Cytokine Network: How the Complement System Works

The complement system is a network of signals that function as an essential part of the body's immune defense. This system consists of specific serum protein messengers that circulate in the blood plasma. These proteins, also known as cytokines, essentially communicate within the immune system, sending signals which turn on and turn off different aspects of immune response.

Most complement proteins are inactive until they are cut. One activated complement then functions as an enzyme to activate the next, and the next, and so on. This pattern of sequential activation results in a cascade of events that ultimately protect the body from infection.

The Classical Pathway

This pathway is dubbed "classical" because it was the first to be discovered. The complement proteins act in conjunction with antibodies of the specific immune response. The binding of an antibody to its antigen often triggers the complement system through the classical pathway. Antibodies are other proteins of the immune system that often bind to, and mark, specific particles that are part of the structure of invading microbes. The particles that antibodies bind to are called antigens.

Complement Proteins

The component proteins of the classic system are labeled C1, C2a, C2b, C3a, C3b, C4a, C4b, C5a, C5b, C6, C7, C8, and C9. The number corresponds to the complement's order in the chain of events.

The "a" and "b" distinctions represent when the original protein is cleaved into two parts. For example, C1 cleaves the proteins C2 and C4, resulting in C2a, C2b, C4a and C4b. These pieces than go on to cleave or combine with other components of the system, continuing the cascade of events.

Cutting Up Pathogens

The end product of this cascade of events is the formation of membrane attack complexes (MACs) that can create holes in the membranes of pathogens ("bad guy" microbes), cutting up, or lysing, bacterial, viral or eukaryotic pathogens.

Cell lysis is the main role of the compliment system, although there are other jobs that compliments do. The complement system also acts in several ways to mobilize defense mechanisms, including:

* the formation of new enzymes
* enhancement of the inflammatory response
* coating of particles to make them more easily recognized for elimination by phagocytic cells that engulf and destroy pathogens
* increase in vascular permeability to allow white blood cells to more easily squeeze their way out of blood vessels and migrate to areas where they are needed

The Alternative (Properdin) Pathway

The complement system can also be triggered without antigen-antibody complexes of specific immunity. This pathway is initiated by the interaction of three proteins (properdin factors B, D and P) and the endotoxins and lipopolysaccharides (antigens) of bacteria and fungi (invaders). This interaction results in a cascade of enzyme creation that ultimately continues in the classical pathway.

The alternate pathway is less efficient that the classical pathway, but is an early responder, useful in the first stages of fungal or Gram negative bacterial infection, before the specific immune response has created the antibodies that are necessary to activate the classical pathway.

Sources

Bauman, R. (2005) Microbiology. Pearson Benjamin Cummings.

Park Talaro, K. (2008) Foundations in Microbiology. McGraw-Hill.