The complement system is a network of soluble and membrane-associated proteins within the immune system that helps defend against infection and remove damaged cells and immune complexes. It is a major component of innate immunity, but also interacts with adaptive immunity. Its principal effects are coating targets for uptake, promoting inflammation, and damaging susceptible membranes. These activities arise through coordinated protein activation and are constrained by regulatory mechanisms that protect host tissues. (pubmed.ncbi.nlm.nih.gov)
Components and organization
Complement includes dozens of activation proteins, regulators, and receptors. Many circulating components are produced mainly by the liver, while other tissues also contribute. Components occur in blood and extracellular fluids; receptors and membrane-bound regulators connect their activity to particular cells. Many activating proteins circulate as inactive precursors and acquire activity through cleavage by an enzyme. Complement therefore combines an enzymatic cascade with surface-bound molecular assembly. (ncbi.nlm.nih.gov)
Components are conventionally designated C1 through C9, alongside named factors such as B, D, H, I, and properdin. These numbers do not represent their activation order. Cleavage generates fragments with different functions: C3a is a soluble signaling fragment, whereas C3b can attach covalently to nearby surfaces. C3 occupies a central position because all three principal activation pathways generate enzymes that cleave it. (ncbi.nlm.nih.gov)
Activation pathways
The three principal pathways differ in their initiating recognition mechanisms but converge on C3 convertase formation.
Classical pathway. The classical pathway commonly begins when C1q binds appropriately arranged antibodies attached to an antigen. IgM and certain subclasses of immunoglobulin G can initiate this process. C1q associates with the proteases C1r and C1s; their activation leads to cleavage of C4 and C2. The resulting C3 convertase is commonly written C4b2a. Classical activation is not exclusively antibody-dependent: C1q can also recognize some microbial surfaces and damaged cellular material. (ncbi.nlm.nih.gov)
Lectin pathway. The lectin pathway begins when recognition proteins, including mannose-binding lectin and ficolins, bind characteristic carbohydrate patterns on target surfaces. Associated serine proteases activate C4 and C2, producing the same C3 convertase as the classical pathway. This route provides recognition without requiring antigen-specific antibodies. (pubmed.ncbi.nlm.nih.gov)
Alternative pathway. The alternative pathway can begin through low-level spontaneous hydrolysis of C3, often called “tickover.” Subsequent interactions involving factors B and D generate C3-cleaving activity. Surface-bound C3b recruits factor B, which factor D cleaves to produce the convertase C3bBb; properdin stabilizes this complex. Newly generated C3b supports further convertase formation, creating a positive feedback loop. This pathway also amplifies C3b deposition initiated through either of the other pathways. (ncbi.nlm.nih.gov)
Effector functions
Target coating and uptake. Opsonization is the marking of a target for recognition by phagocytes. C3b and its processed derivative iC3b coat microbial or cellular surfaces and bind complement receptors on macrophages, neutrophils, and other immune cells. These interactions facilitate phagocytosis. Processing C3b into iC3b removes its ability to form convertases while retaining its capacity to promote uptake. (ncbi.nlm.nih.gov)
Inflammatory signaling. C3a and C5a, termed anaphylatoxins, signal through cell-surface receptors. They influence vascular and immune-cell responses; C5a is particularly important in attracting and activating leukocytes. These soluble signals coordinate cellular recruitment with complement activation at a target surface. (ncbi.nlm.nih.gov)
Membrane damage. Additional C3b associated with convertases enables C5 cleavage into C5a and C5b. C5b initiates sequential assembly with C6, C7, C8, and C9 to form the membrane attack complex, or C5b–9. This complex inserts into a cell membrane and can kill susceptible bacteria. Membrane attack does not invariably cause lysis: nucleated host cells may withstand insertion while experiencing sublethal injury or altered signaling. (immunology.org)
Regulation and immune integration
Complement regulators limit activation in both fluids and on cell surfaces. C1 inhibitor restrains initiating proteases of the classical and lectin pathways. Factor H promotes alternative convertase decay and supports factor I-mediated C3b cleavage. CD46 provides cofactor activity for factor I, CD55 accelerates convertase breakdown, and CD59 inhibits terminal membrane attack complex assembly. Together, these mechanisms restrict amplification and reduce injury to host tissues. (ncbi.nlm.nih.gov)
Complement also contributes to clearance of cells undergoing apoptosis and circulating antigen–antibody complexes. On human erythrocytes, complement receptor CR1 binds coated immune complexes and assists their transport to clearance sites. Complement fragments also influence B-cell responses: antigen-associated C3d binds CR2, helping lower the threshold for B-cell activation. Thus, complement participates in both waste removal and antibody-response regulation. (pmc.ncbi.nlm.nih.gov)
Deficiencies and laboratory assessment
Inherited deficiencies can produce immunodeficiency, with consequences depending on the affected component. C3 deficiency is associated with severe recurrent bacterial infections. Deficiencies of terminal components increase susceptibility to Neisseria infections, while deficiencies of early classical components are associated with systemic lupus erythematosus. Conversely, inappropriate activation or defective regulation can contribute to inflammatory tissue injury. (merckmanuals.com)
Laboratory assessment distinguishes component concentrations from functional activity. C3 and C4 measurements quantify individual proteins; CH50 evaluates classical-pathway-dependent hemolytic activity, and AH50 evaluates alternative-pathway-dependent activity. Abnormal functional results can be followed by assays of individual components. Interpretation depends on the combination of findings, because reduced activity may reflect a missing component, defective function, or consumption during activation. (merckmanuals.com)