The complement system - classical pathway

The complement system is a weapon against infections, especially bacterial infections. It can be activated through three different pathways, directly by bacteria and bacterial products (alternative pathway), through the binding of lectins to sugars on the bacterial cell surface (lectin pathway), or through the complex of antibodies and antigens, known as the classical pathway. Activation of any pathway triggers a series of protein hydrolysis events that cut proteins into "a" and "b" subunits. Eventually, it constructs a molecular drill that can directly kill infectious factors. The "a" subunits (C3a, C5a) attract phagocytic and inflammatory cells to the site, allowing the entry of soluble molecules and cells by increasing vascular permeability (anaphylactic C3a, C4a, C5a) and activating reactions. The "b" subunits are larger and bind to drugs to promote their phagocytosis and elimination. The classical pathway of complement activation is considered part of the adaptive immune response because it begins with the formation of antigen-antibody complexes. These complexes may be soluble, or they may form when antibodies bind to antigen determinants or epitopes located on the bacterial cell membrane. Soluble antibody-antigen complexes are usually called immune complexes, and only those formed by certain subtypes of IgM or IgG antibodies can activate the classical complement pathway. The ability of a single C1 complex to cleave large numbers of C2 and C4 molecules represents an amplification mechanism in complement cascades. The binding of C4b and C2a produces C4b2a, called C3 convertase. This complex binds to cell membranes and cleaves C3 into C3a and C3b fragments. C3b protein has a unique thioester bond that can covalently link C3b to the cell surface or be hydrolyzed. The C3 convertase amplifies the reaction by cleaving many C3 molecules. C3b interacts with C4b2a bound to the cell membrane to produce C4b3b2b, called C5 convertase. The final stage of the classical pathway involves the production of the membrane attack complex (MAC), also known as the lytic unit. The five terminal complement proteins (C5-C9) assemble into MAC on the target cell membrane to mediate damage. The activation of MAC assembly begins with the cleavage of C5 into C5a and C5b fragments. MAC forms and drills holes in the target cell membrane, causing apoptosis or hypotonic lysis. This killing mechanism is very effective against Neisseria bacteria but relatively ineffective against Gram-positive bacteria.