How is the complement system activated?
There are three pathways leading to complement activation with generation of split products and the C5 convertase that results in MAC formation:
• Classical pathway: this pathway links adaptive immune responses with innate immunity. When the antibody isotypes of immunoglobulin (Ig) IgG and IgM are in complex with antigen, C1q binds and activates C1r and C1s. The C1 complex is able to bind and activate C2, followed by C4. The C2C4 complex can cleave C3 into C3a and C3b and form the C5 convertase. Other proteins such as CRP, serum amyloid P, and C4 nephritic factor can also activate the classical pathway in the absence of an adaptive immune response.
• Alternate pathway: this pathway is activated in the absence of antibody by LPS on bacterial cell membranes. C3b is generated by a natural “tickover” of C3 and binds LPS. Factor D cleaves factor B to generate factor Bb which binds C3b, generates more C3b, and forms the C5 convertase.
• Lectin pathway: The liver synthesizes MBL, which can bind microbial carbohydrates. MBL resembles C1q and activates MASPs that are similar to C1r and C1s and can cleave C2 and C4. Like the alternate pathway, the lectin pathway is activated in the absence of an adaptive immune response.