The complement system is a complex network of proteins in the blood that plays a role in the body’s innate immune defenses. It helps to protect against pathogens and clear damaged cells. This system consists of multiple pathways, and this article focuses on the classical pathway.
Initiation of the Classical Pathway
The classical pathway begins when antibodies attach to a pathogen’s surface. Immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies bind to antigens on a microbial surface. This antigen-antibody complex creates a binding site for C1, the first protein of the complement system.
The C1 protein is a complex made up of three subunits: C1q, C1r, and C1s. When C1q binds to the Fc region of attached IgG or IgM antibodies, it undergoes a conformational change. This activates the C1r subunit, which in turn activates the C1s subunit, giving C1s enzymatic capabilities.
While antibody binding is the primary trigger, the classical pathway can also be initiated without antibodies. C-reactive protein (CRP), an acute phase protein produced during inflammation, can bind to microbial surfaces or damaged cells. This binding allows C1q to attach, leading to the activation of the C1 complex.
The Enzymatic Cascade
Once the C1 complex is activated, the C1s subunit cleaves complement protein C4 into C4a and C4b. The C4b fragment then binds covalently to the pathogen’s surface, while C4a is released into the surrounding fluid.
C1s also cleaves complement protein C2 into C2a and C2b fragments. The C2a fragment associates with the surface-bound C4b, forming the C3 convertase of the classical pathway (C4b2a). This convertase is a key enzyme in the cascade, responsible for amplifying the immune response.
The C3 convertase (C4b2a) then cleaves many molecules of complement protein C3, resulting in C3a and C3b. C3a is released into the surrounding environment, while C3b can either bind to the pathogen’s surface or attach to the existing C3 convertase.
When C3b binds to the C3 convertase (C4b2a), it forms the C5 convertase (C4b2a3b). This formation increases the enzyme’s affinity for its next substrate. The C5 convertase then cleaves complement protein C5, yielding C5a and C5b.
Primary Functions and Effects
The fragments generated during the classical pathway cascade perform several distinct functions that contribute to pathogen elimination.
Anaphylatoxins
Two small fragments, C3a and C5a, are known as anaphylatoxins. These molecules act as signaling molecules, attracting phagocytic immune cells like neutrophils and macrophages to the site of infection. This recruitment helps to concentrate immune defenses where they are most needed.
Opsonization
C3b coats the surface of pathogens. This coating acts as an “eat me” signal, a process called opsonization. Immune cells, particularly phagocytes, have receptors that recognize C3b, allowing them to more efficiently engulf and destroy the marked pathogens.
Cell Lysis
The final step of the pathway leads to direct cell lysis. The C5b fragment, generated by the C5 convertase, initiates the assembly of the Membrane Attack Complex (MAC). C5b recruits complement proteins: C6, C7, C8, and C9.
The C9 molecules then polymerize to form a pore within the pathogen’s cell membrane. This pore disrupts the membrane’s integrity, allowing water and ions to rush into the cell. The influx of fluid causes the pathogen to swell and ultimately rupture, leading to its destruction.
Regulation of the Pathway
The complement system requires strict regulation to prevent damage to healthy host cells. The body employs various regulatory proteins present on its own cells, which are typically absent or less effective on microbial surfaces. These regulators ensure complement activation is targeted at pathogens and not at healthy tissues.
C1 Inhibitor (C1-INH)
C1-INH prevents the spontaneous activation of the C1 complex and dissociates its active C1r and C1s subunits from C1q, halting the classical pathway. A deficiency in C1-INH can lead to conditions like hereditary angioedema, highlighting its importance.
Decay-Accelerating Factor (DAF)
DAF (also known as CD55) is a membrane-bound protein found on host cells that accelerates the breakdown of the C3 convertase (C4b2a). By disrupting this key enzyme, DAF limits the amplification of the complement cascade on healthy cell surfaces, preventing unintended damage.