Editorial: Complement in nervous system disease

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FIGURE
The molecular pathways of complement activation. Classical pathway: it starts with the binding of C q to the target cell. C q recognizes the target by the presence of bound antibodies. C q can also bind to distinct molecules, patterns or structures. C q is a subunit of the C complex which is further composed of the C r and C s proteases. Upon binding of C q to the target, C r and C s get activated. C s cleaves the C protein into C a and C b. C a is released whereas, C b is covalently bound to the target. C b attracts C which is cleaved by C s into C a and C b. C a is released whereas, C b binds C b forming the C b b complex, also known as C convertase. C convertase cleaves C into C a and C b. C b may bind the C convertase forming the C b b b complex, also known as C convertase. C convertase cleaves C into C a and C b. C b may associate with C , C , C , and C to form the final product of complement activation, the membrane attach complex (MAC). Lectin pathway: it starts with the binding of mannose-binding lectin (MBL) or ficolins on the target cell. Circulating MBL or ficolins recognize the target by the presence of carbohydrate patterns. MBL is complexed with two components, the MBL-associated serine protease (MASP) and MASP . MASPs get activated upon binding of MBL to the target and cleave C and C to form the C convertase. The pathway continues with the formation of the C convertase and MAC. Alternative pathway: it starts with the spontaneous hydrolysis of C into C (H O) and continues with the binding of factor B to C (H O) for cleavage of factor B into Ba and Bb by factor D. This results in the formation of the fluid phase C convertase, C (H O)Bb. C (H O)Bb converts C into C a and C b. Some C b molecules attach to the target and associate with factor B, which will be cleaved by factor D. This results in the formation of the C convertase C bBb. The pathway continues with formation of the C convertase (C bBb b), cleavage of C and formation of MAC. Created with BioRender.com.
reported significantly higher intraocular levels of the C1q-C3 axis proteins compared to control eyes, and a negative correlation between the amounts of C1q-C3 axis proteins and deep layer retinal thickness. Because complement is a major component of both the systemic and the neuro-inflammation, it can mediate neuroimmune actions in response to infections (Vasek et al., 2016). Hao et al. showed that complement-mediated synaptic pruning and neuroinflammation were boosted in Alzheimer's disease upon entrance of the periodontitis-causing pathogen Porphyromonas gingivalis (Pg) in the brain. Next to its role in synaptic pruning, complement has additional roles in the pathology of the nervous system some of which are (partially) defined whereas, others not. In this Research Topic, Veremeyko et al. present data supporting a novel role for the C4B-encoded C4 protein in epilepsy. This role of C4 is associated with the expression of immediate early genes during an epileptic seizure and affects the cognition of mice receiving convulsant and subconvulsant doses of pentylenetetrazole.
In multiple sclerosis (MS), complement has an established role in demyelination (Prineas et al., 2001;Barnett et al., 2009). In particular, C1q has an antigen recognition-associated effector function that allows the efficient destruction of antibody-targeted myelin (Morgan et al., 2021). Notably, T cells and astrocytes located within a MS lesion respond to activated complement by increasing the expression levels of RGC32, a gene driving neuroimmune responses. A mini review by Tatomir et al. explains how RGC32 regulates astroglial cell reactivity to promote glial scar formation in a MS lesion.
In the gray matter, Evans et al. show that complement deposition and/or activation is associated with compartmentalized inflammation which is a driver of subpial cortical demyelination (Howell et al., 2011;Ahmed et al., 2022) and MS progression (van Olst et al., 2021). By examining human post-mortem MS brains the authors identified an association between the amounts of meningeal/subpial complement proteins and the extent of cortical demyelination. In addition, they reported an increased density of phagocytic C3a receptor (R) 1+ and C5aR1+ microglial cells/macrophages at the expanding edge of subpial and leukocortical lesions, suggesting a role for complement in the expansion of MS lesions.
Therapeutic agents developed to target the complement system carry a clear potential to alleviate diverse diseases including neurological diseases. A study by Seidel et al. demonstrated an immunomodulatory effect of the terminal complement pathway inhibitor BB5.1 in the brain of obese Ldlr −/− .Leiden mice. By means of immunohistochemistry and next generation sequencing, Seidel et al. showed that systemic administration of the BB5.1, a monoclonal antibody that blocks C5 cleavage, affected the microglial cell immunophenotype and modulated brain neuroinflammation in the obese mice. BB5.1 blocks the terminal complement pathway and is used in multiple animal studies as the equivalent of the anti-human C5 monoclonal .
antibody Eculizumab (Zelek et al., 2020). Lekova et al. from Cardiff University published an article characterizing a novel anticomplement inhibitor blocking the C7 protein of the terminal complement system. In this article they assessed the in vitro function, binding epitopes, and mode of action of three monoclonal antibodies targeting the C7 protein. The authors concluded that one of them, the TPP1820 mAb was effective in preventing experimental myasthenia gravis (MG) and provided a stratification assay for the detection of MG patients which are predicted to respond to an anti-C7 therapy. Last but not least in the group of therapy-related articles of this Research Topic, Li et al. moved their focus upstream in the complement cascade to study the response of human and murine macrophages bearing the C3a receptor, the cognate receptor for the complement peptide C3a, to the C3a antagonist TLQP-21. TLQP-21 is a neuropeptide derived from the VGF precursor protein. The authors confirmed the binding of TLQP-21 to C3aR but reported a low potency of the human peptide to activate the human primary macrophages concluding that a C3aR-dependent action of TLQP-21 on macrophages may not be physiologically relevant in humans. This Research Topic show that the complement system is involved in more pathways than only combatting microbes. It has many more important functions in development and maintenance of a healthy nervous system.

Author contributions
IM: Writing-original draft, Writing-review and editing. KF: Writing-review and editing. MB: Writing-review and editing. NG: Writing-review and editing. FB: Writing-review and editing.