REVIEWS Complement in neurological disorders and emerging complement- targeted therapeutics Marinos C. Dalakas 1,2 ✉ , Harry Alexopoulos2 and Peter J. Spaeth 3 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. The human complement system is an effector of innate ongoing tissue destruction in several difficult- to- treat and adaptive humoral immunity. The system comprises neurological diseases. soluble membrane- bound proteins (opsonins) that act In this Review, we provide an overview of the main collectively to recognize pathogens and non- self mate- components of the initial complement activation path- rial and subsequently initiate opsonization and phago- ways, the lytic pathway and the factors associated with cytosis or lysis of pathogens. The proteolytic fragments inappropriate complement activation or control in dis- that derive from complement activation can be tar- ease initiation and progression. We consider the role of geted by white blood cells and endothelial cells, lead- complement in the tissue destruction that is responsible ing to extravasation and migration of immune cells at for the genesis of the most common autoimmune neuro- the sites of inflammation. Other physiological func- logical diseases, including complement-mediated myopa- 1Department of Neurology, tions of complement include timely removal of altered thies, myasthenia gravis, neuropathies and CNS disorders. Thomas Jefferson University, and senescent self, tissue remodelling, cell lysis, chemo- We also discuss the role of complement in some neuro- Philadelphia, PA, USA. 2 taxis, opsonization, inflammation and immune cell degenerative disorders, including Alzheimer disease Neuroimmunology Unit, 1–4 Department of stimulation . (AD), amyotrophic lateral sclerosis (ALS), Huntington Pathophysiology, Faculty Complement activation products link the innate and disease, traumatic brain injury and even schizophrenia. of Medicine, National and adaptive immune systems by acting directly on recep- Finally, we discuss emerging complement-targeted ther- Kapodistrian University tors on T cells and B cells or by modulating dendritic apies, such as monoclonal antibodies, fusion proteins and of Athens, Athens, Greece. cell functions5–8. Disruption of the delicate coordina- cyclic peptides, that inhibit the functions of individual 3 Institute of Pharmacology, tion required for complement activation and control complement proteins, especially therapies that disrupt the University of Bern, Bern, Switzerland. is fundamental in the pathogenic mechanism of sev- lytic pathway. Some of these therapeutic agents have been ✉e- mail: mdalakas@ eral autoimmune neurological disorders, and is even approved or are being tested in phase I–III clinical trials med.uoa.gr emerging as a contributor in some neurodegenerative and promise to change the therapeutic armamentarium https://doi.org/10.1038/ diseases. As a result, interest is increasing in target- for treatment of neurological conditions that respond s41582-020-0400-0 ing complement as a therapeutic approach to prevent poorly to existing immunotherapies. NATURE REVIEWS | NEUROLOGY VOLUME 16 | NOVEMBER 2020 | 601 REVIEWS Key points and IgG3 (but not IgG4) or IgM, enable multivalent C1q binding15. Even in the absence of pathogen-specific anti- • Complement has an important physiological role in host immune defences and tissue bodies, C1q can initiate first- line defences by binding remodelling. directly to the surfaces of pathogens. C1q can also inter- • The physiological role of complement extends to the regulation of synaptic act with molecules such as actin, adiponectin, amyloid development. fibrils, cardiolipin, C- reactive protein, DNA, fibronec- • Complement has a key pathophysiological role in autoimmune neurological diseases tin, laminin, lipopolysaccharides, mucopolysaccharides, and mediates the actions of pathogenic autoantibodies, such as acetylcholine myelin, pentaxrin 3, phosphatidylserine and prion pro- receptor antibodies and aquaporin 4 antibodies. teins, all of which can cause excess inflammation. C1q is • For some autoimmune neurological diseases, such as myasthenia gravis and also produced locally in the CNS and can play a role in neuromyelitis optica spectrum disorders, approved complement- targeted treatments modulating microglia and synaptic pruning13. are now available. Binding of C1q to its target leads to conformational • Complement also seems to be of pathogenic relevance in neurodegenerative diseases changes that generate enzymatically active forms of C1r such as Alzheimer disease, in which innate immune- driven inflammation is receiving 13,14,15 increasing attention. and C1s . The resultant C1qC1r2C1s2 enzyme com- plex mediates cleavage of native C4 followed by cleavage • 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. of C2 and the subsequent formation of the C3 convertase C4bC2a. The C3 convertase activates C3, causing disso- ciation of C3 into C3a and C3b. C3b then binds to the Main complement functions existing C3 convertase to form the C4bC3bC2a complex, Functionally, the complement system can be divided which is a C5 convertase16 (Fig. 1). into two main parts: the enzymatic cascade and the lytic pathway. The enzymatic cascade generates the molecules Lectin pathway. The process of lectin pathway acti- needed to initiate the lytic pathway, in which the soluble vation closely resembles that of classical pathway proteins undergo conformational changes that enable activation, but a wide array of carbohydrates can precip- their insertion into lipid bilayers and ultimately form the itate this pathway. The complexes of the lectin pathway osmolytic membrane attack complex (MAC; also known that become activated have oligomeric structures sim- 9 17 as the C5b–918 complex) . These pathways are described ilar to the pentamolecular C1 complex . The pattern- in more detail below. recognition molecules within these complexes include With respect to the nomenclature of the complement mannose-binding lectin (MBL), ficolins and collectins, proteins, in this Review we have adhered to that offi- which sense danger signals from pathogens and senes- cially adopted by the International Complement Society cent or apoptotic cells. Upon activation by these sig- (ICS) in 2014 (REF.10). Changes to this nomenclature have nals, the enzymes of the complexes — mannan-binding subsequently been proposed by experts of the ICS11 in lectin serine protease 1 (MASP1) and MASP2 — mediate an attempt to harmonize complement nomenclature; the formation of the C3 convertase C4bC2a18,19 (Fig. 1). if universally adopted, these changes could help to C4bC2a mediates activation of the same downstream improve precision. pathways as in the classical pathway19. Activity of the various sensing complexes of the classical and The enzymatic cascade lectin pathways are controlled by C1- esterase inhibi- Opsonization The main functional aspect of the enzymatic cascade tor (C1- INH)20. In the classical and lectin pathways, The molecular mechanism by is assembly of the convertases, which drive subsequent C1- INH binds to the proteases of the active sensing which antigens, microorganisms complement activation, amplification and opsonization. complexes and these proteases cleave C1-INH, leading or apoptotic cells are targeted by antibodies and complement The cascade comprises three activation axes: the classical to formation of a covalent complex of C1- INH with breakdown products so that pathway, the lectin pathway and the alternative pathway C1r, C1s, MASP1 or MASP2. attraction to the cell surface (Fig. 1). In these cascades, the proteolytic enzyme com- receptors of phagocytes and plexes activate each other in a strict order. The lectin The alternative pathway. The alternative pathway natural killer cells increases; when the antigen is coated in pathway and the alternative pathway are evolution- differs from the classical and lectin pathways in that opsonins, binding to immune arily ancient — some of their components are found it is spontaneously and continuously active at a low cells is greatly increased. in invertebrates12,13