Complement: an overview for the clinician

Abstract

The complement system is an essential component of the immune system. It is a highly integrative system and has a number of functions, including host defense, removal of injured cells and debris, modulation of metabolic and regenerative processes, and regulation of adaptive immunity. Complement is activated via different pathways and it is regulated tightly by several mechanisms to prevent host injury. Imbalance between complement activation and regulation can manifest in disease and injury to self. This article provides an outline of complement activation pathways, regulatory mechanisms, and normal physiologic functions of the system.

Keywords: Complement activation; Complement function; Complement regulation; Complement system; Immune response; Inflammation.

Figure 1. The Classical Pathway of Complement Activation

The classical pathway is initiated by the binding of the C1 complex (C1q, C1r and C1s) to bound antibody. C1r activates C1s which first cleaves C4 and then cleaves C2 leading to the formation of the classical pathway C3 convertase (C4bC2a). The C3 convertase subsequently cleaves C3 leading to the formation of the C5 convertase (C4bC2aC3b) and the release of the anaphylatoxin C3a. The C5 convertase then cleaves C5 into C5a and C5b. C5a is the most powerful of the anaphylatoxins and C5b is the first component of the terminal pathway of complement.

Figure 2. The Lectin Pathway of Complement Activation

The steps in components and reaction in the lectin pathway are very similar to those in the classical pathway. The only differences are the initiation steps. The lectin pathway is initiated by binding of the complex of mannose-binding lectin (MBL) and the serine proteases mannose-binding lectin associated proteases 1 and 2 (MASP-1 and MASP-2) to mannose groups on the surface of invading pathogens. Next, MASP-1 activates MASP-2 which acts like C1s in the classical pathway and lead to the formation of the C3 convertase. The remaining steps are the same as in the classical pathway.

Figure 3. The Alternative Pathway of Complement Activation

The alternative pathway is initiated by the spontaneous hydrolysis of C3 and the deposition of C3b on the surface of activating surfaces (non-host surfaces) and the release of C3a. Factor B (FB) binds to C3b and is subsequently cleaved by factor D (FD) leading to the formation of the alternative pathway C3 convertase (C3bBb). Properdin (P, green) then binds to the convertase to stabilize it. The C3 convertase cleaves C3 releasing more C3a and resulting in the formation of the alternative pathway C5 convertase (C3bBbC3b). The C5 convertase then cleaves C5 into C5a and C5b. C5a is the most powerful of the anaphylatoxins and C5b is the first component of the terminal pathway of complement.

Figure 4. The Terminal Pathway of Complement

All three pathways of complement activation converge in the terminal pathway. The terminal pathway begins when C5b binds to C6. C7 then binds to the C5b-C6 complex and the newly formed C5b-C7 complex inserts into the target membrane. C8 subsequently binds to the C5b-C7 complex and creates a small pore in the target membrane. The final step in the terminal pathway is the binding of C9 molecules (up to 21) to the C5b-C8 complex forming the membrane attack complex.