Introduction

The term complement refers to a set of serum proteins that cooperate with both the innate and adaptive immune systems to eliminate blood and tissue pathogens. Like the components of the blood clotting system, complement proteins interact with one another in a catalytic cascade. The complement system comprises approximately 40 proteins of enzymatic, receptor, and regulatory functions that collectively support a well-functioning immune system.

At the Pasteur Institute in the 1890s, Jule Bordet showed that antiserum from sheep causes membrane destruction in bacteria, but this bacteriolytic activity is destroyed by heating the antiserum. The renowned immunologist Paul Ehrlich, working independently in Berlin, conducted similar experiments in 1899 and introduced the term “complements” for the heat-labile substance in serum that, together with antibodies, was responsible for antimicrobial immunity.[1][2]

Issues of Concern

The complement system is a double-edged sword. While it acts as a host defense system, it can also cause immune and inflammatory diseases through its inflammatory mediators, thereby turning this defensive system into an attacking force for the host. These host-offensive actions become more pronounced with age and are exacerbated by multiple genetic factors and autoimmune responses. Several complement components have been identified and numbered in the order of their discovery. Various aspects and functions of the complement system, and its role in the pathogenesis of autoimmune diseases, have been the focus of research. One of the most important mechanisms underlying tissue injury and end-organ damage in autoimmune diseases is excessive activation of the complement system.[3]

Paradoxically, deficiencies in specific components of the complement pathways also lead to manifestations of autoimmune diseases, such as systemic lupus erythematosus (SLE).[3] See Figure. Complement Deficiencies Disorder. Advances in sequencing technology and the identification of genetic variants led to the discovery of mutations in components that regulate complement activation in human disease. Striking is the unexpected and remarkable association of mutations in control proteins causing disparate illnesses that predominantly affect the young and the old. An acute endothelial injury syndrome called atypical hemolytic uremic syndrome (aHUS) is a disease that often arises in early childhood. At the same time, age-related macular degeneration (AMD) is a retinal disease characterized by the accumulation of biological debris. The complement system plays an etiologic role in the pathogenesis of both disorders.

Cellular Level

Complement components constitute approximately 15% of the globulin protein fraction in the plasma, and their combined concentration can be as high as 3 mg/ml. Additionally, several regulatory components of the system are located on cell membranes, so the term complement now encompasses glycoproteins present in blood plasma and on cell membranes. There are 7 functional components of the complement cascade. They are as follows:

1. Initiator complement components: As the name suggests, they are the initiators of their respective complement cascades. These proteins do this by attaching to their activating ligands. These ligands are present in a soluble or membrane-bound state. The ligands are then activated to exert their respective biological activities through conformational changes. C1q complex, mannose-binding lectin (MBL), and ficolins are such initiators. See Figure. Biological Effects of Complement Activation.
2. Enzymatic mediators: These components of the complement cascade activate other members of the cascade through their enzymatic activity. They do this either by cleaving or by inducing conformational changes upon binding to these macromolecules. The C3 and C5 convertases are such enzymatic mediators of the complement cascades.
3. Components binding to membrane or opsonins: The enzymatic mediators cleave the complement proteins into 2 components. One is the larger component, designated with the suffix “b,” and the other with the suffix “a.” For example, C3b and C4b are the larger subcomponents of C3 and C4, respectively, which act as opsonins. They bind to microbial cell-surface receptors and enhance phagocytosis. One exception is for the C2 component.
4. Inflammatory mediators: The smaller fragments of complement cascade proteins formed upon activation are designated with the suffix “a.” Some enhance the local blood supply by binding to endothelial cells of small blood vessels. They act as inflammatory mediators. They are also known as anaphylatoxins because their effects can be destructive in excess.
5. Membrane attack complex: This protein complex comprises complement components C5b, C6, and C7, as well as multiple copies of C9. It is responsible for puncturing the cell membrane and lysing the microorganism.
6. Complement receptor proteins: They are present on cell surfaces and bind complement proteins, thereby eliciting signal-specific cellular functions.
7. Regulatory complement components: protective proteins that prevent complement activation. Examples are factor H and factor I.

Development

In subsequent years, researchers have discovered that the action of the complement system results from interactions among more than 30 glycoproteins. Most complement components are synthesized in the liver by hepatocytes. However, some is also produced by other cell types, including blood monocytes, tissue macrophages, fibroblasts, and epithelial cells of the gastrointestinal and genitourinary tracts.

According to the "evolutionary theory,” the most vital components of nature are revered by multitasking them. The complement system is an example. C3 and FB, like components of the complement cascade, are the earliest part of the cascade. It evolved half a billion years ago as a primitive form of C3 and has been identified in sponges considered as living fossils.

Organ Systems Involved

There is also a growing appreciation of cross-talk between the complement system and other systems, particularly the coagulation system.[4] For example, C5a-mediated neutrophil tissue factor release has been implicated in the pathogenesis of thrombosis in patients undergoing hemodialysis. With the increase in clinical research, awareness of the role of the complement system, and its role in various diseases, some organ systems showed pronounced susceptibility to complement-mediated injury due to their unique anatomic and functional features that made them conducive to complement activation (see Figure. Schematic of Complement Activations). A broad range of disorders involving various systems have been noted to involve the complement cascade in their pathophysiology. They can be acute or chronic and may involve a specific tissue or organ system. Many autoimmune disorders, inflammatory disorders, and age-related disorders are also reported to have the complement cascade as their etiopathology. A severe and rapid activation of the complement cascade in response to PAMPs or DAMPs may lead to hyperinflammation and tissue damage.[5] The overly protective function of the complement cascade leads to destructive outcomes, including transplant- and biomaterial-induced inflammatory responses. This activity affects the outcome of the transplant procedure, sometimes by the immediate rejection of the material or, in the long term, by disrupting the patient's life through dysfunction of the foreign material used.

Chronic diseases like atypical hemolytic uremic syndrome (aHUS), Paroxysmal nocturnal hemoglobinuria(PNH), and age-related macular degeneration (AMD) also have complement cascade overactivity behind their pathology. Autoimmune diseases such as systemic lupus erythematosus (SLE) also involve the complement cascade. However, there is a deficiency in the clearance of immune complexes, which are normally cleared by the early complement components. This deficiency in clearing the apoptotic cells and debris in the central nervous system leads to the generation of an inflammatory microenvironment that has a role in neurodegenerative disorders like Alzheimer disease.[6] All these malfunctions of the complement cascade of an individual have several causes, like alterations in the complement genes and proteins, which may be due to mutations that may lead to deletions or deficiencies, or may be due to the genetic polymorphisms that may have led to the gain of functions or loss of functions of the activators and regulators, respectively.[7] All such alterations are collectively known as the complement type, which determines an individual's susceptibility to complement-mediated diseases and disorders.[8]

Function

Complement is a critical component of the host defense system that, together with the contact and coagulation systems and the various branches of innate and adaptive immunity, helps maintain barrier functions and protect against microbial invasion after injury.[9] The role of complement is to detect, tag, and eliminate microbial invaders with rapid reactivity while maintaining sufficient specificity to avoid damaging host cells.

This reactivity and specificity are mediated by a series of circulating pattern-recognition proteins (PRPs) that detect pathogen-associated molecular patterns (PAMPs) and initiate the complement cascade. The surveillance, immunomodulatory, and effector functions of complement are mediated by a tightly coordinated network of interactions among the 3 canonical activation pathways: the classical, alternative, and lectin pathways. All activation pathways generate the C3 and C5 convertase enzyme complexes, which cleave C3 into the anaphylatoxin C3a and C5 into the anaphylatoxin C5a, respectively. The deposition of C5b on a target initiates membrane attack complex (MAC) formation and target lysis1. The opsonins and anaphylatoxins promote phagocytic uptake of pathogens by scavenger cells and activate neutrophils, monocytes, and mast cells, respectively.[10]

The pro-inflammatory effects of complement are well-acknowledged, but its essential anti-inflammatory properties in immunity are less well appreciated. The anti-inflammatory effects of complement are commonly associated with the lack of complement activation fragment generation, and the recent finding that the absence of anaphylatoxin receptor stimulation during T cell priming induces regulatory T cell development supports this notion.[11] However, new studies suggest that complement has more active, negative regulatory roles in immune responses, cell and tissue homeostasis, and tissue repair. A picture emerges in which cells provide not only the autocrine activating signals via local complement activation but also simultaneous inhibitory signals. Thus, the generation of initial activation fragments C3a, C5a, and C3b mediates the immune cell-mobilizing effects of complement, but further processed forms of these fragments, for example, inactive C3b (iC3b), designated C3a (C3a-desArg), and C5a-desArg, then engage pathways with negative, tolerogenic, and tissue reconstructive capacity.[12] Therefore, the balance between these distinct complement signals and the integration of environmental cues (such as growth factor availability and serum complement activation) instructs cells to continue or shut down.

Beyond its immune-related functions, complement activity also links to non-immune pathways, including development and tissue homeostasis. During normal development, C3a mediates the mutual cell attraction that is necessary for collective cell migration in Xenopus laevis, and collectin 11 (also known as CLK1) of the lectin complement pathway regulates the migration of neural crest cells.[13] Other studies suggest a role for complement in stem cell or progenitor cell fate decisions. It has been shown that CD46 expression induced by the Notch ligand Delta-like ligand 1 (DLL1) is crucial for human epidermal progenitor cell proliferation and self-renewal, and that anaphylatoxins support the maintenance of the pluripotent state of human embryonic stem cells, mediate the mobilization of hematopoietic stem cells from the bone marrow, and promote the migration and proliferation of cardiac pluripotent progenitor cells.[14][15][16] C3a and C5a receptors also facilitate osteoclast differentiation and bone formation.[17] At the level of whole organs, C1q is required for normal neuron maturation as it directs the elimination of excitatory synapses in the brain via ‘synapse pruning.’ It can also protect neurons against fibrillar amyloid beta-mediated injury through the induction of phosphorylated cAMP-response element-binding protein and activator protein 1 (AP-1), which are transcription factors that are associated with neuronal survival and neurite outgrowth.[18][19] By contrast, increased C1q levels correlate with declines in synaptic plasticity, cognitive function, and tissue regeneration during aging, likely through direct induction of WNT pathways , suggesting that targeting C1q could be a potential approach to treating dementia. The designated form of C3a (C3a-desArg; also known as acylation-stimulating protein) and, as shown more recently, adipocytes and stimulate triglyceride synthesis in adipocytes to produce C3a, and systemic complement has an important homeostatic and regulatory role in metabolic organs such as the pancreas, liver, and adipose tissue. The recently discovered link between intracellular C3aR-mediated signals and the mTOR network suggests that complement may also participate in metabolic sensing. mTOR integrates signals from pathways that sense cellular nutrients, oxygen, and energy levels and translates these signals into appropriate responses, such as apoptosis induction, inhibition of autophagy, and/or cell activation and proliferation. Recent research found that CD46 controls the expression of amino acid and glucose transporters and the assembly of mTOR complex 1 (mTORC1) in activated CD4+ T cells. Furthermore, C3a regulates proteasome activity and thereby normal protein turnover in human retinal epithelial cells 88. This relationship suggests that the connection between complement and metabolism may extend to sensing nutrient and/or cellular stress and subsequent modulation of catabolic and anabolic metabolism at the single-cell level.

Mechanism

There are 3 main pathways for complement activation: the classical, lectin, and alternative pathways. All 3 pathways differ in the pattern-recognition molecules (PRMs) that initiate a protease cascade, leading to the formation of a C3 convertase complex that opsonizes complement-activating targets. All three pathways differ in the PRMs that initiate a protease cascade, leading to the formation of a C3 convertase complex that initiates the opsonization of complement-activating targets, eg, C1q, mannose-binding lectin(MBL), ficolins, and properdin, which can recognize pathogen-associated molecular patterns (PAMPs) or DAMPs for autoactivation and initiation of a serine protease cascade, “the complement cascade” leading to opsonization and potentially lysis of the target microbe.[21] See Figure. Opsonization, Complement System.

Initially discovered in 1890, the pathway got its name as “the classical pathway” in the complement cascade. The antigen-antibody complex is the initiating component of the complement pathway. C1 attaches to the Fc region of Ig via the C1q subcomponent. This action initiates the classical complement cascade, which involves multiple proteolytic cleavage steps. The initial 1 is the autoactivation of C1r, which cleaves both subcomponents of C1.In the next step, C4 and C2 are cleaved by C1s. The classical pathway C3 convertase is formed by the association of newly generated C4b with C2a. The C3 convertase then cleaves C3 into C3a and C3b.

Similarly, the C3 convertase of the lectin pathway also gets formed. Here, the lectins bind to mannose residues. These mannose-binding lectin-associated serine proteases are substitutes for the C1 enzymatic subcomponents. They target the unique pathogen-related sugar moieties.

The capacity of the alternative pathway of self-initiation arises from the presence of an internal thioester bond, which enables its deposition on the pathogen surface without prior contact or exposure. This alternative pathway has a self-regulatory mechanism that protects the host cell. If deposited on the microbial surface, it can efficiently amplify via the C3 convertase, generating large amounts of C3b to lyse the pathogen. 

There are host regulators of the complement system in both the fluid (ie, plasma) and the cells and tissues, protecting host cells and tissues from the destructive activity of the complement cascade. Each major step of the complement cascade is tightly regulated.

The regulatory factors present in the fluid state, ie, the host cell plasma, are factor H (FH) and C4b-binding protein (C4BP). Decay-accelerating factor (DAF; CD55),complement receptor 2 (CR2; CD21) complement receptor 1 (CR1; CD35), and membrane cofactor protein (MCP; CD46) are regulatory factors associated with cell membrane

There is a multigene family, the regulators of complement activation (RCAs), which utilizes 2 processes to maintain complement homeostasis. One is called the cofactor activity. In this process, C3b or C4b is permanently cleaved by the serine protease factor 1(FI). This inactivates those complement components. The second regulatory mechanism is called decay-accelerating activity. Here, the catalytic domain (serine protease) of a C3 or C5 convertase is disassociated.

Related Testing

Measurement of the complement system proteins in serum or plasma can be divided into 4 main categories: (a) analysis of complement function or activity; (b) complement factors, individual antigen quantitation; (c) detection of autoantibodies against complement factors; and (d) quantitation of activation fragments, also called split products.[22] Common analytes measured in the classical pathway include CH50 (total complement function), C1q, C2, and C4 (functional and antigen quantitation), and C1-INH (functional and antigen quantitation). Lectin pathway assays are also available, although rarer. Measurement of C3 and the C3 and C4 nephritic factors (autoantibodies against Classical Pathway and Alternative Pathway C3 convertases, respectively) is also of relevance. In the alternative pathway, measurement of AH50 or alternative pathway function, as well as quantitation of Factor B and Factor H (antigen levels) and autoantibodies against Factor B, Factor H, and Factor B split products, Bb and Ba, can be performed. For the analysis of the terminal pathway, C5–C9 individual components quantitation and function, and the soluble membrane attack complex (sC5b-9 or sMAC) are also useful. Several automated and manual methods are available for quantifying complement factor concentrations. These assays measure the amount of antigen in the sample and typically report results in milligrams per milliliter or micrograms per deciliter. Detection of autoantibodies to complement factors aids in differentiating hereditary, genetically mediated complement disorders from acquired conditions. Lastly, quantification of split products provides an estimate of the activation state of the pathways. It determines whether a complement factor is reduced due to increased consumption or reduced production.

Functional screening tests

Laboratory testing for complement components includes assays of functional activity for the CP (CH50 and its equivalents), the AP (AH50 or APH50), and the MBL pathway. The CH50 assay is based on a hemolytic assay in which an immune complex is formed by adding antibodies that react with a surface antigen on sheep red blood cells. When the antigen-fixed antibodies activate complement on the cell surface, the cell lyses, and hemoglobin is released. Since the formation of the MAC on the cell requires the sequential action of all 9 components of the classical (C1, C4, and C2) and terminal (C3, C5, C6, C7, C8, and C9) pathways, titrating the complement source (serum in most cases) so that only a portion of the cells present undergo lysis, the amount of active complement can be calculated, and the results get expressed as the reciprocal of the serum dilution that caused lysis of 50% of the cells in the assay. Two variations of the CH50 are currently in use in clinical laboratories: an assay based on the lysis of liposomes that releases an enzyme that can be read on an analyzer of the sort used for other clinical laboratory tests, and solid-phase assays (ELISAs) that detect the final C9 neoantigen that forms when the complete pathway becomes activated. The CH50 is the single best screen for complement abnormalities, in that the absence or decrease in CH50 activity implies that at least 1 necessary component is missing or low. The analogous AP activity assay, AH50, is less widely available than CH50 but is useful as a screen for complement deficiency, particularly when used in conjunction with CH50. The AH50 depends on the unique properties of erythrocytes from certain species to provide a surface that promotes activation of the AP, with sequential activation of factors D, B, P, C3, C5, C6, C7, C8, and C9. Properdin is necessary for the stabilization of the C3 convertase (C3bBb), and inefficient activation of the AH50 occurs if P is low or absent. The most common variation of the AH50 uses rabbit red cells in combination with a buffer that blocks the activation of the CP or LP. Like the CH50, the AH50 measures the percentage of rabbit erythrocytes lysed by diluted serum and is expressed as the dilution that lyses 50% of the cells used in the assay. If both CH50 and AH50 are used to screen for complement deficiency, the number of additional tests required to pinpoint the defect is minimized.

Because both assays share the same 6 terminal components (C3, C5, C6, C7, C8, and C9), results are low or absent in both assays if 1 or more of these components are missing. If a CP component is missing, the CH50 is low or absent, whereas the AH50 is normal; conversely, if an AP component is low or missing, the reverse is true. Table II provides a general guide to selecting tests for distinguishing between acquired and inherited complement deficiencies. Several assays for C1-inhibitor function have been developed. One commonly used method is ELISA, which measures complexes formed between biotinylated C1s and C1-Inh that are captured on an avidin-coated plate (Quidel). A drawback of this particular assay is that a rare patient might have normal assay function, yet harbor a C1-Inh mutation that allows binding of C1s but not of 1 or more of the other enzymes with which the inhibitor reacts. Another test of C1-Inh function relies on the observation that binding of the inhibitor to C1r masks the site on C1r recognized by certain polyclonal antibodies. After activation of the test serum with aggregated immunoglobulins, the amount of C1r detectable by radial immunodiffusion decreases in proportion to the amount of active C1-Inh present. Functional tests are possible for each component by using variations of the CH50 or AH50 assays, in which an excess of all components except the 1 under evaluation is added to the appropriate cells, and the patient's serum provides the only source of the component in question.

Alternatively, purified components can be added to the patient's serum to determine which component (s) restore activity. The function of the MBL pathway is determined by ELISA, in which the patient's serum is added to wells coated with mannan. After MBL binds to the mannan-coated surface, the MASP enzymes cleave C4, and the resulting C4b and C4d deposited on the plate are measurable using enzyme-conjugated mAbs.

Quantitative tests for component concentrations

 Like most other circulating proteins, the complement components are measurable by standard immunochemical methods available in most laboratories. These include immunoprecipitation assays, such as nephelometry, radial immunodiffusion, RIA, and ELISA. The critical points are the specificity of the antibodies used and the reliability of the standard and controls. There are, as yet, very few complement assays that have been standardized and validated for Food and Drug Administration approval. Most laboratories must rely on in-house methods and established research technologies to perform diagnostic complement analysis. The most definitive method for evaluating complement activation is the quantification of the fragments formed during the enzymatic cleavage steps. Because many complement components are acute-phase reactants, decreases due to activation may be masked by increases in their synthesis rates during an inflammatory episode. The split products can be used to determine whether activation has occurred because their increase occurs only when the complement enzymes are formed and active. A bonus is that the pathway of activation can be established; C4a and C4d are markers for CP or LP activation, Bb is a marker for AP activation, and C3a, iC3b, C5a, and soluble C5b-9 can be used to determine terminal pathway activation.

Complement autoantibody tests

ELISA can detect C1q and C1-Inh autoantibodies. Antibodies to C1-Inh bind to the inhibitor and prevent it from binding to the enzyme, but they don't prevent the enzyme from cleaving the inhibitor. The resulting lower-molecular-weight inhibitor fragment is detectable by PAGE. Several assays for C3v nephritic factors rely on its function, and either measure lysis resulting from C3b generation on a red cell surface or directly quantify the amount of C3 cleaved when the patient's serum mixes with normal serum.

Pathophysiology

In patients with complement protein deficiencies, the key component of the complement cascade, protein C3, plays a primary role in host resistance to bacterial, viral, fungal, and parasitic infections. Numerous studies have confirmed a correlation between C3 deficiency and recurrent infections caused by both Gram-negative (eg, Neisseria spp., Haemophilus influenzae) and Gram-positive (eg, Streptococcus pneumoniae) bacteria. The increased susceptibility to infections in patients with C3 deficiency is directly related to the major role of this component in both the lytic serum activity and opsonophagocytosis. Deficiencies in the late complement proteins involved in MAC formation are associated with meningococcal infections. In patients displaying a deficiency of even 1 of the proteins belonging to the group of C5-C8, recurrent systemic infections, meningitis, purulent otitis media, and bacteremia, usually of severe intensity, may occur.[23] Meningococcal and other bacterial infections are also linked with properdin deficiency.[24] The absence of the C3INA factor, which regulates C3 activity in the clinical setting, resembles the state of agammaglobulinemia and predisposes to recurrent bacterial infections. Researchers have also observed that deficiencies in the alternative pathway factors B, D, P, and H increase susceptibility to infections caused by Neisseria spp., Proteus spp., and Pseudomonas spp.

Researchers have studied the roles of complement in killing invading microorganisms for many decades. Since the system can opsonize and lyse foreign particles and cells and generate inflammatory peptides (C3a, C4a, C5a), it has the capacity, if inappropriately activated, to damage host tissues. From the 1970s onwards, its unwanted activities in damaging host tissue were explored in association with diseases such as rheumatoid arthritis, glomerulonephritis, ischemic stroke, myasthenia gravis, multiple sclerosis, and drug-induced lupus. More recently, genetic, genomic, and gene-targeting studies have yielded new findings on complement heterozygous deficiencies and common polymorphisms, which cause subtle alterations in activation and regulation and are associated with diseases such as age-related macular degeneration (AMD), hemolytic uremic syndrome (HUS), and preeclampsia. Knockout studies in mice also highlighted the contributions of complement and related proteins to homeostasis (apoptotic and necrotic cell clearance). Deficiencies in apoptotic cell clearance, which can arise from diminished complement activity, are associated with autoimmune responses, as occur in systemic lupus erythematosus.

AMD affects more than 50 million individuals worldwide and is the leading cause of blindness in the elderly in developed countries.[25] This slowly progressive, degenerative ophthalmological disease of the retina typically manifests after age 60. The prevailing hypothesis is that an overly exuberant inflammatory response, driven by an inadequately regulated complement cascade, significantly contributes to the pathophysiology of age-related macular degeneration (AMD). Reduced levels of H and B factors are associated with age-related macular degeneration. Mutations in the HTRA1 and CFH genes, encoding the complement regulatory factors H and B, can significantly increase the risk of AMD.[26] Under normal physiological conditions, factor H inhibits the inflammatory response by converting C3b to the inactive iC3b form and by weakening the binding of C3b to factor B. The point mutation in the CFH gene decreases the affinity of its product, factor H, for C-reactive protein (CRP), which likely reduces complement regulatory activity in the ocular fundus and leads to pathological inflammation in the macula.

Research has also confirmed the involvement of complement components in the atypical hemolytic-uremic syndrome (aHUS).[27] aHUS is a disorder caused by excessive complement activation, defects in genes encoding proteins of this system, and the presence of autoantibodies against regulatory proteins that are indispensable for proper complement functioning (see Figure. Excessive Complement Activation).[27] The defects mainly induce ahu in genes encoding factors H and I, deficiencies of which cause severe disorders in complement activation, resulting in kidney failure. A somewhat less frequent cause of aHUS is mutations in the thrombomodulin gene, a glycoprotein with anticoagulant properties that inactivates C3a and C5a anaphylatoxins.[28]

Studies have also observed that a genetically determined deficiency of the C1 inhibitor (C1-INH, C1-esterase inhibitor) occurs in hereditary angioedema (HAE). This is a rare, life-threatening disease of the skin and mucous membranes, characterized by intermittent, recurrent swelling of the face, genitalia, gastrointestinal tract, and larynx. C1-INH is a critical regulator of the complement system, coagulation, and the kallikrein-kinin cascade.[29] C1-INH inhibits the activity of C1s and C1r, thereby preventing uncontrolled activation of the C2 and C4 components and excessive complement activation via the classical pathway. Its deficiency leads to continuous activation of this complement pathway, resulting from increased self-activation of the C1 protein. In patients with HAE, this activation is persistent and independent of clinical symptom onset. C1-INH also inhibits activated coagulation factor XII and kallikrein, thereby promoting the release of bradykinin, which contributes to the formation of edema and pain.[29]

In patients with Alzheimer syndrome, deposition of beta-amyloid plaques in the brain stimulates microglia not only to cytokine secretion, free radicals, and nitric oxide production but also activates the complement system proteins, including the C1 component, Cr3, and Cr4 receptors; this leads to dysfunction of neurons, their degeneration, and, eventually, the patient’s death.[30]

Clinical Significance

Research has uncovered the role of mutation in complement regulatory genes and components in various inflammatory and chronic diseases in the last decade. The advent of next-generation sequencing has helped in these discoveries. However, the definitive association of the complement cascade with genetic variants has yet to be established. The FDA approval of eculizumab for the treatment of aHUS demonstrates the role of the complement cascade involvement in such chronic disorders. Anti-C5 antibodies have also been found to reduce tissue damage in complement-dependent myocardial infarction and stroke. They are proposed as therapeutic agents for chronic inflammation, including rheumatoid arthritis and nephritis. Further research is needed to delineate the associations of complement disease. It helps develop more complementary-targeted therapeutic agents for diseases such as age-related macular degeneration.

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References

1.

Kaufmann SH. Immunology's foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff. Nat Immunol. 2008 Jul;9(7):705-12. [PubMed: 18563076]

2.

Nesargikar PN, Spiller B, Chavez R. The complement system: history, pathways, cascade and inhibitors. Eur J Microbiol Immunol (Bp). 2012 Jun;2(2):103-11. [PMC free article: PMC3956958] [PubMed: 24672678]

3.

Ballanti E, Perricone C, Greco E, Ballanti M, Di Muzio G, Chimenti MS, Perricone R. Complement and autoimmunity. Immunol Res. 2013 Jul;56(2-3):477-91. [PubMed: 23615835]

4.

Kourtzelis I, Markiewski MM, Doumas M, Rafail S, Kambas K, Mitroulis I, Panagoutsos S, Passadakis P, Vargemezis V, Magotti P, Qu H, Mollnes TE, Ritis K, Lambris JD. Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood. 2010 Jul 29;116(4):631-9. [PMC free article: PMC3086498] [PubMed: 20424189]

5.

Ekdahl KN, Soveri I, Hilborn J, Fellström B, Nilsson B. Cardiovascular disease in haemodialysis: role of the intravascular innate immune system. Nat Rev Nephrol. 2017 May;13(5):285-296. [PubMed: 28239169]

6.

Harris CL, Heurich M, Rodriguez de Cordoba S, Morgan BP. The complotype: dictating risk for inflammation and infection. Trends Immunol. 2012 Oct;33(10):513-21. [PMC free article: PMC3460238] [PubMed: 22749446]

7.

Brennan FH, Lee JD, Ruitenberg MJ, Woodruff TM. Therapeutic targeting of complement to modify disease course and improve outcomes in neurological conditions. Semin Immunol. 2016 Jun;28(3):292-308. [PubMed: 27049459]

8.

Scott D, Botto M. The paradoxical roles of C1q and C3 in autoimmunity. Immunobiology. 2016 Jun;221(6):719-25. [PubMed: 26001732]

9.

Ricklin D, Lambris JD. Preformed mediators of defense-Gatekeepers enter the spotlight. Immunol Rev. 2016 Nov;274(1):5-8. [PubMed: 27782322]

10.

Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011 Jan;343(1):227-35. [PMC free article: PMC3097465] [PubMed: 20838815]

11.

Strainic MG, Shevach EM, An F, Lin F, Medof ME. Absence of signaling into CD4⁺ cells via C3aR and C5aR enables autoinductive TGF-β1 signaling and induction of Foxp3⁺ regulatory T cells. Nat Immunol. 2013 Feb;14(2):162-71. [PMC free article: PMC4144047] [PubMed: 23263555]

12.

Kemper C, Köhl J. Novel roles for complement receptors in T cell regulation and beyond. Mol Immunol. 2013 Dec 15;56(3):181-90. [PubMed: 23796748]

13.

Carmona-Fontaine C, Theveneau E, Tzekou A, Tada M, Woods M, Page KM, Parsons M, Lambris JD, Mayor R. Complement fragment C3a controls mutual cell attraction during collective cell migration. Dev Cell. 2011 Dec 13;21(6):1026-37. [PMC free article: PMC3272547] [PubMed: 22118769]

14.

Tan DW, Jensen KB, Trotter MW, Connelly JT, Broad S, Watt FM. Single-cell gene expression profiling reveals functional heterogeneity of undifferentiated human epidermal cells. Development. 2013 Apr;140(7):1433-44. [PMC free article: PMC3596987] [PubMed: 23482486]

15.

Borkowska S, Suszynska M, Wysoczynski M, Ratajczak MZ. Mobilization studies in C3-deficient mice unravel the involvement of a novel crosstalk between the coagulation and complement cascades in mobilization of hematopoietic stem/progenitor cells. Leukemia. 2013 Sep;27(9):1928-30. [PMC free article: PMC5542053] [PubMed: 23511127]

16.

Lara-Astiaso D, Izarra A, Estrada JC, Albo C, Moscoso I, Samper E, Moncayo J, Solano A, Bernad A, Díez-Juan A. Complement anaphylatoxins C3a and C5a induce a failing regenerative program in cardiac resident cells. Evidence of a role for cardiac resident stem cells other than cardiomyocyte renewal. Springerplus. 2012 Dec;1(1):63. [PMC free article: PMC3592996] [PubMed: 23487597]

17.

Kalbasi Anaraki P, Patecki M, Larmann J, Tkachuk S, Jurk K, Haller H, Theilmeier G, Dumler I. Urokinase receptor mediates osteogenic differentiation of mesenchymal stem cells and vascular calcification via the complement C5a receptor. Stem Cells Dev. 2014 Feb 15;23(4):352-62. [PMC free article: PMC3920849] [PubMed: 24192237]

18.

Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012 May 24;74(4):691-705. [PMC free article: PMC3528177] [PubMed: 22632727]

19.

Benoit ME, Hernandez MX, Dinh ML, Benavente F, Vasquez O, Tenner AJ. C1q-induced LRP1B and GPR6 proteins expressed early in Alzheimer disease mouse models, are essential for the C1q-mediated protection against amyloid-β neurotoxicity. J Biol Chem. 2013 Jan 04;288(1):654-65. [PMC free article: PMC3537064] [PubMed: 23150673]

20.

Naito AT, Sumida T, Nomura S, Liu ML, Higo T, Nakagawa A, Okada K, Sakai T, Hashimoto A, Hara Y, Shimizu I, Zhu W, Toko H, Katada A, Akazawa H, Oka T, Lee JK, Minamino T, Nagai T, Walsh K, Kikuchi A, Matsumoto M, Botto M, Shiojima I, Komuro I. Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes. Cell. 2012 Jun 08;149(6):1298-313. [PMC free article: PMC3529917] [PubMed: 22682250]

21.

Bajic G, Degn SE, Thiel S, Andersen GR. Complement activation, regulation, and molecular basis for complement-related diseases. EMBO J. 2015 Nov 12;34(22):2735-57. [PMC free article: PMC4682646] [PubMed: 26489954]

22.

Cataland SR, Holers VM, Geyer S, Yang S, Wu HM. Biomarkers of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP. Blood. 2014 Jun 12;123(24):3733-8. [PubMed: 24695849]

23.

Tedesco F. Inherited complement deficiencies and bacterial infections. Vaccine. 2008 Dec 30;26 Suppl 8:I3-8. [PubMed: 19388157]

24.

Stover CM, Luckett JC, Echtenacher B, Dupont A, Figgitt SE, Brown J, Männel DN, Schwaeble WJ. Properdin plays a protective role in polymicrobial septic peritonitis. J Immunol. 2008 Mar 01;180(5):3313-8. [PubMed: 18292556]

25.

Warwick A, Khandhadia S, Ennis S, Lotery A. Age-Related Macular Degeneration: A Disease of Systemic or Local Complement Dysregulation? J Clin Med. 2014 Nov 03;3(4):1234-57. [PMC free article: PMC4470180] [PubMed: 26237601]

26.

Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006 Nov 10;314(5801):992-3. [PubMed: 17053109]

27.

Kavanagh D, Goodship T. Haemolytic uraemic syndrome. Nephron Clin Pract. 2011;118(1):c37-42. [PubMed: 21071971]

28.

Waters AM, Licht C. aHUS caused by complement dysregulation: new therapies on the horizon. Pediatr Nephrol. 2011 Jan;26(1):41-57. [PMC free article: PMC2991208] [PubMed: 20556434]

29.

Banerji A. Current treatment of hereditary angioedema: An update on clinical studies. Allergy Asthma Proc. 2010 Sep-Oct;31(5):398-406. [PubMed: 20929607]

30.

Heneka MT, O'Banion MK, Terwel D, Kummer MP. Neuroinflammatory processes in Alzheimer's disease. J Neural Transm (Vienna). 2010 Aug;117(8):919-47. [PubMed: 20632195]

Disclosure: Mainak Bardhan declares no relevant financial relationships with ineligible companies.

Disclosure: Ravi Kaushik declares no relevant financial relationships with ineligible companies.