Regulation of the Complement Membrane Attack Pathway

Complement activation, triggered through classic, alternative, or lectin pathways of activation, leads to activation of a final common reaction sequence, the membrane attack pathway, in which five soluble plasma proteins assemble into a multimolecular complex that inserts into and through the membrane, creating a functional pore, the membrane attack complex. The active products of membrane attack are the anaphylactic and chemotactic fragment C5a and the membrane attack complex itself. These active products are important in immune defense but also carry the potential to damage host cells. Regulation of the membrane attack pathway is essential to protect host cells from damage at sites of C activation, and several protective systems have evolved to achieve this in vivo. Nevertheless, in disease these protective systems may be overwhelmed, and the availability of agents that specifically inhibit the membrane attack pathway might be of considerable therapeutic benefit. In this article I first describe the membrane attack pathway, its active products, and its role in disease. Second, I discuss systems operating to prevent damage to host cells by membrane attack, the regulatory proteins and activities that form the core of the article. Finally, I describe recent developments in the production of therapeutic agents with the capacity to inhibit membrane attack pathway.