Definition and General Characteristics
The complement system is a cascade of plasma proteolytic enzymes that provides humoral defense against foreign agents and participates in the immune response. Complement proteins are synthesized primarily in the liver, circulate in an inactive form, and are activated through sequential proteolytic cleavage.
Components are designated as C1–C9. They enter the reaction not in numerical order, but in a strictly defined sequence. Cleavage of each protein yields small fragments (C4a, C2b, C3a, C5a) and large fragments (C4b, C2a, C3b, C5b). Small fragments act as anaphylatoxins, while large fragments participate in building enzymatic complexes known as convertases.
The C1 protein is of particular importance: it consists of six C1q subunits (binding to the Fc region of antibodies), as well as C1r and C1s—serine proteases that are activated when C1q binds to at least two IgG molecules or one IgM molecule. Calcium ions are required for activation.
Functions of the Complement System
Three main functions are distinguished:
- Pathogen opsonization — facilitating phagocytosis through the fixation of C3b and C4b on the microbial surface.
- Recruitment and activation of leukocytes by anaphylatoxins C3a, C4a, and C5a at the site of inflammation.
- Pathogen lysis through the formation of the membrane attack complex (MAC), which creates an unregulated pore in the bacterial membrane.
Additional functions: bridging innate and adaptive immunity, enhancing antibody production, participating in the formation of immunological memory, clearing the lesion site, and eliminating immune complexes from tissues.
Classical Pathway
Evolutionarily recent, but the first pathway to be described. The recognition principle is the binding of highly specific antibodies to an antigen on the pathogen surface. The leading role belongs to the C1 protein, which binds to the Fc region of antibodies (CH2 domain of IgG, CH3 domain of IgM) or to C-reactive protein. Antibodies must be fixed to the antigen; activation requires at least two IgG molecules or one pentameric IgM molecule.
Reaction cascade:
- Activated C1 cleaves C4 (into C4a and C4b) and C2 (into C2b and C2a).
- C4b and C2a form the classical pathway C3 convertase (C4b2a).
- The C3 convertase cleaves C3 into C3a (anaphylatoxin) and C3b.
- The addition of C3b forms the C5 convertase (C4b2a3b), which cleaves C5 into C5a and C5b.
Lectin Pathway
The second oldest pathway. Principle: recognition of pathogen-associated molecular patterns (PAMPs) by innate immunity lectins: mannose-binding lectin (MBL) and ficolins. MBL binds to mannose, while ficolins bind to N-acetylglucosamine on the bacterial cell surface.
In structure, MBL and ficolins are analogous to C1q, but are associated with the serine proteases MASP-1 and MASP-2. Subsequent steps are identical to the classical pathway: cleavage of C4 and C2, formation of the C3 convertase (C4b2a), followed by the C5 convertase and generation of C5b. The key difference lies in the method of pathogen recognition and the initial recognition complex.
Alternative Pathway
Evolutionarily the oldest pathway. Activated by the principle of "missing self"—the absence of complement inhibitor proteins on the target cell. A key role is played by component C3, which belongs to the thioester-containing protein family.
Cascade steps:
- Spontaneous hydrolysis of C3 into C3a and C3b; C3b is covalently fixed to the foreign surface.
- Factor B binds to C3b and is cleaved into Ba and Bb under the action of factor D.
- The alternative pathway C3 convertase (C3bBb) is formed, stabilized by properdin—the only known positive regulator of the complement system, secreted by activated neutrophils.
- The addition of a second C3b molecule forms the C5 convertase (C3bBb3b), which cleaves C5.
Terminal Stages and Membrane Attack Complex
The terminal (lytic) stages are identical for all three pathways. The main task is the formation of an unregulated ion channel in the target cell membrane.
MAC assembly sequence:
- C6, C7, and C8 bind sequentially to the C5b fragment.
- The resulting complex inserts into the membrane and binds C9 molecules, which polymerize to form a transmembrane pore.
- An unregulated influx of ions and water occurs through the pore, disrupting osmotic pressure and leading to osmotic lysis of the cell.
This pore-formation mechanism is universal for other systems as well (such as perforin in cytotoxic lymphocytes) and invariably leads to the death of the target cell.
Key points
- The complement system is a cascade of proteolytic enzymes C1–C9 synthesized in the liver.
- Three activation pathways: classical (IgG/IgM antibodies + C1), lectin (MBL/ficolins + MASP), and alternative (spontaneous C3 hydrolysis, factor B, factor D).
- All pathways converge on the formation of C3 convertase and C5 convertase.
- Anaphylatoxins C3a, C4a, and C5a recruit leukocytes; C3b and C4b opsonize the pathogen.
- Properdin is the only positive regulator, stabilizing the alternative pathway C3 convertase.
- The terminal stage is identical for all pathways: assembly of the MAC from C5b–C9 with pore formation.
- Functions of complement: opsonization, chemoattraction, lysis, elimination of immune complexes, and bridging innate and adaptive immunity.
- Activation of the classical pathway requires at least two IgG molecules or one IgM molecule bound to the antigen.