The complement system: history, pathways, cascade and inhibitors

Abstract

Since its discovery in the 19th century, the complement system has developed into a clinically significant entity. The complement system has been implicated in a variety of clinical conditions, from autoimmune diseases to ischemia-reperfusion injury in transplantation. This article charts the historical progress of our understanding of the complement system and provides a synopsis on the activation pathways and its inherent regulators.

Keywords: complement activation; complement cascade; complement history; complement inhibitors; complement system.

Fig. 1.

Pathways of complement activation: classical, alternative and lectin pathway: IgM or IgG antigen/antibody complexes binding to C1q, the first protein of the cascade, initiates the classical pathway. The alternative pathway is not so much an activation pathway, as it is a failure to regulate the low level continuous formation of a soluble C3 convertase. The third pathway is known as MBL (Mannose-binding lectin)/MASP (MBL associated Serine Protease) pathway. The initiating molecules for the MBL pathway are multimeric lectin complexes that bind to specific carbohydrate patterns uncommon in the host, leading to activation of the pathway through enzymatic activity of MASP. The sites of action of the membrane bound complement regulators–CD35, CD46, CD55 & CD59 (green boxes) and the fluid phase regulators – C1-INH, Factor H, Factor I and C4bp (violet boxes) are represented with arrows. Insert: Membrane Attack Complex (MAC). The interaction of C5b with C6, C7, C8 and C9 leads to formation of C5b–9 or Membrane Attack Complex (MAC), a multimolecular structure that inserts into the membrane creating a functional pore leading to cell lysis

Fig. 2.

Membrane Bound Complement Regulators: DAF, CR1 and MCP belong to a gene super family called as ‘regulators of complement activation’ (RCA)/complement control proteins (CCP) and share a common structural motif called short consensus repeat (SCR). The SCR structure (circles) consists of around 60 amino acids held together by two disulfide bridges formed by cysteine residues. CD59 is a GPI-anchored membrane complement that is expressed on almost all cells in the body. CD59 is the only well-characterised membrane inhibitor acting at the terminal step and prevents the assembly of the MAC