16th February 2024

Complement system activation pathways

Summary

The complement system is activated during pathogen infections and in normal homeostasis. When the system is triggered, a cascade of enzymatic reactions ensues; activated complements transform inactive complements into active components through proteolytic activity.

The complement system can be activated through three main pathways: Classical, Alternative Pathway, and Mannose-binding Lectin (MBL) Pathway.

• The classical pathway:  This pathway is activated by antibody-antigen complex binding to C1q, a part of the C1 complex that contains C1r and C1s. C1s then activates C4 and C2 consequently. Activated C4 and C2 together form C3 convertase.
• The mannan-binding lectin (MBL) pathway: This is very similar to the classical pathway. The MBL protein is similar to C1q. which in turn activates MBL-associated serine proteases, MASP-1 and MASP-2, which stimulate C4 and C2 to form the C3 convertase, C4b2a.
• The alternative pathway:  This third pathway is not activated by protein binding to a pathogen. Instead, it is activated by spontaneous hydrolysis of C3 into C3(H2O), which binds to factor B, allowing it to be cleaved into Ba and Bb. The Bb fragment binds to C3(H2O), forming C3(H20) Bb, the alternative pathway’s C3 convertase. This creates an amplification loop as more C3 is created.

References

• Dunkelberger, J.R. and Song, W.-C. (2009). Complement and its role in innate and adaptive immune responses. Cell Research, [online] 20(1), pp.34–50. Available at: https://www.nature.com/articles/cr2009139/
• A, C., Travers, P., Walport, M. & Shlomchik, M.J. (2010). The complement system and innate immunity. [online] Nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK27100/
• Merle, N.S., Church, S.E., Fremeaux-Bacchi, V. and Roumenina, L.T. (2015). Complement System Part I. Molecular Mechanisms of Activation and Regulation. Frontiers in Immunology, 6.
• Dr Trynaadh, (2018). Common Complement Deficiencies. [online] WordPress. Available at: https://drtrinadh.wordpress.com/2018/08/01/common-complement-deficiencies/ [Accessed Apr 30 2022].