At its core, the complement cascade is a proteolytic amplification machine. It can be triggered through three converging routes: the classical pathway, initiated when the C1 complex binds antibody-antigen complexes or other target structures; the lectin pathway, ignited when pattern-recognition molecules such as mannose-binding lectin and ficolins detect carbohydrate motifs on pathogens or damaged cells; and the alternative pathway, which samples surfaces continuously through spontaneous hydrolysis and is stabilized by properdin. All three routes converge on C3, whose cleavage generates the opsonin C3b that tags targets for phagocytosis and the anaphylatoxin C3a that recruits and activates inflammatory cells. Further cleavage of C5 releases the potent anaphylatoxin C5a and assembles the C5b-9 membrane attack complex, a pore-forming structure that can lyse susceptible cells. In host defence, this is a marvel of efficiency. In the nervous system, where many cell types are exquisitely vulnerable to lysis and inflammation, the same machinery can become an instrument of destruction.

What makes complement particularly fascinating in a neurological context is that it is not merely a circulating defence system but an active participant in normal brain physiology. Seminal experimental work has shown that classical pathway components, including C1q and C3, physically tag synapses during postnatal development, allowing microglia to prune weak or inactive connections in an activity-dependent manner. This complement-dependent synaptic sculpting is essential for wiring the developing brain, and related mechanisms continue to influence adult neural circuit plasticity, including microglia-mediated elimination of synapses linked to forgetting. The complement system also contributes to the clearance of apoptotic cells and cellular debris, processes fundamental to maintaining tissue health. These physiological roles carry a sobering implication: any therapeutic strategy that blanketly suppresses complement risks interfering with brain development, synaptic maintenance, and debris clearance, a concern that hangs over much of the current drug pipeline.

In autoimmune neurological disease, aberrant complement activation is now documented with striking consistency. In myasthenia gravis, autoantibodies against the acetylcholine receptor recruit complement to the neuromuscular junction, where the membrane attack complex destroys the postsynaptic membrane, a mechanism established experimentally decades ago and confirmed ultrastructurally by localization of the lytic component C9 at the motor end-plate. Complement activation profiles correlate with disease severity, and eculizumab, a monoclonal antibody that blocks cleavage of C5, demonstrated efficacy in refractory generalized disease in the pivotal REGAIN trial, earning regulatory approval and opening the floodgates for a broader class of anti-C5 agents, including the longer-acting ravulizumab and the subcutaneous peptide zilucoplan, alongside newer C5-targeting candidates such as gefurulimab now in phase 3 testing.

The antibody-mediated demyelinating diseases of the central nervous system tell a similarly compelling story. In neuromyelitis optica spectrum disorder, aquaporin-4-specific IgG1 antibodies bind astrocytic endfeet, fix complement, and generate astrogliotic, necrotic lesions; passive transfer experiments show that immunoglobulin G plus complement reproduces the pathology in animals. Blocking C5 with eculizumab dramatically reduced relapse rates in aquaporin-4-positive patients, and ravulizumab has since replicated these results with a more convenient dosing schedule. The related condition, myelin oligodendrocyte glycoprotein antibody-associated disease, displays its own distinctive complement activation signatures, with recent work showing that activation patterns downstream of C5 cleavage differ between MOGAD and aquaporin-4 antibody-positive neuromyelitis optica, and that complement profiles can predict clinical outcomes. In multiple sclerosis, complement deposition is a prominent feature of lesions, oligodendrocytes are peculiarly susceptible to complement lysis even in the absence of antibody, and growing clinical evidence links circulating complement activation products to structural brain damage, disease severity, and disability progression, including in primary progressive disease. Notably, animal studies reveal that some complement components, such as C5-derived signals, may actually facilitate remyelination, reinforcing the argument for nuanced, pathway-selective modulation rather than indiscriminate shutdown.

In disorders of the peripheral nervous system, complement has moved from suspected accomplice to validated therapeutic target. In Guillain-Barré syndrome, autoantibodies against gangliosides on motor nerve terminals and perisynaptic Schwann cells recruit the membrane attack complex, and complement inhibition protects nerve terminals in murine models. Eculizumab was tested in a large phase 3 trial and, although the primary endpoint was not met, encouraging signals and real-world comparative data for the proximal inhibitor ANX005, which blocks C1q, suggest that early, pathway-targeted intervention may still prove valuable. Chronic inflammatory demyelinating polyneuropathy has emerged as a particularly fertile field: recent complement profiling of sural nerves, together with the demonstration that terminal pathway activation tracks with disease severity, has set the stage for phase 2 studies of the C1s inhibitor riliprubart, with promising early efficacy and safety findings. Multifocal motor neuropathy and IgM anti-MAG antibody neuropathies are likewise being reinterpreted through a complement lens, with the C2-blocking antibody empasiprubart, derived from the ARGX-117 program, advancing through clinical development on the logic that IgM-driven complement activation depends critically on the classical pathway component C2.

Perhaps the most provocative frontier is neurodegeneration. In Alzheimer disease, genetic association studies first implicated complement genes as susceptibility loci, and mechanistic work then showed that C1q and C3 drive early synapse loss in mouse models, with microglia engulfing complement-tagged synapses. Complement C3 deficiency protects aged, plaque-laden mice from neurodegeneration, yet other data indicate that specific complement components exert tissue-protective effects, promoting clearance of amyloid debris and supporting repair. Similarly, in amyotrophic lateral sclerosis, elevations of C5a and the membrane attack complex in patient blood and dysregulation of the cascade in the hSOD1G93A mouse model motivated a randomized trial of ravulizumab, which did not slow disease progression but provided dose-finding and safety data that will inform future, more precisely targeted efforts. These mixed results crystallize the central dilemma of the field: complement is both arsonist and firefighter, and the therapeutic challenge is to extinguish the destructive arm of the cascade while preserving its reparative functions.

The authors of the review emphasize that the existing complement drug arsenal, which includes C5 inhibitors such as eculizumab, ravulizumab, and crovalimab; the C1s inhibitor sutimlimab; the C3-targeting peptide pegcetacoplan; factor B and factor D blockers such as iptacopan and danicopan; C1-esterase inhibitor concentrates; and the C2-blocking antibody empasiprubart, was largely forged in hematology, ophthalmology, and nephrology before being imported into neurology. Expanding these agents to the brain raises distinctive pharmacological hurdles, including the blood-brain barrier, the need for sustained pathway suppression in a compartment with limited drug access, and the infection risks inherent in disabling a key arm of host defence, particularly meningococcal disease in patients receiving terminal pathway inhibitors. Proximal inhibitors that block C1 or C2 confer broader cascade suppression and may better preserve certain distal functions, but they carry their own trade-offs in infection susceptibility and disruption of physiological opsonization and debris clearance.

Looking ahead, Dalakas and Lünemann argue that the future of complement-targeted neurology will depend on systematic, biomarker-guided patient selection. Reliable, disease-specific measures of complement activation, whether from cerebrospinal fluid, blood, or tissue, will be essential to identify which patients are most likely to benefit from proximal versus distal inhibition, and to time intervention before irreversible tissue injury has occurred. As biologics targeting other axes of autoimmunity, from FcRn antagonists and neonatal Fc receptor blockers to B-cell-depleting agents and, increasingly, CAR T-cell therapies, crowd the neurological treatment landscape, complement inhibitors will need to demonstrate not just efficacy but a rational, mechanistically defined place in therapeutic algorithms. What is no longer in doubt is the direction of travel: from a system once studied almost exclusively by immunologists, complement has become a frontier of clinical neurology, and the coming decade will determine how precisely medicine can wield its power without extinguishing its gifts.

Subject of Research: The role of the complement system and complement-targeted therapeutics in autoimmune and neurodegenerative neurological diseases

Article Title: Role of complement and complement-targeted therapeutics in neurological diseases

Article References: Dalakas, M. C., & Lünemann, J. D. (2026). Role of complement and complement-targeted therapeutics in neurological diseases. Nature Reviews Neurology. https://doi.org/10.1038/s41582-026-01261-4

Image Credits: AI Generated

DOI: 10.1038/s41582-026-01261-4

Keywords: complement system, neuroimmunology, myasthenia gravis, neuromyelitis optica, multiple sclerosis, Guillain-Barré syndrome, Alzheimer disease, amyotrophic lateral sclerosis, eculizumab, ravulizumab, membrane attack complex, complement inhibitors

Neuromyelitis optica spectrum disorder has long been distinguished from multiple sclerosis by its serological signature. In 2004, Lennon and colleagues identified a serum autoantibody that marks the disease and separates it clearly from multiple sclerosis, an antibody directed against aquaporin-4, a water channel protein abundantly expressed on astrocytes at the blood-brain barrier and within the central nervous system parenchyma. The binding of these pathogenic immunoglobulin G antibodies to aquaporin-4 triggers complement activation, inflammatory injury to astrocytes, and secondary damage to neurons and oligodendrocytes. Because the antibody is produced by B lineage cells, the logical therapeutic strategy has been to deplete the cells that generate it.

That strategy has been validated repeatedly. Rituximab, a chimeric monoclonal antibody targeting CD20 on the surface of pre-B cells and mature B cells, entered clinical practice on the strength of open-label series and was later tested in the RIN-1 study, a multicentre, randomised, double-blind, placebo-controlled trial published in The Lancet Neurology in 2020, which established its safety and efficacy in the disorder. Inebilizumab, a humanized anti-CD19 antibody with a broader reach across the B cell lineage because it also targets plasma cell precursors, demonstrated benefit in the N-MOmentum phase 2/3 trial reported in The Lancet in 2019. Complement inhibition with eculizumab, reported in the New England Journal of Medicine in 2019, provided an alternative downstream approach by blocking the terminal complement pathway that the pathogenic antibodies engage.

Now obinutuzumab β, a glycoengineered type II anti-CD20 monoclonal antibody, has produced remarkable results in a phase 3 randomized controlled trial described by Wu and colleagues in Nature Medicine. Unlike type I anti-CD20 antibodies such as rituximab, type II antibodies like obinutuzumab engage CD20 in a manner that promotes direct cell death through non-apoptotic mechanisms and mediates more efficient depletion of certain B cell compartments, including tissue-resident populations that are less accessible to complement-dependent mechanisms. The glycoengineering of the Fc region enhances affinity for activating Fc gamma receptors on effector cells, sharpening antibody-dependent cellular cytotoxicity. These pharmacological distinctions matter, because the depth of depletion achieved within different B cell niches may determine how thoroughly autoantibody production is suppressed.

This is precisely the distinction Nakashima highlights in his analysis. The pathogenic anti-aquaporin-4 antibodies in neuromyelitis optica spectrum disorder are secreted by plasmablasts and plasma cells, differentiated descendants of B cells that express little or no surface CD20 and are therefore invisible to all anti-CD20 therapies. Yet clinical experience shows that depleting CD20-positive B cells nevertheless suppresses disease activity in most patients, implying that the continuously replenished pool of CD20-positive B cells is essential for sustaining the plasmablast population that secretes the pathogenic antibody. Fundamental work by Chihara and colleagues, published in the Proceedings of the National Academy of Sciences in 2011, showed that interleukin-6 signaling promotes anti-aquaporin-4 autoantibody production from plasmablasts, suggesting that the survival and differentiation of antibody-secreting cells depend on signals delivered by the surrounding B cell and immune milieu that anti-CD20 therapy disrupts.

The deeper-versus-broader framing also captures a paradox that clinicians have observed since the earliest rituximab era. Nakashima himself reported, in the Journal of Clinical Neuroscience in 2011, transient increases in anti-aquaporin-4 antibody titers following rituximab treatment, associated with elevated serum levels of BAFF, a B cell activating factor belonging to the tumour necrosis factor family. When B cells are depleted, BAFF levels rise because the cytokine is no longer consumed by its targets, and this surge can paradoxically promote the differentiation of surviving precursors towards antibody-secreting cells. Perumal and colleagues documented disease exacerbation after rituximab induction in a subset of patients, a phenomenon plausibly linked to these humoral dynamics. Any new depleting agent must therefore be evaluated not only for how deeply it depletes circulating B cells but also for how it perturbs the regulatory cytokine networks that govern reconstitution.

Dysregulated B cell differentiation towards antibody-secreting cells is now recognised as a hallmark of the disease, as Hoshino and colleagues described in the Journal of Neuroinflammation in 2022. In patients with neuromyelitis optica spectrum disorder, the balance between naïve B cells, memory compartments, and plasmablasts is shifted, with expanded populations of antibody-secreting cells circulating in the blood and correlating with disease activity. This pathobiology explains why broader depletion strategies, such as those targeting CD19 across a wider span of B cell differentiation including plasmablast precursors, and deeper depletion strategies, such as those using type II anti-CD20 antibodies with enhanced effector function, both hold mechanistic appeal. The phase III results with obinutuzumab β suggest that the depth and character of depletion may translate directly into clinical protection against relapse, the outcome that matters most in a disease where each attack can leave permanent, disabling neurological damage.

The clinical stakes of these distinctions are considerable. Neuromyelitis optica spectrum disorder disproportionately affects women and shows a striking predilection for populations in East Asia, and attacks of optic neuritis and transverse myelitis can cause irreversible blindness and paralysis. Since the identification of the aquaporin-4 antibody, a growing therapeutic armamentarium has emerged, encompassing B cell depletion, complement inhibition, and blockade of the interleukin-6 receptor, each intercepting the autoimmune cascade at a different point. The demonstration that obinutuzumab β achieves striking efficacy adds a potent new option, but it also invites head-to-head comparisons that have not yet been performed, leaving open the question of whether deeper depletion of conventional B cell compartments truly outperforms broader depletion that extends into the plasmablast lineage.

Longer-term considerations also come into focus as depleting therapies mature. Repeated courses of B cell depletion carry implications for humoral immunity, vaccine responses, and infection risk, and the dynamics of B cell reconstitution after obinutuzumab β, with its enhanced potency, may differ meaningfully from those seen after rituximab or inebilizumab. Monitoring strategies based on circulating CD19 and CD27-positive cell counts, serum BAFF levels, and anti-aquaporin-4 antibody titers may ultimately allow clinicians to individualise retreatment intervals, depleting deeply enough to prevent relapse while avoiding the prolonged immunosuppression that extended courses might otherwise impose. Biomarker-driven personalisation of this kind remains aspirational, but the mechanistic groundwork laid over the past two decades makes it increasingly plausible.

What the phase III obinutuzumab β trial ultimately delivers, in Nakashima’s assessment, is both a confirmation and a challenge. The confirmation is that B cell depletion remains the most reliable therapeutic principle yet discovered for aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder, capable of preventing the relapses that define the disease’s destructive course. The challenge is to move beyond the blunt question of whether B cells should be depleted and toward the precise one of which subpopulations sustain the autoimmune process, and how the depth, breadth, and timing of depletion can be tuned to maximize benefit while minimizing risk. As next-generation antibodies push the limits of what depletion can achieve, the field is converging on a richer, more granular understanding of B cell biology in neuroimmunological disease, one in which the architecture of the humoral immune response, rather than its mere suppression, becomes the true target of therapy.

Subject of Research: B cell depletion therapy for aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder

Article Title: Deeper versus broader B cell depletion in neuromyelitis optica spectrum disorder

Article References: Nakashima, I. (2026). Deeper versus broader B cell depletion in neuromyelitis optica spectrum disorder. Nature Reviews Neurology. https://doi.org/10.1038/s41582-026-01269-w

Image Credits: AI Generated

DOI: 10.1038/s41582-026-01269-w

Keywords: neuromyelitis optica spectrum disorder, B cell depletion, obinutuzumab beta, aquaporin-4 antibody, anti-CD20 therapy, plasmablasts, rituximab, inebilizumab, neuroimmunology, phase III trial, BAFF, autoantibody