The complement system is a crucial part of the innate immune system that enhances our ability to eliminate pathogens. It can be activated through three main pathways. The Classical pathway is triggered by antibody-antigen complexes. The Lectin pathway is activated when mannose-binding lectin recognizes carbohydrate patterns on pathogen surfaces. The Alternative pathway is continuously active at low levels, providing constant surveillance. All three pathways converge to activate the central component C3, which initiates a cascade leading to the formation of the Membrane Attack Complex or MAC, resulting in pathogen elimination.
The Classical Pathway is one of the three activation pathways of the complement system. It is triggered when antibodies bind to antigens, forming immune complexes. The activation begins when C1q, part of the C1 complex, recognizes and binds to these antibody-antigen complexes. This binding activates C1r and C1s, which are serine proteases. Activated C1s then cleaves complement component C4 into C4a and C4b. C1s also cleaves C2 into C2a and C2b. The C4b fragment binds to the target surface, and C2a associates with C4b to form the C3 convertase, known as C4b2a. This enzyme complex then cleaves C3 into C3a and C3b. C3b acts as an opsonin, marking pathogens for phagocytosis, while C3a functions as an anaphylatoxin, promoting inflammation.
The Alternative Pathway is unique among complement activation pathways because it's continuously active at low levels, providing constant immune surveillance. This pathway begins with a process called 'tickover,' where C3 spontaneously hydrolyzes to form C3(H2O). Factor B can then bind to C3(H2O), and Factor D cleaves the bound Factor B to form the initial fluid-phase C3 convertase, C3(H2O)Bb. This convertase cleaves C3 into C3a and C3b. The C3b fragment can covalently bind to nearby cell surfaces. On pathogen surfaces, Factor B binds to this surface-bound C3b, and Factor D cleaves it to form the surface-bound C3 convertase, C3bBb. Properdin, a positive regulator, stabilizes this convertase, extending its half-life. The surface-bound convertase then cleaves more C3, generating additional C3b molecules that can form more convertases. This creates an amplification loop that rapidly increases complement activation on pathogen surfaces. Host cells are protected from this amplification by regulatory proteins that disrupt the convertase. This discrimination between self and non-self surfaces is a critical feature of the Alternative Pathway.
The Terminal Pathway represents the final stage of complement activation, culminating in the formation of the Membrane Attack Complex, or MAC, which can directly lyse target cells. This pathway begins when the C5 convertase, which can be formed through any of the three activation pathways, cleaves C5 into C5a and C5b. C5a is a potent anaphylatoxin that promotes inflammation, while C5b initiates the assembly of the MAC. C5b binds to C6, forming C5b6. This complex then binds C7, creating C5b67, which undergoes a hydrophilic-to-amphipathic transition that allows it to insert into the target cell membrane. Once inserted, C5b67 binds C8, which causes an initial small pore in the membrane. Finally, C5b678 binds multiple C9 molecules, which polymerize to form a complete transmembrane pore. This MAC pore disrupts the cell membrane's integrity, allowing free passage of water and ions, leading to osmotic lysis of the target cell. This mechanism is particularly effective against gram-negative bacteria, enveloped viruses, and other pathogens with accessible cell membranes.
Regulation of the complement system is crucial to prevent damage to host tissues and maintain homeostasis. The system is controlled by both fluid-phase and membrane-bound regulatory proteins. In the fluid phase, C1 Inhibitor, or C1-INH, inactivates C1r, C1s, and MASPs, controlling the classical and lectin pathways. Factor H accelerates the decay of the alternative pathway C3 convertase and acts as a cofactor for Factor I. Factor I is a serine protease that cleaves C3b and C4b when bound to cofactors, inactivating these components. C4b-Binding Protein accelerates the decay of the classical pathway C3 convertase. S Protein, also known as vitronectin, prevents MAC insertion into host cell membranes. On host cell surfaces, membrane-bound regulators provide additional protection. CD46, or Membrane Cofactor Protein, serves as a cofactor for Factor I. CD55, or Decay-Accelerating Factor, accelerates the decay of C3 convertases. CD59, or Protectin, prevents the polymerization of C9, inhibiting MAC formation. CR1, or Complement Receptor 1, binds C3b and C4b and acts as a cofactor for Factor I. These regulatory mechanisms ensure that complement activation is focused on pathogens while protecting host tissues from damage. Deficiencies in these regulators can lead to autoimmune diseases and other pathological conditions, highlighting their importance in maintaining immune homeostasis.