The role of the complement system in Multiple Sclerosis: A review

Abstract

The complement system has been involved in the pathogenesis of multiple neuroinflammatory and neurodegenerative conditions. In this review, we evaluated the possible role of complement activation in multiple sclerosis (MS) with a focus in progressive MS, where the disease pathogenesis remains to be fully elucidated and treatment options are limited. The evidence for the involvement of the complement system in the white matter plaques and gray matter lesions of MS stems from immunohistochemical analysis of post-mortem MS brains, in vivo serum and cerebrospinal fluid biomarker studies, and animal models of Experimental Autoimmune Encephalomyelitis (EAE). Complement knock-out studies in these animal models have revealed that this system may have a “double-edge sword” effect in MS. On the one hand, complement proteins may aid in promoting the clearance of myelin degradation products and other debris through myeloid cell-mediated phagocytosis. On the other, its aberrant activation may lead to demyelination at the rim of progressive MS white matter lesions as well as synapse loss in the gray matter. The complement system may also interact with known risk factors of MS, including as Epstein Barr Virus (EBV) infection, and perpetuate the activation of CNS self-reactive B cell populations. With the mounting evidence for the involvement of complement in MS, the development of complement modulating therapies for this condition is appealing. Herein, we also reviewed the pharmacological complement inhibitors that have been tested in MS animal models as well as in clinical trials for other neurologic diseases. The potential use of these agents, such as the C5-binding antibody eculizumab in MS will require a detailed understanding of the role of the different complement effectors in this disease and the development of better CNS delivery strategies for these compounds.

Complement tunes glutamate release and supports synaptic impairments in an animal model of multiple sclerosis

“…In this framework, the C1q or the C3 densities hugely increased in cortical homogenates of EAE mice at the acute stage of the disease and in synaptosomal and gliosomal lysates, consistent with the reported overexpression of these proteins in the CNS of MS patients and EAE mice (Becquart et al, 2020;Hammond et al, 2020;Ingram et al, 2014;Kovács et al, 2021;Michailidou et al, 2015;Saez-Calveras & Stuve, 2022), and, specifically, in presynaptic nerve endings and astrocytic specializations (Acharjee et al, 2018;Aronica et al, 2007;Lu et al, 2021;Matsuda, 2017;Michailidou et al, 2015;Scott-Hewitt et al, 2020;Stephan et al, 2013;Yuzaki, 2010). Whether C1q and C3 colocalize in synaptosomes and/or gliosomes remains to be established, although the finding that the two proteins are mutually exclusive in eliciting glutamate release could support this view.…”

Virus-host protein co-expression networks reveal temporal organization and strategies of viral infection

“…1). Several upregulated proteins of this community are associated with the complement system 5 , whose alteration may be connected to the tight association between EBV infection and multiple sclerosis 43,44 . The most salient topological feature of the connector community, however, is the presence of three host proteins densely connected to the viral subnetwork (Fig.…”

The causal relationship between autoimmune diseases and age-related macular degeneration: A two-sample mendelian randomization study

“…In AMD, vascular loss in the choroid is considered a significant etiological feature [ 32 ]. Conversely, in MS, the complement system may also play a role due to its association with the blood-brain barrier and the imperative of vascular health in preventing the entry of complement proteins into the CNS [ 33 ]. Given the observed hyperactivity of the complement system in both AMD and MS, complement inhibitors could have potential therapeutic value in the treatment of these diseases.…”