The complement system is a sophisticated part of the innate immune response, acting as a rapid defense mechanism in the blood plasma and tissue fluids. This system consists of a cascade of over 20 distinct proteins, primarily synthesized by the liver, that circulate in an inactive form. When triggered, these proteins undergo sequential cleavage and activation, creating an enzymatic chain reaction that amplifies a small initial signal into a potent biological response used to identify and eliminate invading pathogens and clear damaged host cells.
The initiation of this system occurs through three distinct routes: the Classical, the Lectin, and the Alternative pathways. Although each pathway is triggered differently, they all converge on a common terminal sequence to achieve the same protective outcomes. The Classical Pathway serves as a link between the body’s rapid innate immunity and the highly specific adaptive immune response.
Initiation and Recognition
The Classical Pathway is initiated by the recognition of immune complexes, which are formations of antigens bound to antibodies. The pathway’s first component, the C1 complex, is responsible for this recognition and consists of one C1q molecule and two molecules each of the serine proteases C1r and C1s.
The C1q subunit, which possesses a bouquet-like structure with six globular heads, is the physical sensor for activation. It specifically binds to the constant fragment (Fc) region of certain antibody classes, primarily Immunoglobulin M (IgM) and specific subclasses of Immunoglobulin G (IgG). IgM is a potent activator because its pentameric structure provides multiple binding sites, ensuring stable engagement with C1q.
Binding of the C1q globular heads to the clustered antibodies induces a conformational change within the C1 complex. This structural alteration triggers the auto-activation of the C1r molecules, converting them into active proteases. The active C1r then cleaves and activates the C1s subunits, creating a fully functional C1 enzyme complex. While antibody-antigen complexes are the primary activators, C1q can also bind directly to non-antibody ligands, such as C-reactive protein, viral proteins, and components on the surface of apoptotic cells, providing a mechanism for antibody-independent activation.
The Enzymatic Cascade
Once the C1 complex is activated, the C1s enzyme initiates the enzymatic cascade by acting on C4 and C2. The C1s protease cleaves C4 into two fragments, C4a and C4b. The larger C4b fragment contains a reactive internal thioester bond that allows it to bind covalently to the surface of the pathogen or target cell near the activating C1 complex.
The surface-bound C4b acts as a docking site for C2. C1s cleaves C2 into C2b and C2a, and the C2a fragment remains associated with the surface-bound C4b. This assembly, C4b2a, is known as the Classical Pathway C3 convertase. The catalytic activity of this enzyme resides in the C2a subunit, which functions as a serine protease.
The C3 convertase executes its primary function: the cleavage of the abundant complement protein C3. It hydrolyzes C3 into two fragments, C3a and C3b, generating significant signal amplification. The larger C3b fragment, like C4b, possesses a reactive thioester bond, allowing it to covalently attach to the target surface.
A portion of the deposited C3b fragments binds directly to the existing C3 convertase (C4b2a). This addition transforms the complex into C4b2a3b, which is the Classical Pathway C5 convertase. The C5 convertase then cleaves the C5 protein into C5a and C5b, marking the point where the separate activation pathways converge onto the final common pathway.
Terminal Events and Biological Outcomes
The activation of C5 by the C5 convertase initiates the final phase, resulting in the three biological outcomes of the complement system: opsonization, inflammation, and cell lysis.
Opsonization
The C3b fragments coating the pathogen surface serve as a molecular tag, a process called opsonization. Phagocytic cells, such as macrophages and neutrophils, possess receptors that specifically recognize and bind to these surface-bound C3b molecules. This binding significantly enhances the rate at which the pathogen is engulfed and destroyed.
Inflammation
The smaller fragments released during the cascade, C3a and C5a, function as potent signaling molecules known as anaphylatoxins. C3a and C5a are powerful chemoattractants that recruit immune cells, like neutrophils and monocytes, to the site of infection. They also trigger mast cells and basophils to degranulate, releasing inflammatory mediators such as histamine, which increases vascular permeability and contributes to the local inflammatory response.
Cell Lysis
The larger C5b fragment remains surface-bound and acts as the foundation for the Membrane Attack Complex (MAC). C5b sequentially recruits and binds to C6, C7, and C8, forming the C5b-8 complex, which inserts itself into the target cell membrane. This complex then catalyzes the polymerization of multiple copies of the C9 protein to form a transmembrane channel, or pore. The MAC creates an opening in the pathogen’s membrane, disrupting the osmotic balance and leading to rapid cell death through lysis.
Natural Control Mechanisms
The complement cascade requires a strict system of regulation to prevent indiscriminate attack on healthy host cells. The body employs various regulatory proteins, both soluble and membrane-bound, to restrict the Classical Pathway to the surfaces of pathogens and damaged cells. Without this tight control, the system could cause significant collateral damage to host tissue.
One fluid-phase regulator is C1 Inhibitor (C1INH), a serine protease inhibitor that acts immediately upon the initial activation step. C1INH binds to and inactivates the C1r and C1s components, dissociating them from the C1q molecule and shutting down the initial enzymatic engine. This action prevents further cleavage of C4 and C2, limiting the scale of the cascade.
Regulation also focuses on the active C3 convertase enzyme, C4b2a. Membrane-bound proteins on host cells, such as Decay Accelerating Factor (DAF, or CD55) and Complement Receptor 1 (CR1), function to destabilize this complex. DAF accelerates the dissociation of the C2a subunit from the C4b scaffold, rapidly dismantling the active C3 convertase enzyme. This mechanism ensures that any C3 convertase forming inadvertently on a host cell surface is quickly deactivated, providing self-protection.