The complement system is part of the innate immune system, functioning as a rapid response mechanism against invading pathogens. It is a network of more than 30 proteins, primarily found circulating in the blood, that supports the ability of antibodies and phagocytic cells to clear foreign material. This system is activated quickly upon recognizing molecular patterns associated with microbes or damaged host cells.
The primary function of the complement cascade is to initiate a defensive response that flags pathogens for destruction and creates an inflammatory environment to recruit additional immune cells. Although separate from the adaptive immune system, complement serves as a crucial bridge, linking the immediate, non-specific response to the slower, targeted antibody-mediated defense. This protein network is fundamental to neutralizing threats before they establish infection.
Components and Cascade Nature of Complement
The complement system consists of circulating, inactive protein precursors, known as zymogens, which must be cleaved to become active enzymes. Components are designated numerically (C1 through C9) and alphabetically (Factors B, D, and Properdin (P)). These proteins are synthesized largely by the liver and circulate at high concentrations.
The system operates as an enzymatic cascade, where the activation of one protein complex triggers the cleavage and activation of many subsequent proteins. This chain reaction generates a rapid immune response. The cascade converges on the central component, C3, the most abundant complement protein in the blood.
Cleavage of C3 into C3a and C3b is the pivotal turning point, as C3b covalently binds to pathogen surfaces, marking them for destruction. The cascade then proceeds to cleave C5 into C5a and C5b, the final enzymatic step before the formation of the terminal effector complex. The larger, active fragment (e.g., C3b) binds to the target surface, while the smaller fragment (e.g., C3a) is released to mediate inflammation.
The Three Distinct Activation Pathways
The complement system is initiated through three distinct methods: the Classical, Lectin, and Alternative pathways. All three converge to form a C3 convertase enzyme, which is responsible for cleaving C3. These pathways represent different mechanisms for recognizing threats, allowing the immune system to respond to a wide array of foreign invaders.
The Classical Pathway is initiated by the binding of the C1 complex to antibody-antigen complexes. The C1 complex (C1q, C1r, and C1s) recognizes the Fc portion of IgM or certain IgG antibodies bound to a microbial surface. Upon binding, C1r and C1s activate, sequentially cleaving C4 and C2 to form the C4b2a complex, the Classical Pathway C3 convertase. This pathway links the adaptive and innate immune responses.
The Lectin Pathway is antibody-independent and is triggered when pattern-recognition molecules, such as Mannose-binding Lectin (MBL) or Ficolins, bind to specific carbohydrate structures (e.g., mannose residues) on pathogen surfaces. MBL binding activates MBL-associated serine proteases (MASPs), which cleave C4 and C2, forming the identical C4b2a C3 convertase complex.
The Alternative Pathway is constantly active at a low level in the blood (“tick-over”) due to the spontaneous hydrolysis of C3 in the plasma. If the resulting C3 fragment binds to a microbial surface, it attracts Factor B, which is cleaved by Factor D, forming the C3bBb complex, the Alternative Pathway C3 convertase. This convertase is stabilized by Properdin (Factor P). C3b generated by any pathway can amplify the Alternative Pathway, creating a powerful positive feedback loop.
Primary Immune Roles of Complement
Once the C3 convertase is formed, the cascade executes the complement system’s primary roles: lysis, opsonization, and the promotion of inflammation.
Lysis (Membrane Attack Complex)
Lysis, the direct killing of a pathogen, is achieved through the formation of the Membrane Attack Complex (MAC). The C5 convertase (formed when C3b associates with the C3 convertase) cleaves C5 into C5a and C5b. The C5b fragment initiates the sequential assembly of C6, C7, C8, and multiple C9 molecules onto the pathogen’s membrane. This C5b-C9 complex forms a pore in the lipid bilayer, disrupting the osmotic balance and causing the pathogen to rupture and die.
Opsonization
Opsonization is the process of tagging a pathogen to make it more recognizable for phagocytic cells. The C3b fragment, generated by the C3 convertase, covalently coats the surface of foreign particles. Phagocytes, such as macrophages and neutrophils, possess specific receptors that recognize and bind to surface-bound C3b. This tagging enhances the rate at which these immune cells engulf and destroy the marked pathogen.
Inflammation
The small, soluble cleavage products, C3a and C5a, are potent molecules known as anaphylatoxins. These fragments are released locally and act as powerful mediators of inflammation. They function as chemoattractants, actively recruiting immune cells, particularly neutrophils, to the site of infection. C3a and C5a also induce mast cells to release histamine, leading to vasodilation and increased vascular permeability, which allows fluid and immune cells to enter the infected tissue.
Regulation: Preventing Self-Damage
The destructive power of the complement cascade necessitates strict regulatory control to ensure host cells are not mistakenly targeted. The system must distinguish between non-self surfaces, where activation is encouraged, and self-surfaces, where it must be rapidly inhibited. Failure in regulation can lead to tissue damage and autoimmune disorders.
Host cells are protected by regulatory proteins, both soluble and membrane-anchored.
Regulatory Proteins
- Decay-Accelerating Factor (DAF, or CD55): This membrane-bound regulator acts early by destabilizing and accelerating the decay of C3 convertase complexes on host cell surfaces.
- Factor H (FH): This fluid-phase regulator binds to C3b and functions as a cofactor for Factor I, an enzyme that cleaves and inactivates C3b.
- CD59 (Protectin): This protein is anchored to the host cell membrane and prevents the formation of the Membrane Attack Complex (MAC). It binds to the C5b-8 complex, inhibiting the final polymerization of C9 molecules and blocking the lytic pore.
These mechanisms ensure the complement system remains an effective defense without causing self-inflicted injury.