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The Complement System

The complement system is an important part of the immune system. It is a set of proteins that acts (sometimes in concert with antibodies and white blood cells) to kill germs, destroy unnecessary cells that need to be removed, and to clean up the debris afterward. Through these normal processes, the complement system promotes inflammation.1 The complement system consists of more than 40 proteins, which are normally present in an inactive state. However, they can be activated by a process called cleavage, which means that a portion is split off, usually through the action of an enzyme. When one of these complement proteins becomes activated, it can act as an enzyme to activate another kind of complement protein. This chain reaction, in which one kind of complement protein sequentially activates another, is called a cascade. Activation of the complement system can start from any of 3 pathways, all of which trigger the cascade reaction that leads to cell destruction and removal.1 The 3 complement pathways include the classical pathway, the lectin pathway, and the alternative pathway. The classical complement pathway is activated when an antibody binds to an antigen, which is usually a foreign protein, such as a protein on a bacterium or virus. In contrast, the lectin pathway activates complement when a protein called mannose-binding lectin binds to a foreign carbohydrate, such as those found on the outside of many bacteria, viruses, protozoa, or fungi. The alternative complement pathway can be initiated by spontaneously activated complement attaching to pathogens or cells.1 All 3 pathways (classical, lectin, and alternative) eventually lead to the cleavage of complement factor C3 into C3a and C3b. The cleavage of C3 must occur for the complement system to have its intended effects on cells. C3a promotes inflammation, while C3b opsonizes (labels) cells so that they will be cleared from the system by white blood cells. C3b also activates C5 by splitting it into C5a and C5b. C5a promotes inflammation by attracting inflammatory cells. C5b makes up part of the membrane attack complex (MAC), which kills cells by forming a hole in their cell membrane, resulting in their lysis (rupture).1 In a healthy person, the complement system is under tight control, to keep an immune response from damaging the body itself. 1. Murphy K, Weaver C. Innate immunity: the first lines of defense. In: Janeway's Immunobiology. 9th ed. London, UK: Garland Science; 2016.