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  • Review Article
  • Published:

Complement in disease: a defence system turning offensive

Nature Reviews Nephrology volume 12, pages 383–401 (2016)Cite this article

Subjects

Key Points

  • The complement system is a critical modulator of immune responses that triages microbial and other threats through pattern recognition, tailored effector functions, and intensive crosstalk with other systems

  • When disrupted by dysregulation or age-related effects, or excessively triggered by acute and chronic tissue damage, biomaterials or transplants, complement can attack host cells and contribute to inflammatory conditions

  • The kidney is particularly sensitive to complement-mediated damage, exemplified by the involvement of complement in several kidney diseases (such as atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathies) and in complications of kidney transplantation and haemodialysis

  • Therapeutic complement inhibition is successfully used in paroxysmal nocturnal haemoglobinuria and aHUS, and has shown promise in other clinical conditions, raising hope for improved treatment options for other disorders

Abstract

Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists. The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris — such as sensing molecular danger patterns, generating immediate effectors, and extensively coordinating with other defence pathways — can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases. These host-offensive actions become more pronounced with age and are exacerbated by a variety of genetic factors and autoimmune responses. Complement can also be activated inappropriately, for example in response to biomaterials or transplants. A wealth of research over the past two decades has led to an increasingly finely tuned understanding of complement activation, identified tipping points between physiological and pathological behaviour, and revealed avenues for therapeutic intervention. This Review summarizes our current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and, with an emphasis on kidney disease and transplantation, discusses the involvement of complement in clinical conditions and promising therapeutic approaches.

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Figure 1: Mechanisms of differential complement activation and regulation under physiological conditions.
Figure 2: Examples of complement crosstalk with immune cells and defence pathways.
Figure 3: Pathological activation of complement.

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Acknowledgements

The authors thank Deborah McClellan for editing the manuscript before submission. J.D.L. also thanks Ralph and Sallie Weaver for the generous endowment of his professorship. Given the broad scope of this Review, we often refer to specialized review articles rather than primary literature, and we have only been able to include selected examples of the breadth of transformative work in the field; we therefore thank all our colleagues who are not specifically cited for their great contributions and their understanding. This work was supported by grants from the US NIH (AI068730, AI030040, DE021685) and the National Science Foundation (grant No. 1423304) and by funding from the European Community's Seventh Framework Programme, under grant agreement number 602699 (DIREKT).

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  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, 401 Stellar Chance, 422 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Daniel Ricklin, Edimara S. Reis & John D. Lambris

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All authors contributed to researching data for the article, discussion of the article's content, writing, and review/editing of the manuscript before submission.

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Correspondence to Daniel Ricklin or John D. Lambris.

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Competing interests

J.D.L and D.R. are inventors of patents or patent applications that describe the use of complement inhibitors for therapeutic purposes. J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors. E.S.R. declares no competing interests.

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DATABASES

FH aHUS mutation database

Glossary

Convertase

A protein complex transiently formed by an opsonin (C3b, C4b) and a protease fragment (Bb, C2b), which activates complement components C3 or C5 and promotes opsonization, amplification and/or generation of effector molecules.

Anaphylatoxin

A widely used term for complement effector fragments C3a and C5a, which are released upon activation of C3 and C5, respectively, and exert numerous immunomodulatory, chemotactic and/or cell-activating functions.

Opsonization

The process of depositing complement proteins on a particle surface to facilitate its removal. In the complement system, C3b, C4b (and their degradation fragments) and C1q facilitate phagocytosis via their receptors on immune cells.

Amplification

A major function of the 'alternative pathway' of complement, whereby convertase-mediated deposition of C3b on a targeted surface enables the formation of additional C3 convertases and deposition of more C3b. In absence of regulators, these events lead to rapid opsonization of the attacked cell or particle.

Consumption

A result of continuous and poorly controlled activation of complement components in the circulation, leading to a depletion of the native plasma protein and affecting the responsiveness of the cascade.

Fluid phase

Refers to complement activity in the circulation rather than on the targeted surface. Fluid-phase activation maintains alertness of the complement system (tick-over) but needs to be tightly controlled by soluble complement regulators.

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Ricklin, D., Reis, E. & Lambris, J. Complement in disease: a defence system turning offensive. Nat Rev Nephrol 12, 383–401 (2016). https://doi.org/10.1038/nrneph.2016.70

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