Complement System
The complement system consists of several plasma proteins that work together to
opsonize microbes, to promote the recruitment of phagocytes to the site of infection,
and, in some cases, to directly kill the microbes (Figure 1). The first step in activation
of the complement system is recognition of molecules on microbial surfaces but not
host cells, and this occurs in three ways, each referred to as a distinct pathway of
complement activation.
The classical pathway, so called because it was discovered first, uses a plasma protein
called C1q to detect antibodies bound to the surface of a microbe or other structure
(Figure 1A). Once C1q binds to the Fc portion of the antibodies, two associated serine
proteases, called C1r and C1s, become active and initiate a proteolytic cascade
involving other complement proteins. The classical pathway is one of the major
effector mechanisms of the humoral arm of adaptive immune responses. Innate
immune system soluble proteins called pentraxins, can also bind C1q and initiate the
classical pathway.
The alternative pathway, which was discovered later but is phylogenetically older
than the classical pathway, is triggered when a complement protein called C3 directly
recognizes certain microbial surface structures, such as bacterial LPS. C3 is also
constitutively activated in solution at a low level and binds to cell surfaces, but it is
then inhibited by regulatory molecules present on mammalian cells. Because
microbes lack these regulatory proteins, the spontaneous activation can be amplified
on microbial surfaces. Thus, this pathway can distinguish normal self from foreign
microbes on the basis of the presence or absence of the regulatory proteins.
