Complement in immune and inflammatory disorders: pathophysiological mechanisms

Abstract

Although acute or chronic inflammation is a common component of many clinical disorders, the underlying processes can be highly distinct. In recent years, the complement system has been associated with a growing number of immunological and inflammatory conditions that include degenerative diseases, cancer, and transplant rejection. It becomes evident that excessive activation or insufficient control of complement activation on host cells can cause an immune imbalance that may fuel a vicious cycle between complement, inflammatory cells, and tissue damage that exacerbates clinical complications. Although the exact involvement of complement needs to be carefully investigated for each disease, therapeutic modulation of complement activity emerges as an attractive target for upstream inhibition of inflammatory processes. This review provides an update about the functional and collaborative capabilities of complement, highlights major disease areas with known complement contribution, and indicates the potential for complement as a focal point in immunomodulatory strategies for treating inflammatory diseases.

FIGURE 1

Simplified scheme of the complement activation network. *Only part of the functional spectrum of properdin (FP) is visualized: FP may act as pattern recognition molecule and recruit C3b from plasma to the target surface (AP initiation); in addition, it stabilizes both the AP C3 and C5 convertases. Only the AP C5 convertase (C3bBb3b) is shown; a CP/LP C5 convertase (C4b2b3b) is also formed. **The regulation of the CP/LP C3 convertase is depicted a one-step process but follows a two-step mechanism similar to C3b, including decay acceleration (C4BP, CD35) and FI-mediated degradation to iC4b (C4BP, CD35, CD46). ***The function of C5L2 is not fully described and may be content-specific; C5a and C5a-desArg bind equally well to C5L2 whereas their binding and signaling profiles on C5aR is distinct. The binding of C3a-desArg to C5L2 remains controversial. Abbreviations: AP, alternative pathway; C1-INH, C1 inhibitor; C3aR, C3a receptor; C4BP, C4b-binding protein; C5aR, C5a receptor; C5L2, C5a receptor-like 2; Clu, clusterin; CP, classical pathway; CPN, carboxypeptidase-N; CR, complement receptor; FB, factor B; Fcn, ficolins; FD, factor D; FH, factor H; FI, factor I; LP, lectin pathway; MAC, membrane attack complex; MASP, MBL-associated protease; MBL, mannose-binding lectin; RCA, regulator of complement activation; Vn, vitronectin.

FIGURE 2

(A) Triggered directly by foreign and altered surfaces, the complement network resides upstream of most defense and homeostatic systems, thereby acting as an important mediator in physiological and pathophysiological processes. Abbreviations: DAMP, damage-associated molecular patterns; PAMP, pathogen-associated molecular pattern; PMN, polymorphonuclear cells; TLR, Toll-like receptor. (B) While complement-mediate immune surveillance and mediation usually provides adequate physiological response (green arrow) to distinct surfaces (grey), any excessive trigger or inadequate regulation (e.g., due to deficiencies or polymorphisms) may lead to pathophysiological reactions (red arrow) that require therapeutic intervention. In the case of foreign surfaces (i.e., transplants, materials), complement-targeted modulation (orange arrow) may improve tolerance and compatibility. Abbreviations: AD, Alzheimer’s disease; aHUS, atypical hemolytic uremic syndrome; AMD, age-related macular degeneration; DDD, dense deposit disease; PNH, paroxysmal nocturnal hemoglobinuria; SLE, systemic lupus erythematosus.