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Understanding the Critical and Emerging Role of Complement in Neurological Disorders
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Key Takeaways
- The complement system is vital for immune surveillance and tissue homeostasis, with dysregulation linked to neurological disorders and neurodegenerative diseases.
- It consists of an enzymatic cascade and a lytic pathway, with classical, lectin, and alternative activation pathways.
The complement system is critical in immune defense and tissue homeostasis, but its dysregulation can contribute to autoimmune neurological disorders and neurodegenerative diseases like Alzheimer, ALS, and multiple sclerosis.
Marinos Dalakas, MD
The complement system is a complex network of plasma and membrane-bound proteins that play a pivotal role in maintaining tissue homeostasis and supporting immune surveillance through interactions with both the innate and adaptive immune systems. Dysregulation, dysfunction, or unintended activation of complement components has been implicated in the pathogenesis of various autoimmune neurological disorders and may also contribute to the development and progression of neurodegenerative diseases.
A 2020 review provided an overview of the main components of the initial complement pathways, the lytic pathway, and the factors associated with inappropriate complement activation or control in disease initiation and progression. Led by Marinos Dalakas, MD, a neurologist at Thomas Jefferson University, the review broke the complement system down into 2 parts: the enzymatic cascade and the lytic pathway. The enzymatic cascade generates the molecules needed to initiate the lytic pathway, in which the soluble proteins undergo conformational changes that enable their insertion into lipid bilayers and ultimately form osmolytic membrane attack complex (MAC).
The complement system’s enzymatic cascade consists of three pathways—classical, lectin, and alternative—that differ in activation and regulation. The classical pathway is initiated by the C1 complex, which binds to antigen-antibody complexes or directly to pathogens, activating C4 and C2 to form the C3 convertase C4bC2a. The lectin pathway is similar but uses pattern-recognition molecules like mannose-binding lectin (MBL) to detect pathogen-associated carbohydrates, activating MASP1 and MASP2 to form the same C3 convertase. Both pathways are regulated by C1-esterase inhibitor (C1-INH).
The alternative pathway, in contrast, is continuously active at low levels through spontaneous hydrolysis of C3 to C3(H2O), which then activates C3 convertase C3bBb, amplifying the response with a positive feedback loop. The classical pathway evolved with immunoglobulins, while the lectin and alternative pathways are more ancient, with components found in invertebrates. All three pathways ultimately generate pro-inflammatory anaphylatoxins and opsonins, essential for immune defense and tissue homeostasis.
Dysfunction or improper activation of the complement system is linked to various neurological disorders. Deficiencies in complement proteins, like CD59, can lead to nerve damage, as seen in conditions such as paroxysmal nocturnal hemoglobinuria (PNH) or demyelinating neuropathies similar to Guillain-Barré syndrome. Diabetes can also impair CD59 and activate complement, contributing to neurological complications. Inappropriate complement activation by autoantibodies, particularly IgG1, can cause tissue damage, while IgG4 antibodies delay the removal of altered self, promoting autoimmune pathology.
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Complement activation in the brain can occur when the blood-brain barrier is compromised by aging or oxidative stress, allowing complement components to enter and potentially cause damage. Even with an intact barrier, microglia and astrocytes in the brain produce complement proteins that play protective roles in processes like neurotransmitter clearance and synaptic pruning.
In the review, Dalakas et al also highlight some of the diseases of neuromuscular junction impacted by complement. These included myasthenia gravis, Lambert-Eaton myasthenic syndrome, inflammatory muscle diseases, necrotizing autoimmune myositis, and dermatomyositis. Additionally, complement is known to have a profound involvement on diseases of the central nervous system, including multiple sclerosis, acute disseminating encephalomyelitis (ADEM), and a subset of patients with autoimmune encephalopathies.
Neurodegenerative diseases like Alzheimer's (AD) involve progressive neuron loss and synaptic degeneration, with complement activation products (C1q, C3, C4) found around amyloid-β plaques and neurofibrillary tangles. While complement’s role in AD remains unclear, studies suggest that early activation of C1q and C3 contributes to synaptic deficits and neurodegeneration. Inhibition of these components has shown promise in improving cognitive function in animal models, but results are mixed. Complement activation is also implicated in other conditions, including ALS, Huntington's disease, and traumatic brain injury, where it contributes to neuroinflammation. Additionally, high levels of C1q are observed in aging and multiple sclerosis, suggesting a broader role for complement in neurodegeneration.
Complement-targeted therapies hold promise for neurological diseases, but caution is necessary due to the complement system’s role in immune defense and signaling. Prolonged complement suppression may increase susceptibility to infections, particularly bacterial ones, as seen in C3 deficiency, though no major issues have arisen with appropriate prophylaxis.
Complement is also crucial for processes like synaptic pruning and neurogenesis, and inhibition could interfere with these beneficial effects. While safety profiles for eculizumab in conditions like PNH and myasthenia gravis are generally good, it can increase susceptibility to infections, especially life-threatening meningococcal infections, necessitating vaccination and careful monitoring. Other common side effects include headaches, gastrointestinal issues, and musculoskeletal pain, with rare anaphylactic reactions.
