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Complement System Overview

The defense against pathogens such as viruses and bacteria are mediated by the immune system which is in principle divided in two parts.

Adaptive or acquired immune system

The adaptive or acquired immune system is continuously evolving throughout life and continuously one of the key elements is the development of specific antibodies.

Innate immune system

The other part is the innate immune system which is already in place at birth. The innate system is a non-specific first line of defense comprised of cells and mechanism to defend against infection caused by other organisms. The complement system plays an important part of the innate immune system. 

The Complement System and innate immunity

Complement was originally described in the late nineteenth century and the word complement was coined by the famous German physician Paul Ehrlich in his general theory of immunity.

Complement, is something in the blood that "complements" the cells of the immune system. The complement system is a complex system composed of a large number of proteins that acts in a sequential cascade. Many of these proteins are pro-enzymes that require proteolytic cleavage in order to become active.

Since complement acts non-specifically, regulation of the cascade is crucial. This is achieved by a number of regulatory components such as inhibitors. 

The complement can act through three different pathways called the classical, lectin and alternative pathway. The activity of each respective pathway is triggered by different mechanisms/components.

Classical Pathway

Link between innate and acquired immune system

The classical and lectin pathways are composed of identical components except for the factor responsible for the initial activation. The classical complement pathway typically requires antigen-antibody complexes for activation (specific immune response) and is triggered by the activation of the C1 complex.

Lectin Pathway

Activated by carbohydrates on pathogen surfaces

The activation of the lectin pathway is mediated by mannose-binding lectin (MBL), or ficolins instead of the C1 complex. The binding of MBL to mannose residues on the pathogen surface activates the MBL-associated serine proteases, MASP-1, and MASP-2.  Ficolins are homologous to MBL and function via MASP in a similar way but reacts with other carbohydrates than mannan.

Alternative Pathway

Provides a potent amplification loop

The alternative pathway is activated by C3 hydrolysis and is continuously activated at a low level, analogous to a car engine at idle, as a result of spontaneous C3 hydrolysis.

Terminal Pathway

Cell lysis by MAC

All three pathways lead to the formation of homologous variants of protease C3 convertase that cleaves C3 to form C3a and C3b. C3b is in turn part of the C5 convertase that cleaves C5 which eventually leads to the formation of the Membrane Attack Complex (MAC) or soluble Terminal Complement Complex, sTCC.