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Complement regulators and inhibitory proteins

Key Points

  • The complement system maintains tissue homeostasis and integrity and forms the first central and immediately acting line of defence against invading infectious microorganisms.

  • Complement activation generates toxic products, which need to be precisely targeted to the surface of invading microorganisms, and initiates effector functions with the goal of clearing tagged foreign cells as well as modified self cells, such as apoptotic particles.

  • Complement activation is tightly regulated by multiple inhibitors that are distributed as integral membrane proteins, surface-bound regulators and soluble effectors in the body fluids and plasma.

  • The central steps of complement activation are controlled by multiple regulators or inhibitors that have redundant activity.

  • Dysregulation of the delicate balance of complement activation products and regulators results in autoimmune diseases.

  • Some pathogenic microorganisms mimic the surface of host cells and can remain unrecognized by the host immune system.

Abstract

The complement system is important for cellular integrity and tissue homeostasis. Complement activation mediates the removal of microorganisms and the clearance of modified self cells, such as apoptotic cells. Complement regulators control the spontaneously activated complement cascade and any disturbances in this delicate balance can result in damage to tissues and in autoimmune disease. Therefore, insights into the mechanisms of complement regulation are crucial for understanding disease pathology and for enabling the development of diagnostic tools and therapies for complement-associated diseases.

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Figure 1: Complement: a central immunosurveillance system.
Figure 2: The benefits and risks of complement.
Figure 3: Complement regulators and surface receptors.

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Acknowledgements

The work of both the authors is supported by the Deutsche Forschungsgemeinschaft, Germany. P.F.Z.'s work is also supported by Kidneeds, Iowa, USA, the National Institutes of Health, USA, and ProRetina, Germany.

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Glossary

Zymogen

An inactive pre-form of a protease that by itself lacks proteolytic activity. Upon processing or proteolytic cleavage the protein displays enzymatic activity. Using such inactive pre-forms allows targeting of protein activity to the right place at the right time. Most complement proteins, but also components of the coagulation cascade and other proteases, exist and circulate as inactive pre-forms and require modification and proteolytic processing to be converted into an active form.

Opsonization

The deposition of activation products, for example the C3 activation fragment C3b, on the surface of a target to mark the target and facilitate and enhance recognition and uptake by phagocytic cells. Phagocytosis eliminates the particle from the circulation and aids in its destruction.

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Zipfel, P., Skerka, C. Complement regulators and inhibitory proteins. Nat Rev Immunol 9, 729–740 (2009). https://doi.org/10.1038/nri2620

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