Introduction

The complement system (CS) is one of the first lines of innate immune defense and plays an important role in the homeostasis of adaptive immunity response. In humans, it was identified as the heat-labile component of serum that assists, or complements, the action of antibodies which are in charge of killing bacteria. In addition, the CS comprises more than 60 plasma and surface proteins. These are covered by nine central components of the cascade (C1 to C9), multiple activation products (such as C3a and C3b), regulators and inhibitors (e.g. Factor H and C4BP), proteases and newly assembled enzymes (e.g. C4b2a and Factor B), or effector molecule receptors (such as C3aR and C5aR) (Tables 1–3). However, this system works with inactive components that are activated sequentially as a cascade. Thus, the inactive zymogens together with additional components become effector compounds or active enzymes when they encounter a biological surface with the ability to activate the complement system. All of this process will actives new substrates (1,2).

Table 1

Components of the complement cascade.

Table 2

Regulatory factors of complement system.

Table 3

The complement system receptors.

The complement proteins in plasma are more than 3 gr. per liter, which means that they constitute 5% of total plasmatic proteins (10% of the total proteins) and more than 15% of the globular fraction of plasma. Moreover, the nomenclature of complement proteins is given by their historical discovery. The fragments generated during the activation process are designated by a letter. Generally, if the fragment is large, it is labeled “b” and if it is small, it is labeled “a”. However, C2 is an exception: in this case C2a is the biggest one (1). The components of the CS are involved in immune surveillance and in the maintenance of homeostasis in physiological and in stress conditions (3). Thus alterations in complement proteins may trigger diseases states (Figure 1). These proteins interact with non-immune cells (epithelial cells, osteoclast, etc) (4), innate immune cells (macrophages, dendritic cells (DCs), neutrophils, mast cells, eosinophils and basophils) (5) and adaptive immune cells (B and T cells) (6).

Figure 1

Role of complement in the homeostasis and in conditions of stress. Adapted from reference (3).

The majority of complement proteins are synthesized in the liver, but other cells can also produce them. The main source of C1q is DCs, macrophages, and epithelial cells from the spleen, bowel, thymus, lung and heart. It can also be produced by osteoclasts (7). Specifically, the kidney cells produce C3 and C4, spleen cells C6 and C8, fibroblasts C2, C3, C5 and C9, adipocyte factor D, and pneumocyte C3 and C9. In addition, immune cells such as polymorphonuclear (PMN) can also produce complement factors like C7, C3 and C6 while DCs produce C7, C8 and C4BP regulatory proteins (8). Another protein such as properdin is synthesized by neutrophils, monocytes/macrophages and T cells (9).

The CS has multiple functions. It triggers an immune response to foreign pathogens (1), has pro-inflammatory activity (10), regulates cytokine production (11), helps to remove immune complex and dead or modified cells (following injury, hypoxia, after virus-infection or tumor-caused modification) (12). CS can also regulate tolerance to self-antigens (13), and it plays an important role in immunoregulation of adaptive immunity (14). Other physiological functions attributed to CS are angiogenesis, mobilization of hematopoietic stem/progenitor cells, lipid metabolism, coagulation pathway, calcium metabolism, organ regeneration and neuroprotection (including in migration of neurons and synapse elimination) (2,1).Because of their many functions and the implications in the pathogenesis of several diseases, complement proteins are used as biomarkers of disease (15,16). Recently, complement proteins within tissues have been observed in the murine model through radiologic imaging (17).

The complement cascade

Complement activation can be done through three pathways: classical, lectin and alternative (Figure 2).This mechanism is dependent on the external factors. The activation occurs sequentially manner and can be divided into four main steps: 1. initiation, 2. C3 convertase activation and amplification, 3. C5 convertase activation, and 4. terminal pathway activity or membrane attack complex (MAC) assembly. Moreover, the progression of the cascade and the action of the effector molecules are strictly controlled at each level by multiple regulators and inhibitors proteins which are present on normal host tissues (2). The cascade can also be activated by other means such as coagulation system components (18).

Figure 2

The complement cascade.

The classical pathway (CP) is activated by antibodies once those bind to antigens. When this complex is formed the fraction fields (Fc) of IgM, IgG3 and IgG1 interact with the collagen-like tail of C1q. Some pathogens, polyanonic molecules, C reactive protein (pentraxin), DNA, RNA and apoptotic bodies can also activate the CP (19,20).

C1 complex is made up of three proteins (C1q, C1r, and C1s). Likewise, when C1 complex is activated at least two of its six sites in the globular domains should bind to the Ig linked to the pathogen. After this binding, C1q goes through conformational changes that lead to the activation of C1r and cleavage of C1s. At this point, there is also cleavage of C4 and C2 by C1s. The C4b fragment produced by cleavage binds to the cell membrane of the pathogen and allows the binding of C2a. After that C1s cut C2 into C2a and C2b thus forming the C4b2a complex (classical C3 convertase). C4b2a cuts C3 to make C3a and C3b. This step is common to all three complement pathways and is the one all of them have to take to activate complement cascades (21). C4b and C3b bind to the target cell surface through a covalent binding reaction (22). In addition, the C reactive protein recognizes PAMP (Pathogen-associated molecular patterns), DAMP (Damage- associated molecular patterns) on apoptotic and microbial cells and binds to C1q to activate CP. Factor H-related protein 4 (CFHR-4) recruits monomeric C reactive protein from necrotic cells to facilitate activation of CP by C1q (3).

The lectin pathway (LP), like the CP, used the same C4b2a convertase and differed in its recognition and activating factors. Moreover, this pathway does not require antigen-antibody complex. The LP is activated by the binding of C-type lectin and MBL (mannose-binding lectin), or proteins termed ficolins (L-ficolin, H-ficolin and M-ficolin) to some carbohydrates that are rich in mannose and beta glycans respectively. MBL and ficolins may form a complex with MBL-associated serine proteases (MASPs1, 2, 3), and with a smaller molecule called MAP19. MBL and ficolins are structurally similar to C1q, but unlike the latter, MBL is a well-characterized receptor of the collectin family. It was given this particular name because it has a collagenous domain with a calcium-dependant lectin domain. MBL is synthesized in the liver and secreted into the plasma as a component of the acute-phase response. Therefore, MBL can bind to common carbohydrate PAMPs from bacteria, viruses, fungi and parasites. Once it is activated, MBL-MASP complex leads to C4 cleavage by MASP2 and C2 cleavage by MASP1 and MASP2, which results in C3 convertase (14-23). A new mechanism in vitro called “by-passing” has been described and this occurs when target-bound MBL directly actives C3 in the absence of C4 and C2 (24).

While the CP and LP are activated exclusively by exogenous material, the alternative pathway (AP) is also constantly active at low levels in the host, an phenomenon called “C3 tickover” (25). In this process C3 suffers structural changes by spontaneous hydrolysis of the thioester bond, thus resulting in iC3 or C3 (H2O)). At this point, the presence of factor H is fundamental because it inhibits the progression of AP. However, if the iC3 does not bind to the surface of target cells, it remains in the fluid phase and could easily be inactivated. Once the iC3 binds to factor B fraction Bb, it forms iC3B, which is cleaved by factor D to make C3bBb complex (C3 convertase of AP). At the same time, this complex is stabilized by properdin (Factor P) (26), a protein which is released by active neutrophils, macrophages and T cells. This protein stabilizes the C3 convertase and can also initiate the activation of AP by the recognition of PAMPs, DAMPs or apoptotic cells (27).

C3 is a key mediator in the function of all three pathways activation. It circulates as a two-chain molecule (α and β) which is held together by multiple inter-and intra-chain disulphide bonds (20). Once C3 is cleaved by a C3 convertase, it is divided into C3b and C3a. The latter fragment plays a role in the innate immunity cells and has antifungal and antimicrobial activity. C3b, in turn, coats the microbial or apoptotic cell body surface and the cascade can progress. If the cascade progress, C3b binds to the previous C3 convertase and results in C5 convertase (C4b2a3b from CP and LP, and C3b2Bb from the AP). During the cleavage of C3b, iC3b, C3c, C3d/dg are produced and they have several functions (Table 1). Furthermore, C5 convertase cleaves C5 into C5a and C5b. C3a and C5a are anaphylactic peptides (activate neighboring cells to release inflammatory mediators). C5b, turn, starts the terminal pathway (2). In the AP, the Bb portion can also cleave C3 and thus generate C3b and C3a. C3b can bind randomly and covalently to cell or macromolecular surfaces. Once this factor is deposited, it can attract more factor B, which will be cleaved by properdin to form C3 convertase. If more C3b binds to this convertase, this will produce C5 convertase, which in turn will activate and assemble MAC. All of the process described above is called a feedback loop (26).

C3 may also be activated by independent pathways such as proteases that are released by neutrophils and macrophages. However, other factors such as kallikrein, plasmin, elastase and factor XIIa can activate it (18). In contrast, thrombin cleaves C5 and generates C5a in the absence of C3 (28).

Once C5b is released, it binds to C6 to form the complex C5bC6. This binds with the target cell surface to establish the place where the other components of MAC will join it. Furthermore, C5bC6 also binds to C7 on the target surface to induce the C8α and β membrane insertion and thus create pores in the phospholipid bilayer in the target cell. C8α binds to C9and starts the polymerization of multiple C9 molecules to make pores with a diameter of 10nm. Finally, the C5b6789 complex is called MAC and it will cause the target cell to undergo osmolar changes by the entry of water, ions and other molecules. This will lead to cell lyses, and productions of cytokines, prostaglandins and other proinflammatory molecules (14).

During the complement cascade, small peptides named anaphylatoxins (ATs) are liberated. These peptides are C3a (77 amino acids) and C5a (74 amino acids) and have antimicrobial properties though C5a is more potent than C3a. The ATs are regulated by carboxypeptidase N (CPN) which is a plasma protease that cuts off the C-terminal arginine and yields an inactive form of C3desArg and C5desArg (29).The functional response is mediated by a superfamily of G-protein-coupled receptors: C3aR, C5aR (CD88) and C5L2 (C5a receptor-like 2, known as gpr77). These ATs can also bind to the fmlp-receptor (N-formyl-methionine-leucine-phenylalanine), ChemR23, and the chemokine receptors (CXCR1 and CXCR2) (10).

The ATs are very important in inflammatory responses because they enhance cytokine production (30), induce vasodilatation by the relaxation of smooth muscles, and induce permeability in small blood vessels.

C5a is the most powerful AT to induce chemiotaxis of macrophages, neutrophils, basophils, mast cell, and activated B cells and T cells. When ATs interact with basophils and mast cells, the latter two produce histamine. However, in addition to their pro-inflammatory properties, they are involved in tissue regeneration and tissue fibrosis (10).

The complement regulatory factors

The CS has regulatory factors that maintain the immunological homeostasis. Alterations in these regulatory factors can cause tissue damage triggered by all pro-inflammatory molecules.

The cascade has a passive control activation generated by C4b and C3b active sites which have a short half-life in contrast with the C4b2a complex (CP and LP) and C3bBb complex (AP) which are unstable. Control is also handled by regulatory proteins which are located in serum (fluid-phase) and on the surface of the endothelial and immune host cell (Tables 2–3). These are in constant contact with complement proteins and express multiple inhibitory regulatory proteins: membrane co-factor protein (MCP; also known as CD46), decay-accelerating factor (DAF, also known as CD55), complement receptor 1 (CR1; also known as CD35), and protectin (CD59). Another protein which regulates the action of CS is the factor H (the same one that acts on AP) that interacts with the endothelial cell surface and with components of the coagulation cascade (31,32).

The regulatory factors have four important functions in the cascade (Figure 3). (I) The C1 inhibitor (C1inh) blocks the initiation of the cascade by preventing the onset of CP and LP and binding to C1r, C1s and MASP1-2. It also inhibits AP activation but the location is still unknown (33). In addition, LP may also be inhibited by sMAP (MAp19) and MAP-1 (MAp44) which bind to MBL and ficolins (3). (II) Multiple regulatory factors act downstream once the cascade is activated and just before C3 convertases are assembled. At this point, there is an inhibition of C3, C4 and iC3 by factor I and its co-factors such as C4b-binding protein (C4BP) in the CP and LP and factor H in the AP. Note that factor I only acts when it is coupled with its co-factors (34). CR1 and MCP are also involved at this point and act as cofactors with factor I to inactivate iC3 and C4b (35). Therefore, CR1 is an immune adherence receptor for iC3/C4b and together, they remove immune complex (36). CR1 on red cells can transport immune complex coated by CS to the spleen and liver where they are depurated by tissue macrophages. Furthermore, in the CP and LP another regulatory factor known as complement C2 receptor inhibitory trispanning (CRIT) was recently discovered. This factor binds to C2 and prevents its cleavage by C1s (37).There are other regulatory factor that inhibit iC3 such as factor H-like protein 1 (CFHL-1) (38) and complement regulator of the immunoglobulin superfamily (CRIg) which are expressed in macrophages and Kupffer cells (39). (III) Regulatory factors are also involved in the inhibition of C3 and C5 convertase amplification by destabilizing the enzyme complex. As was mentioned before, C3 convertases are the main factor in the amplification on the cascade in the three pathways. However, this convertase is inhibited by C4BP, CR1, and the DAF in the CP and LP. In contrast, the C3 convertase in AP is inhibited by factor H, DAF, and CR1 which also inhibit C5 convertase at the same time. Another factor that can be inhibited is C3b. This inhibition is caused by the action of regulatory factors such as factor H, MCP, CR1, factor I and CRIg. As was mentioned above, ATs are important in pro-inflammatory processes and these proteins will be inhibited by CPN (40). (IV) Regulatory factors such as vitronectin (S-protein), clusterin (SP-40, also known as apolipoprotein J), CFHL1, and protectin play an important role during assembly of MAC. The two first factors interact with C5b-7 complex (41,42) while CFHL1 binds to C5b/C6 (43), and protectin binds with C8/C9 and inhibits the formation of the lytic pore (44).

Figure 3

The regulatory factors. Abbreviations: C4BP:C4-binding protein; MCP: Membrane Cofactor protein; CR1:Complement receptor 1; CRIT:C2 receptor inhibitor trispanning; CPN: Carboxypeptidase-N; CRIg: Complement receptor of the immunoglobulin family; CFHL1: (more...)

The complement receptors

The complement activation products C1q, C3a, C4b, and C3b are recognized by specific receptors on cell surfaces that control cell functions (Table 3). Complement receptor 1 (CR1, also known as CD35) is the principal immune adherence receptor on erythrocytes, and it allows the binding and bloodstream clearance of complement-coated immune complexes. This receptor is also expressed in follicular DCs (fDCs) to retain antigen within lymphoid follicles. Moreover, when CR1 is recognized by C1q, C4b, C3b, and iC3, it promotes phagocytosis (36). Another receptor is complement receptor 2 (CR2, also known as CD21) which interacts with C3b and C3d on B cells, fDCs, tonsils, and the lymphoid node. Just as in the case of CR1, CR2 allows the antigen to be transferred into the lymphoid node and to be retained in germinal centers in order to preserve the immunological memory (6,20,45). Another receptor is complement receptor 3 (CR3, known as CD11b-CD18). It is present in NK cells, PMN, microglia, and phagocytes. In the last one on the list, it interacts with an iC3-coated target cell to promote its elimination in secondary lymphoid tissue. CR3 captures and transports the antigen coated with C3 to B cells (46). Just as in the case of CR3, complement receptor 4 (CR4, known as ITB2 and CD11c/CD18) is present in phagocytes and has a similar function (20). There are other receptors which are present only in DCs and microglia cells such as SIGNR1 which binds to C1q and inhibits the assembly of C3 convertase (47). Furthermore, we can find other types of receptors, which are specific to the aforementioned ATs (C3aR, C5aR, and C5L-2). These are present in several inflammatory cells and smooth muscle cells and their purpose is to promote inflammatory reaction. C5L-2 acts as a decoy receptor (48,49).

The complement system and adaptive immunity

Complement system and B cells. The B cells are involved in several functions: to produce antibodies, lead to neutralization and opsonization of pathogens, and provide immunological memory about infection (See chapter 6). The CS plays key roles in multiple stages of B-differentiation (6). Those stages are achieved by complement receptors, CR1 and CR2, that also bind to opsonins to improve the phagocytic system. Note that CR2 interacts with humoral adaptive immune system three different ways. The first one is by forming CR2-CD19-CD81 complex, which interacts with BCR and thus results in the reduction of B cell clonal expansion. The second is when CR2 is present on fDCs to capture C3d-opsonized antigen and present it to naïve or antigen-engaged B cells in the germinal center of the lymph node, thus generating effectors and memory B cells. And the last one is enhance the delivery of antigen to fDCs (50). Moreover, the ATs such as C3 and C5, apparently help in the expression of B cells, which promotes the trafficking and migration of various B cells populations (14).

Complement and T cells. T cells are activated by interaction with antigen presenting cells (APCs) in lymph nodes. The activation is dependent of microorganisms and environmental factors (first and second signal) (See Chapter 7 and 10). Once activated T cell migrate to inflammatory sites and continue the immunological response. The CS can modulate T cells directly or indirectly though the alteration of immunomodulatory cells (APCs) (51).

The role of CS on T cells has been suggested in murine models. C3-deficient mice were depleted of CD4+ and CD8+ T cells in the presence of viral infections. In contrast, DAF deficient mice had enhanced T cell proliferation (14,52).Furthermore, murine models with complement deficiency attenuate T cell mediated autoimmunity and delay allograft rejection. Increased complement activation results in autoimmune disease and accelerated allograft rejection (53). Moreover, APCs and T cells express C3aR and C5aR which bind to complement proteins to enhance T cell viability, proliferation and differentiation (54,55).

It has been recently discovered that during the antigen presentation to T cells, there are a variety of signal expressions to induce C3a, C5a, factor B and factor I as well as promote the up regulation of C3aR and C5aR, and the transient down regulation of the complement regulator DAF on T cells and APCs. However, when there is an absence of APC activation, it will lead to a deficiency of ATs with a subsequent induction of Treg cells (56).

The complement system and infectious diseases

The CS has five specific functions to defend the body from bacteria. The first function has to do with the phagocytosis and opsonization of microorganisms through the binding of C3b and iC3 to complement receptors, which are expressed on phagocytes, and PMN. The second is the chemotaxis and activation of granulocytes by ATs which induce inflammation. The third function is to lyse foreign pathogens through MAC formation. This complex is only effective against pathogens without cell walls in which the best effector mechanism is opsonization (57). In the fourth function, CS will interact with B lymphocytes to produce antibodies that are important in the activation of adaptive immunity (58). Finally, the last one regulates T cell activation and its effector function (14).

However, activation of CS in normal conditions is caused by bacteria invasion by three different pathways. On the first pathway, the antibody recognizes the bacteria and actives the CP. On the second, the LP is activated by sugar moieties on the bacterial surface while the AP is activated by the presence of carbohydrates, lipids and proteins on the bacteria. And the third one is when C3b coats the bacterial surface and enhances their recognition by neutrophils and macrophages to promote opsonization. Nevertheless, there are other mechanisms helping with bacterial opsonization such as activation of iC3 that interacts with CR3 and CR4 in phagocyte cells. In addition, C3b could bind to CR2 to produce antibodies which will enhance the immunological response and finally produce bacterial lyses by MAC assembly (59).

Even so, the bacteria have five ways to evade the immune response: a) It mimicking and recruiting complement regulators, b) enzymatic degradation of complement proteins, c) inhibition or modulation of complement proteins, d) inhibition of Ig before its interaction with complement, and e) blockage of MAC penetration (Table 4) (59).

Table 4

Bacteria with ability to avoid the complement system.

The CS may also play a role in immune response to viral infections through recognition of several viral glycoproteins by MBL. The viruses that are reportedly capable of activating MBL are HIV, SARS, coronavirus, Ebola, dengue, West Nile and Marbug virus (60,61). In a murine model, the CS is required for enhancement of T cell response to viruses(60). However, the CS could be involved in humoral response through the complement receptor (CR1-2-3), which recognizes C3b on IgM, and IgG coated viruses. However, like bacteria, the viruses may evade the immune response by three mechanisms: a) entering host cells, b) modifying C1q or C3, and c) using the host complement regulatory proteins or virally produced proteins to prevent cell lyses (59).

Moreover, the three CS pathways (CP, LP and AP) can be activated in response to parasites. Mainly, LP will be mainly activated through PAMPS on the parasite surface during early infections while the parasites with the ability to evade activation of CS can still be detected by CP after the production of antibodies (62). Nevertheless, some parasites such as trypanosomes can prevent complement activation by the expression of complement receptors which inhibit of C3 convertase. Other strategies are the stabilization and inhibitionof C4b2a (62).

Activation of CS can be achieved by fungal infections. The main factors that act against fungal infection are ATs, C3a and C3b. The C3a has antifungical activities and C3b is involved in the opsonization. Both factors deposit on the fungal surface and activate the CS to assemble the MAC (63). Recently, it was also found that Candida infection activates C5a to stimulate PBMCs to induce pro-inflammatory cytokines (IL-6 and IL-1β) (64). Note that the pathogens described above utilize the CS to increase their virulence. Some intracellular bacteria, viruses and parasites use cell-bound complement regulatory molecules and receptors to enter host cells (1,67).

Because the CS is fundamental in the response to pathogens, it will play an important role in septic shock. In such cases, AP and CP are activated to clear endotoxins. However, an alteration in LP may increase the risk of developing sepsis (66). Complement proteins such as C5a, C5aR and C5L2 will have a critical role in the development of sepsis and the activation of immune cells like NK and NKT (67,68). Moreover, a decrease in MASP-2 during early phase of septic shock might be correlated with mortality (69). In conclusion, alterations in CS proteins are associated with major susceptibility to infections but mainly encapsulated bacterial infections (Table 5).

Table 5

Diseases associated with deficiences or defects in complement proteins.

The complement system and dead cell clearance

Another one of the anti-inflammatory activities carried out by the CS is to clear immune complexes in circulation and tissues, apoptotic bodies and cells modified by injury or hypoxia after virus infection or tumor-caused modification. This clearance is mediated by pattern recognition molecule (PRM), opsonins and receptors.

During apoptosis, the cell loses lipid bilayer asymmetry (flip-flop), thus exposing molecules such as phosphatidyl-serine, which in turn will activate pro-phagocityc signals (See chapter 13). If the apoptotic cells are not eliminated, they will continue to secondary necrosis. In this step, the cell cytoplasm swells and loses its plasma membrane integrity which triggers cell rupture. This will cause the exposure of intracellular contents including nucleus (HMGB1) and cytoplasm proteins. These will be recognized as foreign molecules and produce inflammation and/or autoimmune response (70). HMGB1 (High mobility group 1) is an alarmin that participes in chromatin architecture and transcriptional regulation. It is associated with induction of chronic autoimmune diseases (See chapter 9) (71,72).

Furthermore, apoptotic bodies which undergo secondary necrosis are recognized by complement proteins, especially CP. However, the other two pathways can be activated under the same conditions (73). The CS is activated by recognition of plasma proteins (histidine rich protein, IgG, IgM, pentraxine 3, serum amyloid P component, C-reactive protein, annexin A2 and A5) and thus binding to apoptotic cells or DNA/RNA from apoptotic cell surfaces (74,75). The CP, in turn, is activated by binding C1q to the surface of calreticulin (also known as collagen-tail C1q receptor, cC1qR) which forms a complex with the endocytic receptor protein CD91 (also known as α-2-macroglobulin or the LDL-related receptor protein, LRP) and other receptors such as CR1, CR2, CR3, CR4 and CRIg, thus promoting phagocytosis (74). Moreover, C1q elicits a specific macrophage phenotype for the removal of apoptotic bodies (76). Once the C1q binds to apoptotic cells, it amplifies the CP and recruits factor H, which inhibits the amplification of CP and C5 convertase formation, thus protecting host cell against unwarranted inflammation (3). A deficiency in C1q may lead to impaired immune complex formation and apoptotic clearance (77).

In contrast, the LP may be activated by MBL bound to late apoptotic and necrotic cells (74). MBL is found in apoptotic cells that express a terminal sugar from cytoskeletal proteins, which makes it possible for macrophages to recognize them and facilitate their phagocytosis (78). As was mentioned earlier in this chapter, LP may be also activated by ficolin B which marks apoptotic and necrotic cells for subsequent removal and maintenance of tissue homeostasis (79). AP, in turn, may participate in apoptotic cell removal by binding iC3 and CR3 to promote the opsonization and phagocytosis. This process is accompanied by IL-12 down regulation and a lack of oxidative burst in macrophages or co-stimulatory molecule expression that impairs maturation of DCs (3).

The complement system and diseases

The CS is involved in several diseases because of alterations in regulatory proteins and deficiencies in complement proteins. Complement disorders are autosomal recessive except for MBL, factor I deficiency, and C1-INH deficiency, which are autosomal dominant, and deficiency of properdin which is X-linked recessive (80). Genetic defects such as single nucleotide polymorphism (SNP) can result in generation of dysfunctional protein or complete gene deletion. Some diseases associated with complement deficiency or alterations are shown in Table 5 (2,7,26,81-105).

The complement system and atherosclerosis

Atherosclerosis physiopathology is complex and several factors are involved in lipid deposition on vessel wall. Inflammatory proteins such as CS proteins, pentraxines, and cytokines produced by immune cells are involved in this process. The CS protein involved in this mechanism is C5L2. This protein is essential in glucose uptake and lipid and triglyceride clearance by induction of C3desArg (3). Moreover, adipocytes secrete factor D, factor B and C3 which stimulate insulin or lipids. This leads to a high turnover of AP and to generation of C3a (3). C1q, C3, C4 and MAC are present in atherosclerotic lesions while a murine models shows that a deficiency of regulatory proteins (protectin) accelerates atherosclerosis (59). Other studies have shown that CS facilitates macrophage extravasations and foam cell formations, which release proinflammatory factors and enhances atherosclerosis. All this is also related to the CS activation by the coagulation system (59). Note that pathologies associated with alterations in CS such as SLE have an increased risk of developing atherosclerosis (106). That is why complement proteins has also been proposed as biomarkers of atherosclerosis (107) (See chapter 38).

The complement system and ischemia-reperfusion injury

An injury is associated with an interruption of the blood flow (ischemia or hypoxia) and, then, with the subsequent restoration (reperfusion). This mechanism is known to occur in myocardial infarction, stroke, transplantation or vascular surgery. During this catastrophic event, there is an increase in the generation of reactive oxygen species (ROS) and activation of various cell types such as endothelial cells and leukocytes. All of this together increases the production of apoptotic bodies which produce neo-epitopes that will be recognized by antibodies with subsequent activation of CS. The ATs produced by CS activation are involved in neutrophil activation and infiltration, thus resulting in more inflammation, cell injury and necrosis. In animal models with ischemia-reperfusion injuries treated with inhibitors such as anti-C5 antibodies and C5a receptor, it was shown an improvement was shown in early graft functions after transplantation (108). Furthermore, CS is activated during acute stroke, mainly within LP. That is the reason patients with decreased levels of MBL, which causes them to express low levels of C3, C4, and C-reactive protein, have better functional outcomes than patients with normal MBL (109).

The complement system and neurodegenerative diseases

Neuronal cells such as astrocytes and microglia have the ability to synthesize complement proteins while neuronal stem cells express receptors, which migrate and differentiate in response to CS. The CS has functions in the regulation of the neuronal development and synapse elimination (110).

Unfortunately, neurodegenerative diseases do not have a known etiology, but recently it has been suggested that neuron death is preceded by aberrant synaptic functioning and massive synapse loss. Based on this hypothesis the CS, mainly the CP pathway, may play an important role in neurodegenerative disease. This is based on the enrollment of CS in the synapse elimination by recognition of C1q and induction of phagocytosis mediated by C3b or iC3. Therefore, alterations in this process result in neuron loss and neurodegenerative progression such as Alzheimer’s disease, glaucoma, Parkinson’s diseases, multiple sclerosis and schizophrenia (110). In the case of Alzheimer’s disease, amyloid-beta peptides are known to accumulate in the extracellular milieu to form amyloid plaques. As result, these plaques are recognized by C1q and they induce CP triggered neuronal damage (110).

The complement system and osteoarthritis

Osteoarthritis is characterized by breakdown of articular cartilage in the synovial joint. Therefore, CS is fundamental in the pathogenesis of the disease as was shown in several experimental studies in which it is observed complement protein deposits in the synovial (fluid and tissues) and diminished levels of regulatory proteins are observed (111). In MAC deficient mice models, the importance of MAC for the development of osteoarthritis is shown (112).

The complement system and allergy

Allergy is normally associated with Th2 response. However, CS (primarily AP) is involved in the progression of the disease just as it is in inflammatory processes. Some studies in mice models have shown the importance of endogenous factor H in regulating airway inflammation (113). High levels of ATs, in turn, have been detected in high levels in bronchoalveolar lavage fluid form asthmatic patients (26). In addition to being potent chemioattractants to PMN and producing proinflammatory factors, these molecules also contribute to smooth muscle cell contraction and mucus production which enhance vascular permeability. At the same time, ATs inside airways are involved in the balance between mDCs (myeloid DCs) and pDCs. However, alterations in this relation are associated with deregulation in Th cell response and high Th17 response, therefore enhancing the development of allergies (114). There are different experimental models in which inhibition of C3, C5, C3aR and C5aR during the allergic phase decreases the allergy symptoms (114). Because of their importance in allergy pathophysiology, the complement proteins have been proposed as biomarkers (115) and therapeutic targets (116).

The complement system and cancer

CS has a dual role in the development of cancer. During the carcinogenesis process, the CP and AP are activated by recognition of cell debris formed by necrosis and apoptosis. Moreover, CP can be activated by Ig production in order to act against tumor proteins by the host cell. In addition, LP can be activated by MBL-mediated recognition of mannose-containing carbohydrates expressed on the tumor cell surface. Furthermore, MAC has dual role in cancer pathogenesis because it induces cell lyses and also protects from apoptosis, thus promoting cell survival (117). All the proteins mentioned above are detectable in the tumor environment. These include, for example, thyroid carcinoma, adenomas, colon, kidney, gastric, and breast cancer. It is also found in ascitic fluid from ovarian cancer patients (117). CS is involved in several mechanisms within tumor cells. First of all, tumor cells are resistant to CS action, especially that of MAC and CR3. This resistance is due to production of regulatory proteins such as CR1, CD46 and DAF which are important in controlling C3 activation (59). Secondly, ATs bind to receptors on the tumor cells and they induce the production of IL-6, thus resulting in cell cycle progression and apoptosis mechanism inhibition. MAC can also induce these mechanisms (See chapter 13). The last mechanism is tumor cell production of C5a which binds to C5aR on myeloid-derived suppressor cells. This results in increased reactive oxygen and nitrogen species that prevent the activation of CD4+, CD8+, NK and stimulate tumerogenesis and angiogenesis (59) Studies have shown that treatment directed toward C5aR slowed tumor progression (118).

The complement system and autoimmune diseases

Innate immune alterations are crucial for development of autoimmune diseases (ADs), but complement pathway alteration has also been associated. Systemic lupus erythematosus (SLE) is the most studied. However, others have been associated such as Sjogren’s Syndrome (SS), antiphospholipid syndrome (APS), rheumatoid arthritis (RA), vasculitis, multiple sclerosis and dermatomiositis.

SLE is characterized by loss of tolerance to nuclear self antigens originated from dead cell nuclei and associated proteins (See Chapter 25). Alterations in complement pathways, mainly CP, are associated with susceptibility to SLE. It is still not clear what the exact mechanisms involved in SLE pathogenesis are. However, six hypotheses have been proposed to explain the role of the complement in this disease (Figure 4). The first hypothesis is the deficiency in clearance of apoptotic bodies. This alteration may be achieved by C1q deficiencies, thus resulting in disruption of apoptotic body removal which leads to the production of self-antibodies that work against intracellular structures (nuclear, double stranded DNA, and histone antibody). That is the reason why C1q deficiencies increase susceptibility to infections in SLE patients. Therefore, vaccination is recommended for these patients. Moreover, studies have shown that ficolins and MBL are also important in apoptotic body clearance. The second hypothesis is the impairment of immune complex handling by alterations of other CP proteins (Table 5). The third one is how alterations on CS trigger inefficient elimination of self-reactive B cells which in presence of T cells could produce autoantibodies. In normal conditions, self-antigens are coated with CS and delivered to specific B cells, thus producing elimination of self-reactive cells. In the fourth hypothesis, CS is involved in regulation of cytokine production, thus alterations in C1q could not inhibit IFN-α which, which is a very important cytokine in the pathogenesis of SLE. The five hypotheses suggest that complement components might be targets of autoantibody responses. This hypothesis is based on patients with high levels to anti-C1q antibodies which go against C1s and C1 inhibitor. Indeed, in nephritic lupus anti-antibodies could join to C1q presented in the kidney and cause severe tissue damage (99,119). Finally, the last one important mechanisms in which CS is involved in SLE pathogenesis is through activation of neutrophils which may produce neutrophil extracellular traps (NETs).(See chapter 13) (120). In addition, alterations in regulatory proteins (DAF, protectin, CR1) are attributed to lower levels of white and red blood cells. Apparently, this regulatory proteins are involved in the maintenance of blood cells homeostasis (121).

Figure 4

Role of complement in the pathogenesis of Systemic lupus erythematosus (SLE). Adapted from reference (99).

As we know, patients with SLE have hypocomplementemia which may be caused by genetic alterations, protein intake in response to self-antigens, or protein sequestration in tissues (119).

Another ADs is APS. In this disease the CS role is mediated by increased production of ATs and MAC which results in endothelial cell activation, monocyte tissue factor expression and platelet aggregation. It has been shown in murine models that blockage of the C5activation prevents complication of APS. As has been shown, mice deficient in C3, C5, C6 or C5aR are resistant to APS antibody-induced trombophilia and endothelial cell activation. APS pregnancy complications in murine C4, factor B, C3, C5 and C5aR deficient models are implicated in placental injury (122).

In RA patients, the CS in the synovial tissue plays an important role in its pathogenesis. C1 genetic variants and deficiency of regulatory proteins have been associated with the risk of developing RA (103,123) (Table 5). Apoptotic granulocytes are found in the synovial tissue which produces immune complexes that are recognized by CS proteins. This causes a pro-inflammatory response, activation of the three pathways of CS, and consumption of complement components. The presence of anti-CCP, type II collagen and IgA in the immune complex activate CP and AP (99).

At the same time, cartilage proteins such as osteomodulin and fibromodulin could bind to CS, thus this proteins bind to collagen fibers in cartilage and interact with C1q, resulting in CP activation and increased osteclastogenesis. In contrast, other proteins such as decorin, biglycan and cartilage oligomeric matrix protein (COMP) are inhibited by C1 activation. An alteration in LP, in turn, is associated with high severity of RA and an increased risk of erosive disease. However, COMP also binds to MBL, thus inhibiting the LP and activating CP by properdin and C3. COMP-C3 complex has been detected in patients with RA and it has been proposed a biomarker of the disease (99,124).

SS has also been related to CS. C4BP is associated with SS and is increases during periods of activate disease (125). Moreover, other regulatory proteins such as protectin, MCP, DAF and clusterin have been observed in gland biopsies of patients with SS (126). CS is also involved in other ADs such as systemic vasculitis. The mice deficient in C5, factor B, C5aR are protected for ANCA-associated glomerulonephritis development. The final common pathway is known to be activated in this disease because levels of C5a, C5aR, and MAC are elevated in plasma and urine (127). Therefore, high levels of these proteins could reflect the severity of the disease (128). Moreover, the activation of neutrophil is caused by C5a and this interaction is mediated by cytokines or coagulation factors which are able to activate the AP (127). As is the case with LES, the NETs are important in the pathogenesis of this disease (129).

Other proteins are involved in other ADs. CTRP family proteins or C1q and tumor necrosis factor-related proteins belong to a group of 15 members expressed in several tissues (brain, eyes, lung, heart, liver, placental, muscle, prostate, ovary, etc). Furthermore, adiponectin (a member of the CTRP family) has several functions such as regulating of immune cell activity, insulin metabolism, cancer cell proliferation, angiogenesis, etc. Therefore, variants in CTRP members such as CTRP6 have been associated with high susceptibility to type 1 diabetes and vitiligo (130).

The complement system and therapeutic target

As we have seen throughout this chapter, the CS is involved in several homeostasis mechanisms and pathological conditions. Hence, the CS could be an important therapeutic target for the treatment of diseases associated with defects or deficiencies in this system (Table 5). It could also be an important target in the pathogenesis of ADs, cancer, allergy, atherosclerosis, etc. Therefore, these treatments could function as complement components inhibitors, enhancers of regulatory protein activity or supplements for complement proteins in deficiency diseases.

At present, only drugs that inhibit the complement on two key points: C1 and C5 have been approved for clinical use (20).

Eculizumab is a recombinant and fully humanized hybrid IgG2/IgG4 monoclonal antibody. It is specific to C5, thus inhibiting C5a generation and MAC formation. Currently, it is used for PNH, aHUS and C3 glomerulopathy (131). It has also been proposed to treat preeclampsia and HELLP syndrome (132),acute antibody-mediated transplant rejection (133), asthma (116) cold aglutinine disease (134), and myasthenia gravis (135). The most common adverse effect from its use is Neisseria infections (136). Moreover, a single-chain version of the C5-specific humanized monoclonal antibody is named Pexelizumab and it has been used in coronary disease complications but without any statistically significant differences (137).

C1 inhibitor drugs as Cinryze, Berinert and Rhucin have been utilized in HEA and they control bradykinin generation (20).

A complement-regulatory activity is achieved by immunoglobulins (IVg). Interestingly, they inhibit complement deposition on target cells when activation is triggered by antibodies through the CP. The complement proteins intercepted by IVg are C3b, C4b, and ATs. This treatment is used in ADs as Kawasaki disease, idiopathic thrombocytopenic purpura and SLE (20).

There are more drugs currently under development. These act to inhibit C3, ATs, factor B and regulatory proteins (DAF, MCP, CR1).

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