Classical pathway

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The classical pathway is the first complement activation pathway to be discovered[1]. It is initiated by antibodies (IgM or IgG) bound to specific antigens on pathogen surface. The first component of the classical pathway is C1, which is a complex consisting of a 6-headed recognition unit termed C1q and two molecules each of C1r and C1s. C1r and C1s are the enzymatic units of the C1 complex. Assembly of the C1 complex is Ca2+-dependent.

Once C1q binds to the Fc regions of the antibody, it undergoes conformational change and triggers autocatalytic activation of the C1r unit. Activated C1r cleaves C1s to activate it. C1s then cleaves its substrate C4 into two small fragments C4a and C4b. C4b binds covalently to the pathogen surface. The next component C2 then binds onto C4b, allowing it to be cleaved by the adjacent C1s. The fragment C2b is released, leaving behind the C4b2a complex, also known as the C3 convertase.

The main function of C3 convertase is to cleave large numbers of C3 into C3a and C3b. C3b is an opsonin, it has a reactive thioester bond which is exposed after cleavage. This allows C3b to bind covalently to pathogen surface and activates opsonisation of the pathogen. If it does not bind to the pathogen it is rapidly inactivated by hydrolysis. This acts as a self-protective mechanism. Some of the C3b formed will bind directly to C4b2a to form C5 convertase (C4b2a3b). The C5 convertase cleaves C5 into C5a and C5b. C5b binds C6 and C7 forming C5b67 complex. The complex binds onto pathogen surface and binds C8. C8 consists of two subunits, C8-beta and C8alpha-gamma. C8-beta binds to C5b whilst C8alpha-gamma anchors itself into the lipid bilayer. C8alpha-gamma also induces polymerisation of 10-16 molecules of C9, forming a ring structure, the membrane attack complex (MAC). This forms a pore in the membrane, eventually leading to lysis of the pathogen.

References

  1. Male D, Brostoff J, Roth DB, Roitt IM. Immunology. 8th Edition. Elsevier Ltd. 2013
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