From Arthritis to Zoster

Among the many components of a healthy immune system, the complement system – so named because it “complements” antibodies in their attempts to rid our bodies of foreign antigens – serves as one of the principal bridges between innate (“instinctive”) and acquired (“learned”) immune responses. The complement system is composed of a group of enzymes that, when activated, initiate a biological cascade that helps to defend us from infection.

The individual enzymes in the complement pathway are identified with a C and a number (e.g., C1, C2, C3, etc.) based on the order in which they were identified. Over two dozen proteins and protein fragments make up the complement system. 

Complement’s main tasks are to amplify antibody responses, assist in the destruction of foreign cells, clear out aging or dead cells, and remove immune complexes (e.g., antigen-antibody aggregates) that are part of the “battleground debris” resulting from destruction of foreign antigens. In performing its tasks, complement components stimulate the movement of white blood cells (chemotaxis) and induce immune cells to release cytokines and other important molecules.

Many of the complement system’s components circulate through the bloodstream in their inactive forms, called complement precursors or zymogens. These zymogens must be activated by contact with some sort of triggering molecule before the complement cascade begins.

Three pathways of complement activation have been described:

1. Classical pathway
2. Mannose-binding lectin pathway
3. Alternative pathway

The classical pathway can be either antibody-dependent or antibody-independent. This pathway is activated when C1 interacts with antigen-antibody complexes, with certain anions (DNA or RNA from dying cells, heparin, protamine, etc.), with polysaccharides in bacterial cell walls, or with bound C-reactive protein.

The mannose-binding lectin (MBL) pathway is antibody-independent. In this pathway, complement is activated when MBL, a serum protein, binds to mannose molecules on bacterial cell walls. This creates a molecular complex that resembles activated C1 and initiates the complement cascade.

The alternative pathway is activated when C3 is cleaved by various components from the cell surfaces of microorganisms (yeasts and bacteria) or by conglomerates of antibodies. Cleaved C3 then interacts with other proteins in the bloodstream, thus initiating the complement cascade.

All three pathways are ultimately regulated by both inhibitory and stimulatory molecules, and they all converge into a common pathway that results in the formation of a membrane attack complex (MAC). The MAC is an aggregate of activated complement that punches holes in the membranes of foreign cells, resulting in their destruction.

Another critical function of complement is its ability to act like immunologic “butter.” Whenever a foreign antigen gains access to our bodies, complement quickly coats the potentially harmful invader – a process called opsonization – and makes it appear “tasty” to circulating immune cells. The foreign antigen is then more efficiently consumed due to the presence of complement. Once consumed by a white cell, the antigen is presented to surrounding immune cells so they, too, will recognize and respond to the invader.

Finally, fragments of activated complement serve as molecular messengers to educate immature immune cells. By adhering to specialized receptors on the surfaces of various cells, complement assists in antibody production and the development of immune memory. Henceforth, when a given antigen returns, a defensive response can be initiated much more quickly.

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