The complement system: an evolution in progress

Abstract

The complement system, which consists of three independent but interacting pathways, constitutes a powerful arm of innate immunity. Its major function is to recognize and destroy pathogenic microorganisms as well as eliminate modified self-antigens. Although it is a fine-tuned system with innate capacity to discriminate self from non-self as well as danger from non-danger signals, an unwarranted activation can nonetheless occur and cause tissue destruction. To prevent such activation, specific regulators present both in plasma and on the cell surface tightly control it. Data accumulated over the past four decades have also shown that the complement system is capable of not only cross-talk with the activation cascades of plasma--i.e. blood coagulation, contact activation, and the kinin/kallikrein system--but also serving as a bridge between innate and adaptive immunity. It is for these reasons that the various activation steps of the complement system have been recently targeted for therapy to treat diseases in which the role of complement is beyond doubt. This trend will certainly continue for years to come, especially as novel concepts guiding the field into areas never contemplated before are continuing to be discovered.

Keywords: cascade; complement; innate immunity.

Figure 1.. The three pathways of the complement system.

The three independent pathways are known as the classical, alternative, and lectin pathways and were discovered in that order. Immune complexes activate the classical pathway, whereas the mannose-binding lectin (MBL) and alternative pathways are directly activated by mannose-rich or complex carbohydrate structures on pathogenic microorganisms, respectively. Regardless of how they are activated, the three pathways lead to the sequential activation of first C3 followed by C5, before the assembly of the membrane attack complex. The “stop” sign identifies critical steps that are or could be targeted for potential therapeutic interventions. Ab, antibody; FD, Factor D; MASP, mannose-associated serine protease.

Figure 2.. Activation of the kinin system.

The kinin system is activated on the endothelial cell surface when Factor 12 (FXII) first binds to a tri-molecular receptor complex comprising gC1qR, urokinase-type plasminogen activator receptor (uPAR), and cytokeratin-1 (CK-1) and undergoes an autocatalytic conversion to generate FXIIa. FXIIa in turn converts prekallikrein (PK) to kallikrein, the enzyme that digests high-molecular-weight kininogen (HK) to generate bradykinin (BK). BK induces vascular permeability with the help of two receptors––bradykinin receptor 1 (B1R), which is inducible, and B2R, which is constitutively expressed on most cells. In the absence of C1-INH, uncontrolled generation of BK can cause vascular permeability resulting in angioedema (AE). The currently available therapeutic agents target specific checkpoints in the activation process, including a monoclonal antibody that prevents the binding of HK to gC1qR. Abbreviations: ACE, angiotensin-converting enzyme; mAB, monoclonal antibody.