Complement Activation - an overview (2023)

Complement activation is an early event after injury and the inhibition of complement activation or its components offer tissue protection after reperfusion.29 Finally, complement proteins transduce various cell signals.

From: Pediatric Critical Care (Fourth Edition), 2011

The Complement System

A. Wesley Burks MD, in Middleton's Allergy: Principles and Practice, 2020

Regulation of Complement Activation

Unregulated complement activation would lead to host cell lysis, the inappropriate production of inflammatory mediators, and aberrant B cell activation. Nearly as much metabolic energy is spent in the regulation of the complement system as in production of the main constituents of the complement cascade. Traditionally, the regulators of complement are divided into fluid-phase regulators and membrane-bound regulators; although this division is somewhat arbitrary, it is the format used in this chapter (Table 8.2). Another categorization strategy groups the regulators by targeted component. For example, C3 is the most important complement component and the most tightly regulated component. C3 is regulated by factor H, factor I, properdin, C4 binding protein, membrane cofactor protein (MCP), CR1, CR2, and decay accelerating factor (DAF) (i.e., CD55). Several of these molecules have a conserved motif of 60 amino acids termed theshort consensus motif and belong to theRCA gene cluster on chromosome 1 (Fig. 8.8).

C1 inhibitor is perhaps the most clinically important of the regulatory proteins. Heterozygous deficiencies of C1 inhibitor lead to hereditary angioedema (HAE). C1 inhibitor is a serine protease inhibitor that inhibits both the low-level autoactivation of C1 and the fluid phase activation of C1 (Fig. 8.9). Immune complex activation of C1 is preserved and is not affected by C1 inhibitor. The mechanism by which C1 inhibitor regulates C1 is by binding to C1s and C1r, leading to dissociation from C1q. C1 inhibitor also regulates MASP-1 and -2 through a similar mechanism. C1 inhibitor has important roles inhibiting factor XII (Hageman factor) and prekallikrein of the contact system of coagulation. Activation of these two pathways is thought to be of paramount importance for the clinical manifestations of C1 inhibitor deficiency. C1 inhibitor has also action in fibrinolytic system. Other regulators of C1 have been described but are less well characterized. Certain defensins appear to inhibit activation of C1, and a molecule termedfactor J has inhibitory activity. Their roles are not understood.

C4 binding protein is another fluid phase regulator of complement and also shares the short consensus motif configuration of many of the complement regulators. It acts to displace C2a and dissociates the classical pathway convertase. In addition, C4 binding protein is a cofactor for factor I cleavage of C4b (Fig. 8.9).

Factor I, alongside factor H, regulates the alternative pathway (Fig. 8.10). Factor H identifies nonactivator surfaces though the recognition of nonpathogen oligosaccharides and displaces Bb from C3b on those surfaces. Factor H also can prevent factor B from ever binding to C3b in the first place. Factor I inactivates C3b by cleaving it to iC3b, and its activity is enhanced in the presence of factor H. Together, these two regulators ensure that the spontaneous activation of the alternative pathway remains at a low level unless an activator surface is available to support a more intensive and sustained activation.

COMPLEMENT

N. Rawal, in Encyclopedia of Respiratory Medicine, 2006

Anaphylaxis

Complement activation does not occur in systemic anaphylaxis because IgE immune complexes do not activate complement. In this immediate hypersensitivity reaction, the antigen binds to an IgE antibody on mast cells or basophils, causing release of mediators that produce life-threatening symptoms. However, studies with mice that lack IgE suggest that generation of C3a and C5a via complement activation contributes to the bronchoconstriction and hypotension of anaphylaxis. Indeed, additional animal studies implicate C3a and C5a as putative mediators of anaphylactic shock. Both C3a and C5a peptides contract airway smooth muscle in the guinea pig independent of histamine, and treatment with soluble CR1 (sCR1), which inhibits complement activation, eliminates the antigen-induced hypotensive response in these animals.

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Complement and Deficiencies

John E. Bennett MD, in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 2020

Regulation of the C3 Convertases

The classical-pathway and alternative-pathway C3 convertases are functionally analogous molecules (seeFig. 9.1). Control of their activity occurs via three basic mechanisms that use functionally identical or shared regulator proteins (Table 9.2)30,41:

1

Spontaneous decay: Both convertases (C4b2a and C3bBb) are inherently labile and undergo spontaneous decay, with the loss of C2a or Bb from their respective complexes.

2

Accelerated decay: Spontaneous decay can be accelerated by C4b-binding protein (C4BP) and especially by factor H. These regulatory proteins compete with C2a and Bb for binding sites on C4b and C3b. In doing so, they inhibit new convertase formation and enhance the rate of dissociation of already formed convertases.

3

Facilitated inactivation: Exposed C4b and C3b molecules are highly susceptible to enzymatic cleavage by factor I. C4BP and factor H serve as cofactors to promote factor I–mediated cleavage and production of inactivated C4b (iC4b) and C3b (iC3b), respectively. Inactivation eliminates the ability of these molecules to re-form the C3 convertases.66,67 Under typical circumstances, the functional half-life of C3b is just 90 seconds, whereas its cleavage product, iC3b, has a half-life of approximately 35 minutes.

Several additional points have emerged from the many studies on C3 convertase regulation. First, control of C3 convertase activity is expressed both in the fluid phase and on host cell surfaces. C4BP and factor H modulate convertase activity in both locations, whereas membrane-bound proteins (complement receptor 1 [CR1], membrane cofactor protein [MCP], and decay-accelerating factor [DAF]) primarily control convertase activity on cell surfaces. Second, all control proteins either accelerate the decay of the C3 convertases (DAF) or promote factor I–mediated cleavage of C4b or C3b (MCP), or both (CR1, C4BP, factor H). Third, C4BP and factor H, unlike their membrane-bound counterparts, exhibit relative specificity for the classical-pathway and alternative-pathway C3 convertases, respectively.64,67 Of these two serum proteins, factor H plays the dominant regulatory role.

These regulatory molecules contain a structural motif calledshort consensus repeats (SCRs).68 SCRs are tandem repeats of approximately 60 amino acids that share a conserved consensus sequence. The number of repeats varies considerably among the control proteins, from a low of 3 in MCP and DAF to a high of 59 in C4BP. SCRs constitute the binding domains for C3b and other molecules. Two to four SCRs are typically required to form a complete binding site, but the number of SCRs and which ones in a sequence form a specific binding site differ among the proteins and their binding ligands.68,69

Decompression Sickness

Richard E. Moon MD, FACP, FCCP, FRCPC, Des F. Gorman MBChB, MD, PhD, in Physiology and Medicine of Hyperbaric Oxygen Therapy, 2008

Complement Activation

Complement activation by bubbles has been observed both in vitro51,52 and in vivo in experimental animals,53 and has been proposed as a mechanism in the evolution of DCS. Decomplemented rabbits appear to be resistant to DCS.53 In humans, erythrocyte-bound C3d increases after repetitive dives, although there does not appear to be a correlation between complement activation and ultrasound bubble score.54 Some studies have demonstrated a relation between complement activation and susceptibility to DCS in humans55,56; however, others have failed to confirm it.57,58 Complement does not appear to be necessary for bubble-induced endothelial damage.59 It is possible that the different strength of evidence for a role of complement in rabbit versus human DCS reflects species specificity.

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Maternal-Fetal Immunology

Mark B. Landon MD, in Gabbe's Obstetrics: Normal and Problem Pregnancies, 2021

Tolerance Through Regulation of Complement, Chemokines and Cytokines

Local inhibition of complement activation in the placenta may be important in preventing fetal rejection or preterm labor, particularly in the setting of inflammation or infection. In a murine model of abortion induced by antiphospholipid antibodies, protection against abortion was conferred by antagonizing factor B, an alternative complement component. Defects of placental formation were also observed in a murine model associated with activation of the alternative complement pathway and maternal C3. Finally, several negative regulators of complement are expressed by trophoblast cells, including CD59 (MAC antagonist), membrane cofactor protein, and decay accelerating factor (inhibitors of C3 and C5 convertases).69 When a negative regulator of murine complementCrry was genetically ablated, embryo survival was compromised and placental inflammation observed.70 C3 activation plays a major role in fetal rejection in this model, because the embryos survived when genetically deficientCrry mice were mated to C3-deficient mice.Several studies suggest that inhibition of complement activation may contribute significantly to fetal tolerance particularly in the setting of inflammation.

Expression of chemokines and some cytokines at the maternal-fetal interface could be dangerous for the fetus, because these small proteins may be inflammatory and may attract immune cells.Regulation of chemokine expression (CXCL9, CXCL10, CXCL11, CCL5)by decidual stromal cells in mice was found to prevent the accumulation of T cells in the decidua after an inflammatory challenge.53 Chemokine expression was effectively silenced by epigenetic changes that involve histone repressor marks on chemokine gene promoters that appeared after transformation of endometrial stromal cells into decidual stromal cells. T cells are known to be relatively rare in decidua, which may be the result of a lack of chemokine production by decidual stromal cells.

The presence and quantities of cytokines in the decidua reflect, in part, the balance of multiple CD4+ T helper cell subsets.Shifts in CD4+ T helper cell subsets and cytokine profiles have been hypothesized to impair fetal tolerance.71 Historically, only the Th1/Th2 subsets were analyzed and it was thought that a Th2-type immune response predominated during healthy pregnancy. Although several studies reported a Th2-type profile in the blood of healthy pregnant women, not all studies supported the Th2 bias.72–74 In an early study of Th17 cells in pregnancy, it was observed that quantities of Th17 cells were increased in the decidua compared to the peripheral blood of healthy pregnancies; this observation was surprising because Th17 cells are typically proinflammatory.75 Further, secretion of CCL2 by decidual stroma cells recruits Th17 cells into the decidua, where IL-17 enhances trophoblast invasion in the first trimester to establish normal placentation.76 Th17 cells may also play a role in enhancing progesterone secretion, which is critical for maintenance of fetal tolerance.77 Despite an important role for Th17 cells in placentation and tolerance, elevated levels of Th17 cells in the chorioamniotic membranes are associated with preterm birth and acute chorioamnionitis; in this case, an excess of Th17 cells may facilitate the inflammatory response.Newer paradigms focused on CD4+ T helper cell subsets in the maintenance of fetal tolerance emphasize the importance of a healthy balance between Th1, Th2, Th17, and TREG cells.71

(Video) Complement System Made Easy- Immunology- Classical Alternate & Lectin pathway

Leukocytosis and Leukopenia

Nancy Berliner, in Goldman's Cecil Medicine (Twenty Fourth Edition), 2012

Neutropenia Due to Increased Margination and Hypersplenism

Complement activation can result in both acute and chronic neutropenia as a result of increased margination of the circulating neutrophil pool. This is attributed to the fact that C5a renders neutrophils more adherent and thereby prone to aggregation within the pulmonary vasculature. This has been seen in patients suffering from burns and transfusion reactions. Complement activation may also lead to neutrophil destruction, as in paroxysmal nocturnal hemoglobinuria. The circulating neutrophil pool can also be diminished in association with hypersplenism, although this is typically less common and less pronounced than the anemia and thrombocytopenia seen in patients with an enlarged spleen.

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Antiphospholipid Syndrome

Tatsuya Atsumi, ... Takao Koike, in Systemic Lupus Erythematosus (Fifth Edition), 2011

Antiphospholipid antibodies andcomplement activation

Complement activation has received much attention since it was determined to be relevant to the pathophysiology of APS, especially with regard to pregnancy morbidity [198]. Placenta trophoblast cells are targeted by phospholipid-binding protein–aPLs complexes, leading to activation of the complement cascade through the classical pathway. C3 and subsequently C5 are activated. Generated C5a recruits and activates polymorphonuclear leukocytes and monocytes and stimulates the release of mediators of inflammation, which ultimately results in thrombosis and fetal injury.

Elevated levels of C3 and C4 predicted subsequent miscarriages in patients with unexplained recurrent pregnancy loss [199]. Moreover, higher levels of complement activation products were detected in the plasma of APS patients with cerebral ischemic events compared to patients with non-APS-related cerebral ischemia [200].

The involvement of complement activation in the pathogenesis of thrombosis is supported by data from animal models. Pierangeli etal. [201], using an in vivo murine model of thrombosis and microcirculation, showed that activation of complement C3 and C5 by aPLs mediates the induction of thrombosis and the activation of endothelial cells. Fischetti etal. [202] demonstrated the implication of complement in the development of thrombosis in a rat animal model. In this in vivo animal model, polyclonal IgG aPLs purified from the serum of APS patients were transferred to rats pretreated with lipopolysaccharide. Rats receiving IgG aPLs developed thrombus, whereas those receiving polyclonal IgG from healthy subjects did not.

Oku and colleagues [203] have clarified the profile of complement activation in patients with APS. The serum complement levels were clearly lower in patients with primary APS than in healthy persons or controls with non-SLE rheumatic diseases. The hypocomplementemia was related to consumption of complement as a result of complement activation. In primary APS patients, the serum complement levels correlated with LA activity and plasma levels of tumor necrosis factor-α, implying that complement activation induced by aPLs may be one of the responsible mechanisms of the thrombophilic state in APS.

The IgG isotype of aPLs is the most frequently found isotype in patients with APS, and the IgG2 subclass is the most prevalent [204, 205]. IgG2 and IgG4 subclasses have a relatively weak ability to fix complement via the classical pathways; thus, other additional mechanisms may be involved in the enhancement of complement activation in patients with aPLs. The inflammatory process accompanied by complement activation is an important phenomenon that mediates the crossroads between the immune response and thrombosis.

(Video) The Complement System: Classical, Lectin, and Alternative Pathways

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The complement system

Maria Alice V. Willrich, in Contemporary Practice in Clinical Chemistry (Fourth Edition), 2020

Complement activation products

Complement activation may be assessed by measurement of complement activation fragments or split products, which reflect the stimulation of any of the activating pathways. The main challenge for analysis of the activation fragments is to stabilize the sample, so that complement activation is inhibited in vitro. Plasma samples are required for the majority of the tests in this category, especially when performed by reference laboratories, because time to analysis and transportation play a significant role in accidentally activating the complement system in vitro.

The main methodologies available for analysis of activation fragments are ELISAs or fluid phase immunoassays using electrochemiluminescent detection approaches [14], which may use polyclonal or monoclonal antibodies against the many different unique epitopes to each of the specific fragments. Cross-reactivity is a challenge, and different assay manufacturers do not use antibodies for the same targets, making study results inconsistent and reference intervals very different, all of which should be taken into consideration when interpreting results.

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The Antiphospholipid Syndrome

Jacob H. Rand, Lucia R. Wolgast, in Hematology (Seventh Edition), 2018

Antiphospholipid-Mediated Activation of Complement

Complement activation has also been proposed to play a significant role in the APS disease process. Evidence from a mouse model has indicated that blockade of complement activation using a C3 convertase inhibitor or genetic deletion of C3 protected against pregnancy complications induced by aPL antibodies. Complement activation in APS appears to involve aPL antibody-stimulated direct injury to endothelial cells and monocytes, promotion of cell lysis and inflammation, modulation of downstream signaling via protease activated receptor-2 (PAR-2), and enhanced expression of tissue factor by myeloid cells. In addition, anti-β2GPI antibodies may interfere with the role of β2GPI as a regulator of the complement cascade.

Complexes of β2GPI and human leukocyte antigen (HLA)-DR7 have been found in uterine decidual tissues from placentas of patients with APS, but not on normal placentas. aPL antibodies that recognize these β2GPI–HLA-DR7 complexes on cell surfaces can trigger complement-mediated cytotoxicity. This mechanism may play a role in the pregnancy complications of APS.

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(Video) 𝐀𝐜𝐭𝐢𝐯𝐚𝐭𝐢𝐨𝐧 𝐎𝐟 𝐂𝐨𝐦𝐩𝐥𝐞𝐦𝐞𝐧𝐭 𝐒𝐲𝐬𝐭𝐞𝐦 𝐈𝐦𝐦𝐮𝐧𝐨𝐥𝐨𝐠𝐲 [𝐇𝐃 𝐀𝐧𝐢𝐦𝐚𝐭𝐢𝐨𝐧 ]

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Creating Animals for Cell Xenotransplantation

David White, in Cellular Transplantation, 2007

Regulators of Complement Activation (RCA)

Complement activation triggers powerful effector mechanisms against which host cells must be protected. Regulatory proteins of the complement system provide a means of preventing lysis of the organism's own cells (autologous lysis). These regulatory proteins may be classified into two categories:

•

Inhibitors that down-regulate activation of complement in the fluid phase

•

Regulators that control complement activation on target cells

A range of proteins fall into the second category of regulators. These include the following proteins.

•

C1 inhibitor

•

Decay accelerating factor (DAF, CD55)

•

Membrane cofactor protein (MCP, CD46), factor H, complement receptor 1 (CR1, CD35)

•

Complement receptor 2 (CD21)

•

C4 binding protein (C4bp)

•

CD59

All of these proteins are involved in down-regulating complement action on host tissue. C1 inhibitor acts at the initial stage of the complement cascade, inhibiting C1 activation. CD59 functions by inhibiting the assembly of the MAC. The final common pathway of both the alternative and the classical complement pathway is the production of C3b, controlling both the alternative and classical pathways. DAF, MCP, and the other RCA molecules act at this critical stage of C3 activation.

There is a degree of species specificity in the action of complement regulators. Indeed, complement regulatory molecules help separate self from non-self. Thus, pig RCA is not active against human complement and human regulators and is only partially active in nonhuman primates. Atkinson and colleagues have discussed these concepts in detail [2].

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FAQs

What are the 3 pathways of complement activation? ›

Complement Activation during Normal Homeostasis and Pathogen Infection. The central component of the complement system is C3. The activation of each of the three pathways (CP, LP, and AP) results in cleavage of inactive C3 protein into the functional fragments C3a and C3b.

What are the 3 important outcomes of complement activation? ›

Its activation results in three major potential outcomes for microbes: cell lysis upon assembly and insertion of the terminal membrane attack complex (MAC), complement mediated opsonization, and the release of anaphylatoxins that enhance local inflammation.

Why is complement activation important? ›

Complement activation mediates the removal of microorganisms and the clearance of modified self-cells. Thus, complement regulators are important for preventing host cell damage and the inappropriate removal of modified self-cells. Complement dysregulation is known to be involved in several autoimmune diseases.

What are the components of complement activation? ›

The complement activation products C1q, C3a, C4b, and C3b are recognized by specific receptors on cell surfaces that control cell functions (Table 3).

What are the 4 functions of complement? ›

The complement system has four major function, including lysis of infectious organisms, activation of inflammation, opsonization and immune clearance.

What are the main functions of complement system? ›

The principal function of the complement system is protection of the host from infection/inflammation by recruiting (chemotaxis) and enhancing phagocytosis by innate immune cells (opsonisation), leading to lysis of the target cells.

What are the main effects of complement activation? ›

Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules.

What happens after complement activation? ›

Complement activation triggers powerful effector mechanisms against which host cells must be protected. Regulatory proteins of the complement system provide a means of preventing lysis of the organism's own cells (autologous lysis).

What are the harmful effects of complement activation? ›

However, harmful inappropriate or excessive complement activation can lead to tissue injury with serious consequences including death. This is normally avoided by a number of circulating (C1 inhibitor, factor H, C4b-binding protein) and membrane-associated (CD46, CD55, CR1, CD59) complement regulators [6].

What is the principle of complement? ›

complementarity principle, in physics, tenet that a complete knowledge of phenomena on atomic dimensions requires a description of both wave and particle properties. The principle was announced in 1928 by the Danish physicist Niels Bohr.

What are the applications of complement? ›

In set theory, complement refers to all the objects in one set that are not in another set. Complements are used in digital circuits, because it is faster to subtract by adding complements than by performing true subtraction. The binary complement of a number is created by reversing all bits and adding 1.

Where is complement found in the body? ›

The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the innate immune system. The complement system consists of a number of small proteins found in the blood, made by the liver. Normally they circulate as inactive precursors.

Where do the 3 complement pathways converge? ›

All three pathways of complement activation converge in the terminal pathway. The terminal pathway begins when C5b binds to C6. C7 then binds to the C5b-C6 complex and the newly formed C5b-C7 complex inserts into the target membrane.

Which of the three complement pathways becomes activated soonest? ›

Which of the three complement pathways becomes activated soonest after an initial infection? the alternative pathway.

What are the three most important products of the complement system? ›

Activated complement generates three major types of effectors: (1) anaphylatoxins (C3a and C5a), which are potent proinflammatory molecules that attract and activate leukocytes through interaction with their cognate G-protein–coupled receptors, C3a receptor (C3aR) and C5a receptor (C5aR); (2) opsonins (C3b, iC3b, and ...

How is the classical pathway of complement activated? ›

The classical complement pathway is activated by antibody–antigen complexes on the bacterial surface and has been considered predominately to be an effector of the adaptive immune response, whereas the alternative and mannose-binding lectin pathways are activated directly by bacterial cell surface components and are ...

What are the effects of complement activation? ›

Complement activation leads to opsonization and phagocytosis by C3b deposition, bacterial lysis by C5b–9 complex formation and inflammation by recruitment of immune cells, endothelial and epithelial cells activation, and platelets activation.

Which antibodies can activate complement? ›

It is well known that both IgG and IgM can activate complement via the classical pathway by binding of C1q to the Fc regions of these immunoglobulins. Recent advances have shown that also IgA is capable of activating the complement system.

What are the types of complement system? ›

There are three pathways of complement activation: the classical pathway, which is triggered directly by pathogen or indirectly by antibody binding to the pathogen surface; the MB-lectin pathway; and the alternative pathway, which also provides an amplification loop for the other two pathways.

Where does complement activation occur? ›

Complement can be activated through three pathways: classical, lectin, and alternative. The classical pathway is activated when C1q binds to antibody attached to antigen, activating C1r and C1s, which cleave C4 and C2.

What regulates the complement pathway? ›

The complement system is regulated by complement control proteins, which are present at blood plasma and host cell membrane.

Where is complement produced? ›

The bulk of the complement proteins that are present in serum are produced and secreted by the liver, in particular by hepatocytes.

Which type of antibody is most effective in activating complement? ›

IgM is specialized to activate complement efficiently upon binding antigen. IgG antibodies are usually of higher affinity and are found in blood and in extracellular fluid, where they can neutralize toxins, viruses, and bacteria, opsonize them for phagocytosis, and activate the complement system.

What is the most important complement component? ›

The complement system is made up of a collection of proteins found in the bloodstream and is comprised of nine major complement proteins; complement C3 is one of them.

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