THE COMPLEMENT ACTIVATION PATHWAYS
The complement system has evolved early during evolution. Already invertebrates such as ascidians (subphylum Urochordata), Amphioxus (subphylum Cephalochordata) or Nematostella vectensis exhibit an almost complete set of complement gene family members [1-3].
In vertebrates the complement system consists of more than 30 proteins present in an inactive state [4]. Activation of the classical, the lectin or the alternative pathway triggers a cascade multiplier by generating an intrinsic amplification loop. The classical pathway is initiated by binding of C1q, a subcomponent of the C1-complex, to IgM or IgG molecules in complex with antigens. Activation of the C1-complex leads to formation of C3-convertase by activation and association of C2 and C4 components. The lectin and alternative pathways can be activated independently of the presence of immunoglobulins. The lectin pathway is induced by recognition of carbohydrate patterns on the surface of pathogens by mannose binding lectin (MBL). Beside its permanent background activation by the spontaneous decay of C3 into C3(H2O), the alternative pathway is activated by molecules embedded in the surface membranes of invading microorganisms. All three pathways converge in the activation of C3. Cleavage of C3 to C3b induces the formation of C5-convertases and the sequential activation of complement components C5, C6, C7, C8 and the assembly of C9 within the membrane attack complex (MAC). The arrangement of the MAC on the cell surface results in death of the target by osmotic lysis. To prevent damage from the host cell, several regulatory proteins, referred to as regulators of complement activation (RCAs) disrupt the complement activation process [4]. Key elements of the complement cascade (C4, C3, C5 and formation of MAC) are controlled by different plasma and membrane-localized RCAs. Soluble factors such as factor H (fH) act in concert with membrane-anchored structures such as membrane cofactor protein (MCP, CD46), decay accelerating factor (DAF, CD55) and CD59, to protect the host-cell against possible selfdestruction by the complement system. A further important mechanism in controlling the complement cascade is degradation of C3b to inactive iC3b and C3d. The key protein in this process is factor I (fI), a soluble serine protease, which requires co-factors such as fH, complement receptor 1 (CR1) or DAF for efficient cleavage of C3b. Although iC3b and C3d do not further participate in the complement cascade, they are important opsonins mediating several complement receptor-dependent actions, such as phagocytosis [4].
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