The role of complement in inflammatory diseases from behind the scenes into the spotlight

Abstract

Our understanding of the biology of the complement system has undergone a drastic metamorphosis since its original discovery. This system, which was traditionally primarily described as a "complement" to humoral immunity, is now perceived as a central constituent of innate immunity, defending the host against pathogens, coordinating various events during inflammation, and bridging innate and adaptive immune responses. Complement is an assembly of proteins found in the blood and body fluids and on cell surfaces. Soluble complement components form the proteolytic cascade, whose activation leads to the generation of complement effectors that target various cells involved in the immune response. Membrane-bound receptors and regulators transmit signals from complement effectors to target cells and limit complement activation to the surfaces of pathogens and damaged or activated host cells. The multiple interconnections among complement proteins, immune cells, and mediators provide an excellent mechanism to protect the organism against infections and support the repair of damaged tissues. However, disturbances in this "defense machinery" contribute to the pathogenesis of various diseases. The role of complement in various inflammatory disorders is multifaceted; for example, the activation of complement can significantly contribute to inflammation-mediated tissue damage, whereas inherited or acquired complement deficiencies highly favor the development of autoimmunity.

Figure 1

Pathways of complement activation. The complement cascade is composed of proteins that are activated through the partial cleavage by an upstream enzyme. Complement is activated through the classical (1), lectin (2), or alternative (3) pathways that converge at the central molecule of the complement system, C3. In addition, C3 and C5 can be cleaved, independent of conventional convertases, by proteolytic enzymes that are released from leukocytes or by thrombin or kallikrein. In this diagram, enzymes that cleave complement proteins, independently of conventional convertases, are grouped in the “extrinsic protease pathway” (4). The binding of the C1 complex to antigen-antibody complexes initiates proteolytic cleavage of complement components by C1s in the classical pathway (1). C1s first cleaves C4, which binds to the bacterial surface, then cleaves C2, leading to the formation of a C4b2a enzyme complex, the C3 convertase of the classical pathway (5). The lectin pathway begins with binding of the complex MBL and mannose-binding lectin-associated proteases 1 and 2 (MASP1 and MASP2, respectively) to a bacterial cell wall (2). MASP2, similarly to C1s, leads to the formation of the C3 convertase C4b2a (5). The alternative pathway is initiated by the spontaneous hydrolysis of C3, leading to the formation of C3(H₂O) (3). C3(H₂O) forms a complex with factor B, followed by the cleavage of factor B within this complex by factor D. The final product of these enzymatic reactions is the C3(H₂O)Bb complex. The C3bBb complex has the capacity to cleave C3 to C3b and C3a. Once deposited on the surface of cells or pathogens, C3b binds more factor B, and this binding gradually amplifies the activation cascade. The binding of properdin stabilizes the C3bBb complex, the C3 convertase of the alternative pathway (6). C3 convertases generated through various pathways cleave C3 to C3a and C3b. C3b contributes to the formation of the C5 convertase (7), which cleaves C5 to C5a and C5b. C3a, C5a, and the C5b-9 complex are complement effectors that contribute to inflammation (8). In addition, the C5b-9 complex induces lysis of gram-negative bacteria of the Neisseria genus.

Figure 2

Contribution of complement anaphylatoxins to vascular events of acute inflammation. A: Cytokine signaling contributes to an up-regulation of anaphylatoxin receptors (C3aR, C5aR) by endothelial cells in arterioles and on circulating leukocytes. B: Binding of C3a and C5a to the reciprocal receptors on these cells enhances the release of cytokines and eicosanoids that contribute to an increase in vascular permeability, vasodilation, and leukocyte extravasation.

Figure 3

Anaphylatoxin-mediated extravasation of leukocytes. Anaphylatoxins up-regulate adhesion molecules on endothelial cells and leukocytes, facilitating the adhesion of leukocytes to the vascular wall and their subsequent transmigration into the interstitial tissue at sites of inflammation. C3a and C5a stimulate mast cells to release histamine and proteases that also contribute to vascular alterations. Monocyte-derived macrophages are among the first cells encountering non-self-antigens, and through the pattern recognition system they initiate an innate immunity response.