The complement system is an ancient and essential component of innate immunity, consisting of over thirty circulating and membrane-bound proteins that work together to eliminate pathogens. Despite being part of the innate response, complement activation enhances and is enhanced by adaptive immunity, creating a bridge between the two arms of the immune system.
The Three Activation Pathways
The classical pathway is initiated by the binding of C1q to the Fc region of IgG or IgM antibodies that have bound to antigen, making it a link between adaptive and innate immunity. C1q, together with C1r and C1s, forms the C1 complex, which cleaves C4 and C2 to generate C3 convertase (C4b2a). The lectin pathway is triggered by mannose-binding lectin (MBL) or ficolins binding to carbohydrate patterns on microbial surfaces, leading to activation of MBL-associated serine proteases (MASPs) that also cleave C4 and C2 to form the same C3 convertase. The alternative pathway is constitutively active at low levels through the spontaneous hydrolysis of C3 (tickover), generating C3(H₂O) that binds factor B, which is cleaved by factor D to form an initial C3 convertase. This pathway is amplified on pathogen surfaces that lack complement regulatory proteins.
The C3 Convertase and the Amplification Loop
All three pathways converge at the formation of C3 convertase, which cleaves C3 into C3a and C3b. C3b is opsonically active, covalently binding to pathogen surfaces through a reactive thioester bond. The deposition of C3b on a surface forms additional C3 convertase (C3bBb) through the alternative pathway, creating a powerful positive feedback loop — each C3 convertase molecule can generate multiple C3b molecules, rapidly coating the pathogen surface with opsonin. C3a is released into the fluid phase as an anaphylatoxin that promotes inflammation.
The Terminal Pathway and Membrane Attack Complex
The C5 convertase (C4b2a3b in classical/lectin, C3bBb3b in alternative) is formed when C3b binds to an existing C3 convertase, changing its specificity from C3 to C5. C5 convertase cleaves C5 into C5a, a potent anaphylatoxin and chemoattractant, and C5b, which initiates the terminal pathway. C5b sequentially recruits C6, C7, C8, and multiple copies of C9 to form the membrane attack complex (MAC). The MAC inserts into the lipid bilayer of target cells, forming a pore that disrupts membrane integrity, causing osmotic lysis of gram-negative bacteria, enveloped viruses, and other pathogens.
Biological Functions of Complement
Opsonization is the coating of pathogen surfaces with C3b and iC3b, which are recognized by complement receptors (CR1, CR3) on phagocytes, greatly enhancing phagocytosis. The anaphylatoxins C3a, C4a, and C5a bind to specific G protein-coupled receptors on mast cells (triggering degranulation), basophils, neutrophils, and endothelial cells, promoting increased vascular permeability, smooth muscle contraction, and recruitment of immune cells to the infection site. C5a is particularly potent, acting as a chemoattractant for neutrophils, monocytes, and macrophages. Complement also enhances adaptive immunity: C3d bound to antigens is recognized by CR2 (CD21) on B cells, lowering the threshold for B cell activation by up to 10,000-fold and promoting the generation of memory B cells.
Regulation of Complement
Complement is tightly regulated to prevent damage to host tissues. Soluble regulators include C1 inhibitor (C1-INH), which blocks C1r and C1s activity; factor H and factor I, which inactivate C3b in the fluid phase; and C4b-binding protein (C4BP), which accelerates the decay of C3 convertase. Membrane-bound regulators include decay-accelerating factor (DAF/CD55), which dissociates C3 convertases on host cells; membrane cofactor protein (MCP/CD46), which serves as a cofactor for factor I-mediated cleavage of C3b; and CD59 (protectin), which blocks MAC formation by preventing C9 polymerization. The importance of regulation is demonstrated by paroxysmal nocturnal hemoglobinuria, where a mutation in the PIG-A gene causes loss of GPI-anchored complement regulators (DAF, CD59) on erythrocytes, leading to complement-mediated hemolysis.
Complement Deficiencies and Disease
Genetic deficiencies of complement components predispose to specific infections. C1q, C4, C2 deficiencies are strongly associated with systemic lupus erythematosus (SLE), as impaired clearance of apoptotic debris and immune complexes leads to autoimmunity. C3 deficiency results in severe, recurrent pyogenic infections, while deficiencies of the terminal components (C5–C9) increase susceptibility to recurrent Neisseria meningitidis and Neisseria gonorrhoeae infections because MAC formation is essential for killing these bacteria. MBL deficiency is relatively common and may increase susceptibility to respiratory infections in early childhood. Therapeutic complement inhibitors such as eculizumab, a monoclonal antibody that blocks C5 cleavage, are used to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.
