Version May 2024
INTRODUCTION — The complement system is a major component of innate immunity and a "complement" (from which its name is derived) to antibody-triggered responses [1]. It consists of nearly 60 plasma and membrane proteins that form three distinct but overlapping activating pathways, as well as a common terminal lytic cascade and a network of regulators and receptors [2].
This topic review will discuss the functions of the complement system, the pathways involved, the measurement of complement activity, and the clinical significance of abnormally low or high complement tests. More detailed descriptions of the complement pathways, regulatory proteins, and clinical disorders related to the complement system are found separately:
●(See "Complement pathways".)
●(See "Regulators and receptors of the complement system".)
●(See "Inherited disorders of the complement system".)
●(See "Acquired disorders of the complement system".)
●(Related Lab Interpretation Monograph(s): "Low total hemolytic complement (CH50) in adults".)
●(Related Lab Interpretation Monograph(s): "Low C1q in adults".)
●(Related Lab Interpretation Monograph(s): "Low C4 and/or C3 in adults".)
BACKGROUND — Complement was initially recognized in the 1880s as "a lytic substance in blood," although the biochemical complexity of the system was not appreciated until the 1960s and 1970s.
It is recognized that complement has three major functions:
●Identification of foreign materials and damaged self (tagging with complement proteins such as C3b, ie, opsonization)
●Elimination of these targets (phagocytosis or lysis via the membrane attack complex)
●Promotion of inflammatory and immune responses to these targets (release of anaphylatoxins to induce mast cell degranulation and cellular chemotaxis)
These proinflammatory processes require tight control to avoid damage to host tissues. Thus, nearly one-half of complement proteins function to regulate (control) the system.
NOMENCLATURE — Complement components were commonly named as they were identified, leading to some inconsistencies in terminology. An updated nomenclature has been suggested [3].
●Components of the classical pathway are designated by the capital letter "C" combined with a number (eg, C1, C2, C3, and C4). This scheme is also used for components of the membrane attack complex (MAC) (C5, C6, C7, C8, and C9). The numbers are in order of reactivity, except that C4 is activated before C2 and C3 in the classical and lectin pathways.
●Alternative pathway components are designated as factors, such as factor B and factor D.
●Upon proteolytic activation, a liberated smaller fragment is designated by a lowercase letter (such as C3a or Ba). The larger fragment attaches to a target and is then listed with a "b," as in C3b or Bb.
●Inactivation by limited proteolysis produces further breakdown products designated with additional lowercase letters. For example, C3c and C3d are produced when C3b is cleaved.
●Receptors are variably defined by their function (eg, immune adherence receptor), order of discovery (eg, complement receptor type 1 [CR1]), ligands to which they bind (eg, C3b/C4b receptor), or via their "cluster of differentiation" (CD) assignments (CR1 is CD35). Receptors have a more limited expression pattern (ie, usually expressed only by hematopoietic cells).
●Membrane regulators are widely expressed, including by hematopoietic cells, and are named via the same designations as indicated above (eg, the designation of decay-accelerating factor [DAF] as CD55 or membrane cofactor protein [MCP] as CD46). Plasma regulators, on the other hand, are synthesized primarily by the liver, such as factors H and I and C4b binding protein (C4BP).
PATHWAYS AND ACTIVATING CONDITIONS — There are three major divisions or pathways of complement activation: the classical, lectin, and alternative cascades (figure 1). Each is triggered in a distinct manner, yet all lead to the activation of C3 and its deposition on a target as C3b, which is the major goal of complement [4-6].
●Classical – The classical pathway is triggered by antibodies. It becomes engaged when immunoglobulin M (IgM) or immunoglobulin G (IgG) antibodies bind to antigens (such as viruses, bacteria, or autoantigens). The C1q subcomponent of the C1 complex attaches to the Fc portion of antibody. In complex with C1q are the two proteases C1r and C1s. Upon C1q engagement by antibodies, C1r autoactivates and cleaves C1s, which subsequently cleaves C4 and C2, the next two proteins in the cascade. IgG subclasses 1 and 3 efficiently fix complement. IgG2 fixes complement, although less efficiently than IgG1 or IgG3. IgG4 does not activate the complement system. In addition to antibodies, C-reactive protein and a few other plasma proteins can engage the classical pathway. (See "IgG subclasses: Physical properties, genetics, and biologic functions", section on 'Biologic functions'.)
●Lectin – The lectin pathway is specialized for the prompt recognition of repetitive carbohydrate patterns on the surface of microbial pathogen targets. The activation scheme of the lectin pathway is similar to the classical pathway, except that the initiating antibodies are replaced by lectins (ie, carbohydrate-binding proteins). While C1q is the major pattern recognition molecule (PRM) of the classical pathway, the list of PRMs for the lectin pathway has been growing since the discovery of mannose-binding lectin (MBL, also called mannan-binding lectin) and include ficolin-1, ficolin-2, ficolin-3, collectin-10, and collectin-11 [7,8]. Also associated with the large PRMs (such as MBL) are serine proteases (ie, MBL-associated serine proteases [MASPs]), which are structurally and functionally similar to the classical pathway subcomponent proteases of C1 (ie, C1r and C1s). Also, like C1s in the classical pathway, the MASPs activate C4 and C2 by proteolytic cleavage [9].
●Alternative – The alternative pathway is an ancient surveillance system and represents the original extracellular complement system. It does not require the presence of antibodies or lectins to become activated. It is continuously turning over (so called "tickover") at a low level due to the presence of a labile thioester bond in C3. This may result in deposition of C3b on a target and engagement of the alternative pathway's feedback loop mechanism. C3 "ticks over" at approximately 1 percent per hour in blood. If this form of C3 lands on healthy self-tissues, it is rapidly inactivated by host regulators. If it engages cell debris or a pathogen, it is amplified by the feedback loop of the alternative pathway. If it does not engage a target, within a few microseconds, it is hydrolyzed and altered by plasma (fluid-phase) regulators to facilitate removal from the circulation.
All three pathways lead to C3b deposition on a target and then the assembly of the membrane attack complex (MAC). The MAC perturbs cell membrane integrity and in organisms such as gram-negative bacteria, results in lysis of the microbe. Also, each pathway promotes the inflammatory response by releasing proinflammatory peptides known as anaphylatoxins (C3a, C4a, C5a). While C3a and C5a are well-recognized anaphylatoxins with known receptors, C4a also has been found to be a ligand for protease-activated receptors 1 and 4 (PAR1 and PAR4), with effects on cellular activation and endothelial permeability [10]. A more detailed discussion of each pathway is available. (See "Complement pathways".)
FUNCTIONS OF THE COMPLEMENT SYSTEM
Destruction of microbes — The primary goal of the complement system is the elimination of microbes and secondarily, other particulates of biological debris. The process requires the covalent deposition of C3b on a target. Targets can include microbes, immune aggregates, apoptotic cells, and necrotic tissue. The process of coating of targets with complement molecules to promote their elimination is known as opsonization. Opsonization occurs rapidly. In less than five minutes, several million C3b fragments may be deposited on a single bacterium.
Once a target is coated with C3b, it can then be recognized by host cells bearing complement receptors. The process of C3b on a target engaging its receptors is known as the immune adherence reaction. It is commonly followed by ingestion by phagocytic cells or transfer from erythrocytes (that express the C3b/C4b receptor, complement receptor type 1 [CR1]) to tissue macrophages in the liver and spleen. Further, CR1 converts C3b to iC3b and C3dg fragments, thereby facilitating transfers to CR2, CR3, and CR4.
Opsonization also facilitates the adaptive immune response, including antigen presentation and retention by immune cells, as well as immunologic memory and costimulation of B lymphocytes through the antigen receptor. (See "The adaptive humoral immune response", section on 'Antigenic stimulation'.)
Based on this host defense profile, it becomes apparent why infections and autoimmunity are two major consequences of a defective complement system.
Clearance of cellular debris and apoptotic cells — Programmed cell death (apoptosis) followed by rapid phagocytic clearance is a common mechanism, whereby organisms dispose of dead and dying cells. The process of apoptosis results in alterations in the architecture of the cell membrane, as well as loss of host regulators. These changes expose sites for binding by lectins and natural antibodies and induce complement activation and immune clearance [11].
Promotion of inflammation — Activation of the complement system leads to the release of peptides of approximately 10 kDa, which are potent mediators of inflammatory and immune responses. These fragments, known as "anaphylatoxins," bind to their respective receptors on cells to initiate inflammation and vasodilation that in turn activate many cell types [12]. Functions of anaphylatoxins include:
●Directed movement of motile cells to an inflammatory site (ie, chemotaxis and chemokinesis of polymorphonuclear leukocytes [granulocytes])
●Release of mediators, such as histamine from mast cells
●Activation of many cell types, including epithelial and endothelial cells, as well as cells involved in inflammatory and immune responses
●Contraction of smooth muscles
●Dilation of blood vessels with exudation of plasma and cells
A development in the anaphylatoxin field is the discovery that C3a and C4a (although not C5a) have direct antimicrobial activity and that this property has been preserved throughout vertebrate evolution [13]. This finding provides an additional mechanism through which complement can kill micro-organisms. Further, as noted above, the long sought after receptor for C4a has been identified as the protease-activated receptors 1 and 4 (PAR1 and PAR4), revealing another indication of the importance of cross-talk between the complement system and other host defense pathways [10].
Other functions — In addition to its key role in host defense, complement participates in several other beneficial processes:
●Clearance of immune complexes – Complement activation leads to deposition of activation fragments (C4b and C3b) on immune complexes. These are subsequently cleared by complement receptors on hematopoietic cells and tissue macrophages. Serum sickness is an example of activation of complement by immune complexes. (See "Serum sickness and serum sickness-like reactions".)
●Angiogenesis – Complement activation leads to the generation of the proinflammatory anaphylatoxins. They, in turn, cause release of mediators, such as interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and soluble vascular endothelial growth factor receptor 1 (sVEGFR1) from multiple cell types, including monocytes and macrophages [14]. In mouse models of retinopathy of prematurity, these mediators surprisingly played an inhibitory role and induced an antiangiogenic signature [14]. On the other hand and in apparent contrast, complement can also lead to neovascularization as seen in the retina of age-related macular degeneration (AMD) patients. (See "Age-related macular degeneration" and 'Detrimental functions' below.)
●Mobilization of hematopoietic progenitor cells – Our understanding of the most primitive of hematopoietic progenitor cells, human stem cells (HSCs), has fundamentally changed. We know that HSCs are first responders during infection, and their regulation by proinflammatory cytokines helps maintain homeostasis [15]. By generation of proinflammatory anaphylatoxins, complement activation can indirectly promote HSC mobilization via granulocyte egress [16].
●Tissue regeneration – While the mammalian liver is one of the few organs capable of regeneration, complement has a role in this process, such as by modulating stem cell responses via anaphylatoxin receptors [17]. Other lines of investigation (especially from animal models) suggest a more subtle role of complement in basic development, vertebrate embryogenesis, and tissue homeostasis [17].
●Intracellular complement – An intracellular complement system has been identified (reviewed in [18]). This system mounts a potent intracellular immune response to nonenveloped viruses [19]. The deposition and covalent attachment of C3 onto pathogens in the extracellular compartment serves as a marker upon intracellular invasion. The C3 fragments are recognized by an unknown receptor in the cytosol to signal the inflammasome [4]. Further, C3 activation can occur intracellularly, resulting in the production of autocrine-produced proinflammatory cytokines [20]. Additionally, T cells also possess intracellular C5 stores that are cleaved to C5a, which then binds its receptor [21].
Although complement is involved in these and other processes, complement-deficient humans develop two major problems: bacterial infections and autoimmunity (primarily systemic lupus erythematosus [SLE]). Therefore, the two main functions of the complement system are host defense against pathogens and prevention of autoimmunity to nuclear constituents. C3-deficient humans are not known to have developmental problems, defects in hemostasis or angiogenesis, or problems with wound healing, which suggests that the role of complement in these processes may be less critical.
Detrimental functions — In pathologic conditions featuring autoantibodies and immune complexes, complement activation contributes to cell and tissue damage [22,23]. In acute injury states (membrane damage, apoptosis, necrosis), the system plays an important role in the host's response to altered self. Failure of this clearance role predisposes to autoimmunity, particularly SLE. Complement activation occurring in early pregnancy predicts an adverse outcome in patients with SLE and/or antiphospholipid antibodies [24]. Similarly, the proper handling of self-debris is also associated with other common illnesses of the developed world, including AMD (retinal debris), atherosclerosis (lipoproteins/lipids), Alzheimer disease (misfolded protein/amyloid), and gout (urate crystals) [25-27].
While the complement system is engaged in these common diseases of aging humans, its role in pathogenesis is uncertain. Complement deposits at the sites of lipoproteinaceous debris, such as plaques, but this may largely be a bystander process. In contrast, there are unequivocal genetic data implicating the complement system's alternative pathway in the pathogenesis of AMD [28-30]. (See "Age-related macular degeneration".)
New links between complement components and schizophrenia have been suggested. In particular, complement component C4 and CSMD1 (CUB and Sushi multiple domains 1) variation each has been linked to the development of schizophrenia [31,32]. C4 is a duplicated gene and 1 of approximately 300 human genes that feature copy number variation. Increasing copies of the C4A gene were shown to be associated with the development of schizophrenia. C4 localized to neuronal synapses may trigger runaway pruning of the communications infrastructure. Additionally a single nucleotide polymorphism in CSMD1 was identified as one of the top genome-wide risk alleles for schizophrenia [32]. Thus, new results are implicating excessive complement activity in the development of schizophrenia. (See "Schizophrenia in adults: Epidemiology and pathogenesis", section on 'Genetic factors'.)
COMPLEMENT MEASUREMENT — Complement levels are evaluated by antigenic and functional assays [33-36]. The most frequently used complement tests are immunoassays for antigenic levels of C3 and C4 and functional assessment via the total hemolytic complement (THC or CH50). Functional assays are also commercially available for the lectin pathway and alternative pathway.
CH50 — The total hemolytic complement (THC or CH50) assesses the ability of serum to lyse sheep erythrocytes optimally sensitized with rabbit immunoglobulin M (IgM) antibody. All nine components of the classical pathway (C1 through C9) are required to give a normal CH50. CH50 is therefore a useful screening tool for detecting a deficiency of the classical pathway, resulting from either an inherited defect of a single component or from activation of a pathway, leading to lowered levels of several components. It does not assess the entire alternative pathway, because factors B and D and properdin are not required for the classical pathway activation. They are early components of only the alternative pathway.
A normal CH50 value/titer ranges from 150 to 250 units/mL in a commonly employed functional (hemolytic) assay system. The titer is the reciprocal of the dilution of serum required to lyse 50 percent of the antibody-coated sheep erythrocytes (eg, a CH50 titer of 200 units means that the human test serum lysed 50 percent of the erythrocytes at a dilution of 1:200).
Low CH50 — A very low or zero CH50 can result from a genetic deficiency of one or more complement proteins in the classical pathway. Less dramatic reductions in CH50 are seen in pathologic processes secondary to immune complex formation. It is the classical pathway that is most commonly involved in these autoantibody-mediated diseases. The underlying problem is the production of the autoantibody. In this case, the complement system is responding as it was intended to do. (Related Lab Interpretation Monograph(s): "Low total hemolytic complement (CH50) in adults".)
The following are clinical examples:
●A child presents with recurrent pyogenic bacterial infections in the setting of a normal white blood cell count and normal gamma globulin levels. An extremely low CH50 value (eg, ≤10 units/mL) is consistent with a homozygous deficiency of a classical pathway component. C1q, C4, C2, or C3 deficiency could present this way. If the infecting organism is a Neisserial species, then C5, C6, C7, C8, or C9 deficiency should also be considered. If the child is male with a family history of Neisserial infections and the CH50 is normal, diagnosis of properdin deficiency should be considered. The clinical presentations of inherited complement deficiencies are reviewed separately. (See "Inherited disorders of the complement system".)
●Less dramatic reductions in the CH50 are characteristic of activation of the classical pathway (as may be seen in systemic lupus erythematosus [SLE]), reflecting consumption by immune complexes more rapidly than the components can be replaced by the liver. CH50 is also moderately reduced in neonates, as it takes several years to reach adult levels. (See 'Impact of age on complement pathways' below.)
Laboratory error — A common cause of a low CH50 is improper specimen handling. The CH50 assay requires appropriate collection, processing, and storage of specimens, since several complement proteins are unstable. C3 and C4 antigenic levels will be normal in this situation, but they will lack functional activity. Serum samples should be assayed the day of collection or immediately frozen for subsequent analysis. A very low CH50 should be checked on a separately obtained sample.
Cold activation — Another cause of a falsely low CH50 is "cold activation," which can occur in the presence of complement-activating immune complexes, such as mixed cryoglobulins or cold-reacting complexes that do not precipitate in the cold. The usual presentation is a very low (even zero) CH50 with moderately reduced or normal antigenic levels of C4 and C3 in a patient with an inflammatory disease (eg, SLE or chronic viral hepatitis) [37].
Elevated CH50 — CH50 or individual proteins, such as C3 or C4, may increase up to 50 percent of baseline values as part of the acute-phase response. Beyond this, an elevated CH50 has no specific clinical significance. This is an expected part of the host's response to infection and injury. High levels in themselves do not lead to tissue damage, as the proteins are not in their activated state, and regulators tend to increase in parallel.
Cytokines, such as interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor (TNF), are typically released at sites of inflammation and then travel via the circulation to the liver, where they increase hepatic synthesis of complement proteins. Chronically, very high C3 levels, up to five times baseline, have been reported, albeit rarely, in hematopoietic malignancies [38]. Resolution of the inflammation or removal of a tumor will promptly lead to the values returning to baseline. (See "Acute phase reactants".)
AH50 — The AH50 is a measure of the total functional activity of the alternative pathway. This assay is similar to the CH50 but measures lysis of unsensitized rabbit red blood cells under conditions that allow only alternative pathway activation. It can be performed in referral laboratories. The most common indication for obtaining an AH50 is the evaluation of certain renal diseases in childhood, especially those featuring a thrombotic microangiopathy or glomerulonephritis. Additionally, a very low or undetectable AH50 occurs in patients with factor B or factor D deficiency who almost always present with Neisserial infections. Note that properdin, a positive regulator of complement, is not assessed in some AH50 assays, while in others, it is required. Further, the gene for properdin is on the X chromosome. Thus, males are affected, and there is commonly a positive family history. As noted, the alternative pathway's AH50 and the classical pathway's CH50 will be very low or undetectable in C5, C6, C7, C8, or C9 deficiency, since the terminal cascade is common to both pathways. (See "Membranoproliferative glomerulonephritis: Treatment and prognosis" and "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis".)
Measurement of specific components — Antigenic levels of C3 and C4 are commonly used in clinical practice and are accurately performed by clinical laboratories. They are usually measured by nephelometric immunoassays. The antigenic and functional levels of other complement proteins can also be assessed, although such testing is usually performed by specialized laboratories. Tests of specific complement components are indicated to evaluate a very low CH50 and determine which component is deficient or dysfunctional. In most cases, the antigenic level of a component accurately reflects its functional capacity. (See "Inherited disorders of the complement system".)
Serum C3 and C4 levels — The measurement of C3 and/or C4 can assist in the diagnosis of certain diseases (especially SLE), as well as in monitoring the course of the disease. Other diseases featuring autoantibodies leading to immune complex formation are the antiphospholipid syndrome, mixed cryoglobulinemia, Sjögren syndrome, and membranoproliferative glomerulonephritis. Low C4 and C3 or low C3 alone can indicate the presence of any of these disorders. On the other hand, increasing levels indicate a response to treatment. (Related Lab Interpretation Monograph(s): "Low C4 and/or C3 in adults".)
Normal C3 levels range from approximately 80 to 160 mg/dL. Normal C4 levels range from 16 to 48 mg/dL.
●Lupus is the prototypic disease for which the most clinical information is available, relative to interpreting and following C3 and C4 levels. A typical scenario is the following: a 20-year-old female presents with pleurisy, pericarditis, thrombocytopenia, and nephritis. The antinuclear antibody (ANA) is positive with a high titer, and DNA antibodies are present. The C4 is low at 8 mg/dL, and the C3 is low at 60 mg/dL, indicating classical pathway activation due to immune complexes. Treatment is initiated with glucocorticoids and a cytotoxic agent. Over the next three months, the C4 and C3 levels return to normal values. These are then followed subsequently to help define clinical status. Normalization of complement values is a good prognostic sign. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Laboratory evaluation'.)
●Low C4 (with normal C3) is useful in the diagnostic evaluation of disorders that cause angioedema, such as hereditary angioedema and acquired C1 inhibitor deficiency. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis" and "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)
●Normal C4 and a low C3 suggest alternative pathway activation.
Other complement tests
●There are assays for the activation or cleavage fragments of certain components, such as the anaphylatoxins (C5a and C3a), iC3b and C3d, Ba and Bb, or soluble C5b-9. Increased levels reflect ongoing activation of the complement system. However, because the interpretation of these tests is problematic and their role in evaluating a variety of human diseases has not been firmly established, these tests are uncommonly used or required for routine clinical practice. Complement activation products are being increasingly measured, particularly in patients with SLE [39].
●Immunofluorescence staining with antibodies can be used to assess tissue deposition of components, such as C1q, or activation fragments of C4 and C3. This is most commonly performed on kidney and skin biopsies. Deposition of C1q and C4b in tissues supports activation of the classical pathway, while deposition of C3b alone suggests alternative pathway activation.
●The presence of C3 fragments on erythrocytes in hemolytic anemias can be assessed by agglutination of the erythrocytes with specific antibodies. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Direct antiglobulin (Coombs) testing'.)
●In cold agglutinin disease and other autoimmune hemolytic anemias, C3 and C4 fragments can be detected as a clinical disease marker on the surface of red blood cells. CH50, C3, and C4 levels may also be low in hemolytic anemias, especially cold agglutinin disease [40]. (See "Cold agglutinin disease", section on 'Pathogenesis'.)
●The measurement of proteolytically-derived complement component fragments (split products) of C3, C5, C2, and factor B is technically difficult and expensive, although they can be helpful in the setting of normal or persistently low complement levels. Some companies are promoting tests of complement split products and of complement fragments bound to cells. Their role in routine clinical practice, such as for monitoring SLE, remains to be established. The measurement of split products has two advantages over the measurement of whole components. Split products are not affected by the acute-phase response, since they are only produced by complement activation. In addition, split products appear to be more sensitive markers for in vivo complement activation. However, these tests are uncommonly pursued for the reasons noted above, as well as their possible generation following blood drawing.
Impact of age on complement pathways — There does not appear to be significant maternal transfer of complement proteins across the placenta. Term infants have high variability in both classical and alternative pathway activity, secondary to reduced levels of individual components of the complement system. Thus, variable decreases in alternative and classical pathway hemolytic activity (AH50 and CH50) may be observed.
Preterm infants have a more consistent decrease in these measurements and in levels of C3 and C4, when compared with term infants. Complement levels increase after birth and reach adult levels between 6 to 18 months of age.
In contrast, there are no comprehensive data indicating that plasma complement function is reduced with normal aging, although one study found a large increase in C1q in the central nervous system of humans and mice in association with aging [41].
PATTERNS ASSOCIATED WITH ACTIVATION OF SPECIFIC PATHWAYS — Complement activation accompanies many infectious and inflammatory processes. The pattern of complement abnormalities can provide diagnostic clues to the underlying disease process (table 1).
Classical pathway activation — Classical pathway activation is commonly indicated by low levels of C4 and C3. Another pattern seen with classical pathway activation is low C4 and normal C3.
There are three common explanations for how levels of C4 can be reduced in the setting of normal C3:
●The basal concentration of serum C3 is three to six times higher than that of C4. Thus, classical pathway activation may lower the C4 out of the normal range, while the amount of C3 is reduced but remains within normal limits. The clinician is unlikely to recognize this point initially, since a patient's predisease C3 concentration is rarely known. To illustrate, a systemic lupus erythematosus (SLE) patient could have a predisease C3 level of 150 mg/dL, which decreases to 100 mg/dL at clinical onset of disease. Thus, C3 remains in the "normal range," despite considerable C3 consumption, while C4 is below the normal range.
●In hereditary angioedema, C1 excessively cleaves C4 and C2 in plasma because of a deficiency of the C1 inhibitor. However, a C3 convertase does not form efficiently in plasma (fluid phase) because the complement system is designed to work on a biologic membrane. Thus, patients with hereditary angioedema have very low C4 but normal C3. A similar phenomenon may occur in syndromes involving excessive soluble immune complexes, such as mixed cryoglobulinemia, SLE, and membranoproliferative glomerulonephritis. In this situation, the C3 convertase would form on a soluble immune complex, and this is inefficient in developing C3 convertases.
●The third mechanism by which C4 can be reduced in the setting of normal C3 is genetic partial deficiency of C4. This is discussed separately. (See "Inherited disorders of the complement system", section on 'C4 deficiency'.)
Therefore, the finding of low C4 and normal C3 should prompt consideration of SLE, mixed cryoglobulinemia, membranoproliferative glomerulonephritis types I and III, and hereditary or acquired angioedema. The combination of a low C4, normal C3, and a positive test for cryoglobulins should prompt further investigation for the presence of hepatitis B and C. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Laboratory testing' and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis" and "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis".)
Alternative pathway activation — Alternative pathway activation is indicated by decreased factor B and C3 and normal levels of C4 (figure 1). Complement activation via alternative pathway activation is uncommon in clinical medicine. However, the combination of low C3 and normal C4 in a patient with an inflammatory/vasculitic disease process, especially with kidney involvement, almost always indicates alternative pathway activation. This can be further confirmed by measuring factor B and/or an AH50. Both factor B and the AH50 should be low. However, tests for factor B and the AH50 are not widely available and will need to be sent to a commercial laboratory. Usually, this is not necessary for diagnosis.
●Alternative pathway activation is observed in several types of pediatric renal disease, especially in association with membranoproliferative glomerulonephritis and the C3 glomerulopathies. Many of these patients have a C3 nephritic factor (C3NeF) (autoantibody that stabilizes the alternative pathway C3 convertase), while a more limited subset have mutations in C3 or one of its regulators (factor H, factor I, or membrane cofactor protein [MCP]). (See "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis".)
●An occasional patient with lupus will also demonstrate activation via the alternative pathway instead of the classical pathway. Immunoglobulin G (IgG) subclasses 2 and 4 do not efficiently activate the classical pathway. However, upon binding antigens, they can provide a protected (from regulators) site to allow for activation of the alternative pathway. A second point is that two antibody molecules (possibly up to six) need to be in close proximity to bind the C1q subunit of the C1 complex [42]. Thus, antibody subclass and antigenic density can play a role in determining which pathway of complement is activated.
●The alternative pathway is also engaged by many types of micro-organisms, as well as during dialysis and heart-lung bypass procedures [43]. Alternative pathway activation commonly occurs at the onset of dialysis and heart-lung bypass but is transient and rarely of clinical significance. In addition, it may be involved in contrast dye reactions and several other types of noninfectious foreign body reactions (eg, some nanoparticles) (table 1) [44]. In most of these interactions, alternative pathway activation is minimal and results in no or transient decreases in C3 or factor B, such that clinical tests are rarely performed. (See "Reactions to the hemodialysis membrane", section on 'Type B reactions' and "Diagnosis and treatment of an acute reaction to a radiologic contrast agent" and "Diagnosis and treatment of an acute reaction to a radiologic contrast agent", section on 'Signs and symptoms'.)
●Heterozygous genetic deficiencies of regulatory complement proteins leading to excessive activation of the alternative pathway have been identified in atypical hemolytic uremic syndrome (aHUS) [25,45,46]. However, the pattern described above (decreased C3 and normal C4) may only be seen in approximately 50 percent of cases, limiting the diagnostic utility of these types of complement studies. Heterozygous gain-of-function mutations in C3 or factor B also lead to a low C3 with a normal C4. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Diagnosis'.)
●Age-related macular degeneration (AMD) features alternative pathway activation in retina. However, this type of local complement engagement is of an insufficient magnitude to lead to substantially altered serum levels and therefore is of limited clinical utility in the diagnosis of this common disease or other conditions featuring localized cellular and tissue injury (atherosclerosis, trauma, Alzheimer disease). In many of these diseases, immunohistochemistry will demonstrate C3 deposition at the injured site. (See "Age-related macular degeneration".)
●While complete deficiency of components commonly leads to bacterial (eg, pus-forming and Neisserial infections), the fact that viruses (eg, the pox viruses and flaviviruses groups) synthesize complement-like inhibitors indicates that they are important in control of certain viral infections as well. Smallpox and related viruses synthesize a regulatory protein (smallpox inhibitor of complement enzymes [SPICE]) that is 30 to 40 percent identical to human complement regulators CD46 (MCP) and CD55 (decay-accelerating factor [DAF]) [47].
Lectin pathway activation — A deficiency of mannose-binding lectin (MBL) appears to be a cause of recurrent infections in children, although MBL deficiency predisposing to infectious or noninfectious tissue damage is controversial [48,49]. Although lectins increase in inflammatory states, they are usually not present in sufficient quantities to cause a reduction in C4 or C3 outside of the normal range. One could view the lectin pathway as a low level alarm system that facilitates the early response to bacterial infections and/or tissue damage (secondary to the presence of altered sugar moieties).
The lectin pathway has been implicated in the pathophysiology of a variety of cardiac conditions but sometimes with opposite or ambiguous functions [50]. The lectin pathway appears to play an important role in the susceptibility to rheumatic fever and clinical progression to rheumatic heart disease [50]. Additionally, activation of the lectin pathway in the glomerulus in immunoglobulin A (IgA) nephropathy has been associated with more severe renal disease [51]. The study implicated a contribution of both MBL and L-ficolin in the progression of disease. As more studies focus on the clinical outcomes of lectin pathway activation, additional associations may be expected.
COMPLEMENT-BASED THERAPIES — Because complement can mediate cell and tissue injury in autoimmune syndromes, it has been a longstanding goal to harness complement inhibitors to prevent undesirable activation. Interest in the complement system has undergone a renaissance, and the search for inhibitors has intensified [52-54]. (See "Regulators and receptors of the complement system".)
●A monoclonal antibody (mAb) to C5, eculizumab, has been shown to inhibit complement-mediated hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH). Also, most patients with complement-mediated atypical hemolytic uremic syndrome (aHUS) are haploinsufficient for a complement regulator, thus leading to excessive alternative pathway activation. Theoretically, eculizumab could be efficacious in any humoral antibody syndrome in which complement is activated, and C5a or the membrane attack complex (MAC) mediates tissue damage. It has also been used in delayed hemolytic transfusion reaction [55]. It may prove to have utility in other diseases in which the complement system is activated, including systemic lupus erythematosus (SLE). (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria" and "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement blockade (eculizumab)'.)
●A second generation eculizumab, called ravulizumab, has been engineered for longer lasting effects and has been approved for treatment of PNH and aHUS [56].
●Pegcetacoplan, a pegylated pentadecapeptide that targets C3, is also being utilized in patients with PNH [57].
●Following the success of anti-C5 mAb therapy in treating PNH and aHUS, there is substantial interest in developing anticomplement reagents. Many mAbs to complement components are in development. Large clinical trials are underway to treat age-related macular degeneration (AMD) by injecting into the eye mAbs to block alternative pathway activation [22,58].
●Avacopan, an orally administered small molecule C5a receptor antagonist, is approved for the treatment of ANCA-associated vasculitis [59].
●C1 inhibitor replacement – Recombinant and serum-derived preparations of C1 inhibitor have been used for decades to treat hereditary and acquired angioedema. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'C1 inhibitor (plasma derived)' and "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Recombinant C1 inhibitor'.)
●Organs from transgenic pigs that can be made to express human complement regulatory proteins are relatively resistant to hyperacute rejection mediated by complement when transplanted into primates (xenotransplantation). This experimental technology may someday allow for xenotransplantation of various organs. (See "Kidney transplantation in adults: Xenotransplantation".)
SUMMARY
●Biologic roles of complement – The complement system is important in the defense of host against microbes, particularly bacteria. It also serves as a mechanism to identify and clear injured tissue and cellular debris. Thus, it is a major player in innate immunity and an effector arm of the humoral immune system. (See 'Introduction' above.)
●Pathways – The three well-recognized divisions of the complement system are the classical, alternative, and lectin cascades (figure 1). Each pathway is activated by a different mechanism. The major goal of all three cascades is the deposition of substantial quantities of C3b on a target (opsonization), which marks it for elimination. Engagement of each pathway also leads to the release of proinflammatory anaphylatoxins (C3a and C5a) and assembly of the membrane attack complex (MAC). (See 'Pathways and activating conditions' above.)
●Functions of complement – In pathologic conditions featuring autoantibodies and immune complexes, complement activation contributes to cell and tissue damage. In acute injury states (membrane damage, apoptosis, necrosis) and with deposition of debris (lipids, proteins, pigments, crystals), the system plays an important role in the host's response to altered self. Failure of this clearance role predisposes to autoimmunity, particularly systemic lupus erythematosus (SLE). (See 'Functions of the complement system' above.)
●Assessing complement function – Complement levels can be evaluated either by antigenic or functional assays. The CH50 is a functional assay that requires all nine components of the classical pathway (C1 through C9) for a normal result. A homozygous deficiency of classical pathway components is indicated by an extremely low CH50 value (≤10 units/mL). Less dramatic reductions in CH50 are seen in pathologic processes secondary to immune complex formation. A low CH50 can also result from laboratory error and "cold activation." (See 'CH50' above.)
●C3 and C4 – The measurement of C3 and/or C4 can assist in the diagnosis of certain diseases (especially SLE), as well as in monitoring the course of the disease. Other diseases featuring autoantibodies leading to immune complex formation are the antiphospholipid syndrome, mixed cryoglobulinemia, Sjögren syndrome, and membranoproliferative glomerulonephritis. Low C4 and C3 or low C3 alone can indicate the presence of any of these disorders. (See 'Serum C3 and C4 levels' above.)
●Complement deficiencies – Genetic deficiencies (usually haploinsufficiency of complement inhibitory proteins) leading to excessive activation of the alternative pathway have been identified in atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy, and age-related macular degeneration (AMD). Genetic variation in the copy number of C4 genes in the brain is associated with increased risk of schizophrenia. (See 'Alternative pathway activation' above.)
●Complement-based therapies – A monoclonal antibody to C5 is available to treat paroxysmal nocturnal hemoglobinuria (PNH) and aHUS. Many novel therapeutic agents are in development to treat undesirable complement activation. (See 'Complement-based therapies' above.)
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