The complement system consists of plasma and membrane proteins that act as a bridge between innate and adaptive humoral immunity. Beyond host defense, complement has defined roles in brain development and in maintaining nervous system homeostasis. Experimental studies cited in the source show complement-dependent processes such as microglia-mediated synaptic pruning during development and classical pathway–mediated synapse elimination, highlighting physiological roles within the CNS.
The review includes an illustration of core complement pathways (Fig. 1) to summarise the classical, lectin and alternative activation routes and downstream effectors, including formation of the membrane attack complex. These pathways can contribute to immune surveillance, clearance of altered or senescent cells and modulation of inflammatory responses in neural tissues.
Inappropriate or excessive complement activation is a prominent feature of many autoimmune neurological disorders. When complement activity is misdirected or uncontrolled, it can exacerbate tissue injury and impede effective disposal of altered or damaged cells, potentiating autoimmune processes affecting central and peripheral nervous systems and muscle.
The clinical relevance of complement in autoantibody-driven diseases has driven therapeutic development. The source notes that existing approved drugs largely target conditions in which pathogenic antibodies fix complement, with myasthenia gravis and neuromyelitis optica spectrum disorder given as example indications where complement inhibition has therapeutic value.
Complement activity has been implicated in neurodegenerative diseases as well. The source discusses that aberrant complement activation is observed in conditions such as Alzheimer disease and is considered a contributor to neuroinflammatory processes. However, experimental evidence also indicates that specific complement components can exert tissue-protective effects in some CNS diseases, including Alzheimer disease and multiple sclerosis. This duality—potentially deleterious and potentially protective roles—supports the concept that therapeutic strategies should aim for nuanced, pathway-selective modulation rather than indiscriminate inhibition.
The therapeutic landscape for anti-complement drugs is rapidly expanding. Several agents targeting the complement cascade are already marketed and approved for neurological indications, and a robust pipeline of biologic agents is in phase I–III clinical testing. The source emphasises that most currently approved treatments focus on downstream complement effects in antibody-mediated disease, but developing agents now target more proximal components of the cascade as well.
Figure 2 in the review provides a visual summary of the expanding spectrum of complement therapeutics, mapping target sites across the cascade and showing the increasing number of agents under development.
Targeting complement, particularly proximal components such as C1, raises specific safety concerns. Because complement contributes to host defense against certain pathogens, proximal blockade can increase susceptibility to invasive infections and disturb physiological complement functions. The review underlines the need to balance therapeutic benefit against infection risk and other unintended consequences of disrupting normal complement roles in immunity and tissue maintenance.
Furthermore, the presence of tissue-protective complement functions in some contexts argues against broad complement blockade and supports the development of selective inhibitors that preserve beneficial pathways while preventing pathogenic activation.
Advancing complement-targeted therapeutics will require systematic diagnostic guidance and reliable disease-specific biomarkers. The source highlights that personalised therapeutic approaches depend on the ability to identify patients and disease states in which complement inhibition is likely to be effective and safe. Biomarkers that reflect pathway-specific complement activation and the mechanistic role of complement in an individual’s disease will be crucial for patient selection and monitoring.
The article includes two key figures referenced in the source content: Fig. 1, depicting complement pathways, and Fig. 2, illustrating the expanding spectrum of complement therapeutics. These figures are intended to summarise pathway relationships and therapeutic targets across the complement cascade.
Anti-complement therapeutics are set to change treatment of autoimmune neurologic conditions. The review concludes that while current approvals mostly address antibody-mediated complement-fixing diseases, emerging drugs could expand indications to a broader range of autoimmune and possibly degenerative conditions. However, future development must consider pathway selectivity, infection risk associated with proximal blockade, and the potentially protective roles of specific complement components in some CNS diseases.
Realising the promise of complement-targeted therapy will rely on rigorous clinical testing, careful safety monitoring and integration of disease-specific biomarkers to support personalised treatment decisions. The source positions complement modulation as a rapidly growing, but complex, therapeutic domain within neurology.