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  • Review Article
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Novel mechanisms and functions of complement

Abstract

Progress at the beginning of the 21st century transformed the perception of complement from that of a blood-based antimicrobial system to that of a global regulator of immunity and tissue homeostasis. More recent years have witnessed remarkable advances in structure–function insights and understanding of the mechanisms and locations of complement activation, which have added new layers of complexity to the biology of complement. This complexity is readily reflected by the multifaceted and contextual involvement of complement-driven networks in a wide range of inflammatory and neurodegenerative disorders and cancer. This Review provides an updated view of new and previously unanticipated functions of complement and how these affect immunity and disease pathogenesis.

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Figure 1: Complement-mediated intracellular and autocrine regulation of the activation of CD4+ T cells.
Figure 2: Differential intracellular fates of microbes opsonized by complement in the extracellular space.
Figure 3: Complement components suggested to be drivers of chronic, non-resolving inflammation in neurodegenerative, aging-related and ocular pathologies.
Figure 4: Role of complement in cancer.
Figure 5: Molecular mechanisms of C3-mediated activation and amplification of complement and generation of effector molecules.

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Acknowledgements

Supported by the US National Institutes of Health (AI068730, AI030040, DE021685, DE015254 and DE026152) and the European Community's Seventh Framework Programme (602699 (DIREKT)).

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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 analogs such as AMY-101), and is the inventor of the compstatin technology licensed to Apellis Pharmaceuticals (4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives); and J.D.L., G.H. and D.R. are inventors of patents or patent applications that describe the use of complement inhibitors for therapeutic purposes, some of which are developed by Amyndas Pharmaceuticals.

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Hajishengallis, G., Reis, E., Mastellos, D. et al. Novel mechanisms and functions of complement. Nat Immunol 18, 1288–1298 (2017). https://doi.org/10.1038/ni.3858

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