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  • Review Article
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Complement in neurological disorders and emerging complement-targeted therapeutics

Nature Reviews Neurology volume 16, pages 601–617 (2020)Cite this article

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Abstract

The complement system consists of a network of plasma and membrane proteins that modulate tissue homeostasis and contribute to immune surveillance by interacting with the innate and adaptive immune systems. Dysregulation, impairment or inadvertent activation of complement components contribute to the pathogenesis of some autoimmune neurological disorders and could even contribute to neurodegenerative diseases. In this Review, we summarize current knowledge about the main functions of the complement pathways and the involvement of complement in neurological disorders. We describe the complex network of complement proteins that target muscle, the neuromuscular junction, peripheral nerves, the spinal cord or the brain and discuss the autoimmune mechanisms of complement-mediated myopathies, myasthenia, peripheral neuropathies, neuromyelitis and other CNS disorders. We also consider the emerging role of complement in some neurodegenerative diseases, such as Alzheimer disease, amyotrophic lateral sclerosis and even schizophrenia. Finally, we provide an overview of the latest complement-targeted immunotherapies including monoclonal antibodies, fusion proteins and peptidomimetics that have been approved, that are undergoing phase I–III clinical trials or that show promise for the treatment of neurological conditions that respond poorly to existing immunotherapies.

Key points

  • Complement has an important physiological role in host immune defences and tissue remodelling.

  • The physiological role of complement extends to the regulation of synaptic development.

  • Complement has a key pathophysiological role in autoimmune neurological diseases and mediates the actions of pathogenic autoantibodies, such as acetylcholine receptor antibodies and aquaporin 4 antibodies.

  • For some autoimmune neurological diseases, such as myasthenia gravis and neuromyelitis optica spectrum disorders, approved complement-targeted treatments are now available.

  • Complement also seems to be of pathogenic relevance in neurodegenerative diseases such as Alzheimer disease, in which innate immune-driven inflammation is receiving increasing attention.

  • The field of complement-targeted therapeutics is rapidly expanding, with several FDA-approved agents and others currently in phase II and phase III clinical trials.

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Fig. 1: The main proteins involved in the complement activation cascades.
Fig. 2: The role of complement in neurological diseases.
Fig. 3: Complement involvement in synaptic pruning in health and disease.

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Authors and Affiliations

  1. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA

    Marinos C. Dalakas

  2. Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece

    Marinos C. Dalakas & Harry Alexopoulos

  3. Institute of Pharmacology, University of Bern, Bern, Switzerland

    Peter J. Spaeth

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Glossary

Opsonization

The molecular mechanism by which antigens, microorganisms or apoptotic cells are targeted by antibodies and complement breakdown products so that attraction to the cell surface receptors of phagocytes and natural killer cells increases; when the antigen is coated in opsonins, binding to immune cells is greatly increased.

Anaphylatoxins

Small pro-inflammatory oligopeptide fragments, such as C3a and C5a, that are produced during activation of the complement system and have important functions in the immune response and host defence.

Zymogens

Inactive precursors of enzymes that requires a biochemical change to become an active enzyme; also called pro-enzymes.

Quantitative Myasthenia Gravis

A physician-administered scale that assesses the severity of myasthenia gravis, ranging from 0 to 39, with higher scores representing more severe impairment.

Myasthenia Gravis Activities of Daily Living

A patient-reported index of daily living assessment, where a score >6 suggests that patients are moderately or severely affected by myasthenia gravis.

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Dalakas, M.C., Alexopoulos, H. & Spaeth, P.J. Complement in neurological disorders and emerging complement-targeted therapeutics. Nat Rev Neurol 16, 601–617 (2020). https://doi.org/10.1038/s41582-020-0400-0

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