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

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 classical, lectin and alternative pathway, respectively. The activity of each respective pathway is triggered by different mechanisms/components.

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.

The lectin pathway is dependent on specific carbohydrate moieties such as mannan located on the surface of the microorganism. 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.

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

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.

The complement system has four major functions, including:

  • Lysis of infectious organisms - rupturing membranes of foreign cells
  • Activation of inflammation
  • Opsonization - enhancing phagocytosis of antigens
  • Immune clearance

Complement Overview Illustration

For more information please click one of the separate pathways in the illustration or use the navigation to the left.
Overview - Complement SystemClassical Pathway Lectin Pathway Alternative Pathway



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