds to antibody, C1r undergoes an autoactivation cleavage process. Activated C1r then cleaves and thereby activates C1s. C1s, in turn, cleaves C4 and then C2. The large fragments derived from C4 (C4b) and C2 (C2b) assemble on the target, forming the complex called the C3 convertase, C4b2b. C4b is covalently bound to the target and binds the C2b fragment that is a serine protease (catalytic domain).
The function of a C3 convertase is to activate (again by limited proteolytic cleavage) many molecules of the key next component, C3. These activated fragments bind covalently to the target and form clusters at the site where antibody is bound (a complement-fixing site). C4b and C3b become attached to the antigen as well as to the antibody. A complex of IgG-C3b is a particularly potent opsonic partner, being able to engage both complement and immunoglobulin receptors.
C4 and C3 possess an internal thioester bond. Upon cleavage of C4 to C4a and C4b or C3 to C3a and C3b, the highly reactive thioester bond is broken. The nascent C4b or C3b has a few microseconds to covalently bind to the target by forming an ester or amide linkage. Thus, through this mechanism, C4 and C3 are able to transfer from the fluid phase onto a target. Because the structures of C3 and C3b have been solved, new insights have been gained into the function of C3 [16,17].
Amplification occurs since the activated proteins are enzymes that cleave the next component(s) in the cascade. Each activated C1 generates many C4b and C2b fragments. Most C4b fragments serve as opsonins, while some bind C2b and form C3 convertases. In turn, each C3 convertase rapidly generates many activated C3bs. These C3bs serve as opsonins and also form C5 convertases that cleave C5 to initiate the terminal or lytic sequence. (See 'Attack (the membrane attack complex)' below.)
One study of classical pathway activation determined that following a saturating amount of antibody affixing to a mammalian cell, 2.5 million C4b molecules became bound and about 0.5 million C2 molecules subsequently attached to form C3 convertases . Within five minutes, 20 million molecules of C3b were deposited and 1 million MACs were formed. The number of anaphylatoxin fragments (C3a and C5a) would be several-fold more than the number of C3b and C5b fragments bound, because only 10 to 20 percent of the latter group of fragments actually attach to the target (table 2). Studies employing other types of targets, including bacteria, have given similar results in the setting of large amounts of antibody.
Attack (the membrane attack complex) — Most C3b molecules deposited on foreign surfaces serve as ligands for receptors, although some generate the C5 convertase (C4b2b3b). The C5 convertase cleaves C5 to C5a and C5b:
●C5a is a potent anaphylatoxin.
●C5b begins the formation of the MAC, a multimolecular unit composed of individual molecules of C5b, C6, C7, C8, and multiple molecules of C9 [19-21].
After C5b is generated by the C5 convertase, it binds C6 and then C7. The C7 protein confers lipophilicity and thereby membrane attachment capability to the trimeric complex. Upon insertion into the lipid bilayer, this complex acts as a high affinity membrane receptor for C8. While some lytic activity is expressed by the C5b-8 complex, more efficient lysis is dependent upon an interaction with multiple molecules of C9.
The fully functional MAC forms transmembrane channels or pores that displace lipid molecules and other constituents, resulting in membrane perturbation and osmotic lysis. The concept of membrane damage by pore-forming proteins, such as C9, is a mechanism that is also used by bacterial cytolysins, fungal toxins, parasitic metabolites, and perforins of cytotoxic T lymphocytes and natural killer cells .
During complement activation, nearby host cells are protected from being excessively damaged as innocent bystanders by plasma and membrane regulatory proteins [4,23,24]. (See "Regulators and receptors of the complement system".)
Lectin pathway — Overall, the lectin pathway (also called the mannan- or mannose-binding pathway) is similar to the classical pathway [25,26]. Lectins are proteins that bind to sugars. The lectin pathway is activated by pattern recognition molecules (PRM) of two major protein families . One family, the ficolins, consists of ficolin-1, ficolin-2, and ficolin-3. The second PRM family of the lectin pathway is called the collectins and is comprised of mannose-binding lectin (MBL), collectin-10 and collectin-11. These PRM family members associate in the blood with associated serine proteases MASP-1, MASP-2, and MASP-3 [6,27-29]. The recognition of ligands by the PRM-MASP complexes activates the lectin pathway via the MASP-2-mediated cleavage of C4 and C2 (see below).
Attachment — The overall scheme for the lectin pathway is similar to the classical pathway. Lectins (ficolins and collectins) substitute for antibodies, sugars on pathogens are analogous to "antigens," and MASPs replace C1r/C1s (figure 1).
Thus, the lectin pathway begins with the binding of collectins or ficolins to repeating sugar residues on the surface of pathogens . These sugar residues include mannose, N-acetylglucosamine (GlcNAc), N-acetylmannosamine, fucose, and glucose. However, neither MBL nor ficolins bind D-galactose or sialic acid (terminal sugar moieties commonly found on mammalian cell surface glycoproteins). This selectivity promotes pattern recognition of surface carbohydrates to distinguish pathogens from host cells . Other mechanisms used in the innate immune system to distinguish between self and foreign tissues are described separately. (See "An overview of the innate immune system".)
Activation and amplification — Following formation of lectin-sugar complexes, MASP-1 activates MASP-2 in a manner analogous to that of C1r and C1s of the classical pathway . This results in cleavage of C4 and C2. The C4b binds to the surface of the antigen, and C4bC2b functions as a C3-convertase, just as in the classical pathway. The C3 and C5 convertases and MAC are identical in the classical and lectin pathways. Thus, the key differences are that lectins and a sugar substitute for an antibody and an antigen, respectively, and MASP replaces the C1 complex proteases.
Alternative pathway — The alternative pathway is an ancient pathway of innate immunity that formed more than one billion years ago. It preceded adaptive immunity . Thus, the alternative pathway does not require antibody or prior contact with a microbe to function and serves as an independent immune system, capable of recognizing and destroying infecting elements [33-35]. Another arm of the innate immune system is provided by toll-like receptors, which mediate defense against bacteria, fungi, and viruses  (see "Toll-like receptors: Roles in disease and therapy"). Interactions between these two systems have been described . The interesting story of the identification of the alternative pathway, its early dismissal and subsequent rediscovery has been chronicled .
Activation and amplification — A small amount of autoactivated C3 is always present [so-called "C3 tickover" that refers to the formation of C3(H2O)] due to the presence of a labile thioester bond. C3 tickover is a mechanism by which the complement system monitors and probes the environment. The process is rapidly terminated on healthy human cells or in the fluid phase, but amplification occurs on foreign or damaged cells. The alternative pathway is engaged when this activated C3 binds factor B (figure 1). Bound factor B undergoes proteolytic cleavage mediated by another serine protease, factor D, to produce the fragments Bb and Ba (figure 3) . Ba is released into the surrounding milieu. The alternative pathway C3 convertase, C3bBb, is then stabilized by properdin (P), creating the complex C3bBbP. As the convertase cleaves more C3 to C3b, an amplification loop is set in motion, resulting in the deposition of large amounts of C3b on the target.
C3b, deposited by the classical or lectin pathway, can serve as a nidus for amplification by the alternative pathway. In many clinical situations, the initial deposition of C3b is mediated by the classical (via natural antibodies) or lectin pathways. C3b deposition is then amplified many-fold by the feedback loop of the alternative pathway. Indeed, engagement of the amplification loop may be necessary for tissue injury when the classical or lectin pathways initiate amplification via pathogenic autoantibodies .
Attack — The alternative pathway also engages the MAC. Another C3b binds to the C3 convertase to form C3bBbC3b, the C5 convertase. Thus, the binding of the second C3b shifts the substrate specificity from C3 to C5. Just as it stabilizes the C3 convertase, the binding by properdin also stabilizes and becomes part of the C5 convertase (C3bBbC3bP). The assembly of the MAC is then the same as for the classical pathway .
Additional pathways — Other means to activate complement have been reported [40-43]. These additional pathways may be important particularly at extravascular sites as a means of initiating an inflammatory process.
●Beta-amyloid and certain viral proteins interact directly with the C1q subcomponent of C1 to activate the classical pathway, without a requirement for antibody [41-43].
●C-reactive protein (CRP), which is structurally and functionally related to lectins, can activate the classical pathway by binding C1 .
●Trypsin-like proteases may directly cleave C3 to release C3a (to trigger a local inflammatory process) and C3b (to attach to a nearby target to initiate the alternative pathway). These types of proteases may also directly cleave C5 to produce C5a and C5b. C5a could then initiate an inflammatory response while the C5b could begin the formation of the MAC . Other examples include the proteases thrombin and kallikrein . A pathway for intracellular complement activation (referred to as the complosome ) was described subsequently, involving cathepsin L-mediated cleavage of intracellular stores of C3 . Further, other modes and locations for complement activation have been suggested, promoting interaction with other cell effector systems, such as coagulation, inflammasomes, metabolic pathways, and growth factors . These types of interaction are under intense study.
●If a component, such as C4 or C2, is completely lacking in blood, "bypass" pathways are available to allow for complement activation [48,49]. However, these mechanisms of activation are much less efficient and autoimmunity (SLE) is the most commonly associated disease process. (See "Inherited disorders of the complement system".)
●Properdin, released from granules upon neutrophil activation, can bind activated C3 to form a C3 convertase. Further, C3 and factor B may also be released from granules. Properdin likely also serves as a platform for efficient C3 activation by the alternative pathway .
●Functions of complement – The complement system is an ancient proinflammatory and membrane-altering host defense system that is part of both innate and adaptive immunity. There is also growing recognition of the complement system playing a role in instructing the adaptive immune response, removal of damaged cells, tissue regeneration, and angiogenesis. (See 'Biologic functions of complement' above.)
●Three major cascades – The complement system may be divided into three major cascades: the classical, lectin, and alternative pathways (figure 1). Each pathway is activated by a distinct set of conditions, but all three pathways result in the creation of a proinflammatory environment, deposition of large amounts of C3 on the target cell (opsonization), and membrane perturbation including lysis by the membrane attack complex (MAC). (See 'Attack (the membrane attack complex)' above.)
•Classical pathway – The classical pathway is activated by the binding of C1q in the C1 complex to the Fc portion of immunoglobulin G (IgG) or immunoglobulin M (IgM) in immune complexes. (See 'Classical pathway' above.)
•Lectin pathway – The lectin pathway is activated by collectins and ficolins binding to sugar moieties on the surface of pathogens leading to the engagement of MASP proteases, analogous to C1r and C1s of the classical pathway. (See 'Lectin pathway' above.)
•Alternative pathway – The alternative pathway does not require antibody or contact with a microbe to become activated. Instead, C3 is constantly autoactivated (C3 tickover) at a low level, a process that is rapidly amplified in the presence of a microbe, a damaged host cell, or lack of a complement regulatory protein. Deposition of C3b on a target by any means (usually by the classical pathway or the lectin pathway) can be efficiently amplified by the alternative pathway's feedback loop. (See 'Alternative pathway' above.)
●Additional pathways – Additional pathways to trigger complement activation exist, such as C5 activation by thrombin. These mechanisms may contribute to inflammatory responses within specific tissues and may be important in patients with an inherited deficiency of a component. (See 'Additional pathways' above.)
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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