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A guide to complement biology, pathology and therapeutic opportunity

Nature Reviews Immunology volume 24, pages 118–141 (2024)Cite this article

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Abstract

Complement has long been considered a key innate immune effector system that mediates host defence and tissue homeostasis. Yet, growing evidence has illuminated a broader involvement of complement in fundamental biological processes extending far beyond its traditional realm in innate immunity. Complement engages in intricate crosstalk with multiple pattern-recognition and signalling pathways both in the extracellular and intracellular space. Besides modulating host–pathogen interactions, this crosstalk guides early developmental processes and distinct cell trajectories, shaping tissue immunometabolic and regenerative programmes in different physiological systems. This Review provides a guide to the system-wide functions of complement. It highlights illustrative paradigm shifts that have reshaped our understanding of complement pathobiology, drawing examples from evolution, development of the central nervous system, tissue regeneration and cancer immunity. Despite its tight spatiotemporal regulation, complement activation can be derailed, fuelling inflammatory tissue pathology. The pervasive contribution of complement to disease pathophysiology has inspired a resurgence of complement therapeutics with major clinical developments, some of which have challenged long-held dogmas. We thus highlight major therapeutic concepts and milestones in clinical complement intervention.

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Fig. 1: Overview of the complement cascade, its topology, regulation and key effector functions.
Fig. 2: Role of complement in microbial dysbiosis-driven inflammatory disease.
Fig. 3: Complement shapes tissue regenerative responses across evolution.
Fig. 4: Contextual roles of complement in cancer biology and immunotherapy.
Fig. 5: Role of complement in CNS development and neurodegeneration.
Fig. 6: Complement dysregulation drives pathology in PNH.
Fig. 7: Pathogenic role of complement dysregulation in ocular inflammatory diseases.
Fig. 8: Complement dysregulation supports COVID-19-associated immunothrombosis.

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Acknowledgements

This work was supported by the Dr Ralph and Sallie Weaver Professorship of Research Medicine to J.D.L. and by a grant from the US National Institutes of Health (DE026152 to G.H.).

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Authors and Affiliations

  1. National Center for Scientific Research ‘Demokritos’, Athens, Greece

    Dimitrios C. Mastellos

  2. Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA

    George Hajishengallis

  3. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    John D. Lambris

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  1. Dimitrios C. Mastellos
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All authors contributed equally to all aspects of the article.

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Correspondence to John D. Lambris.

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Competing interests

J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors (including third-generation compstatin analogues such as AMY-101). J.D.L. is an inventor of patents or patent applications that describe the use of complement inhibitors for therapeutic purposes, some of which are developed by Amyndas Pharmaceuticals. J.D.L. and G.H. have a joint patent that describes the use of complement inhibitors for therapeutic purposes in periodontitis. J.D.L. is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals (namely 4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives such as APL-2/pegcetacoplan/Empaveli/Aspaveli/Syfovre). D.C.M. has provided paid consulting services to 4D Molecular Therapeutics and Merck KGaA.

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Nature Reviews Immunology thanks Idris Boudhabhay, Claudia Kemper, Natalia Kunz, Xaria Li, Lubka Roumenina and Trent Woodruff for their contribution to the peer review of this work.

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Mastellos, D.C., Hajishengallis, G. & Lambris, J.D. A guide to complement biology, pathology and therapeutic opportunity. Nat Rev Immunol 24, 118–141 (2024). https://doi.org/10.1038/s41577-023-00926-1

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