The validity of animal models to explore the pathogenic role of the complement system in multiple sclerosis: A review

Abstract

Animal models of multiple sclerosis (MS) have been extensively used to characterize the disease mechanisms in MS, as well as to identify potential pharmacologic targets for this condition. In recent years, the immune complement system has gained increased attention as an important effector in the pathogenesis of MS. Evidence from histological, serum, and CSF studies of patients supports an involvement of complement in both relapsing-remitting and progressive MS. In this review, we discuss the history and advances made on the use of MS animal models to profile the effects of the complement system in this condition. The first studies that explored the complement system in the context of MS used cobra venom factor (CVF) as a complement depleting agent in experimental autoimmune encephalomyelitis (EAE) Lewis rats. Since then, multiple mice and rat models of MS have revealed a role of C3 and the alternative complement cascade in the opsonization and phagocytosis of myelin by microglia and myeloid cells. Studies using viral vectors, genetic knockouts and pharmacologic complement inhibitors have also shown an effect of complement in synaptic loss. Antibody-mediated EAE models have revealed an involvement of the C1 complex and the classical complement as an effector of the humoral response in this disease. C1q itself may also be involved in modulating microglia activation and oligodendrocyte differentiation in these animals. In addition, animal and in vitro models have revealed that multiple complement factors may act as modulators of both the innate and adaptive immune responses. Finally, evidence gathered from mice models suggests that the membrane attack complex (MAC) may even exert protective roles in the chronic stages of EAE. Overall, this review summarizes the importance of MS animal models to better characterize the role of the complement system and guide future therapeutic approaches in this condition.

Mice deficient in complement C3 are protected against recognition memory deficits and astrogliosis induced by status epilepticus

“…It is also well established that activation of the immune complement system can occur as a result of brain injury and in neurodegenerative disorders ( Schartz and Tenner, 2020 ). Under pathological conditions such as those associated with traumatic brain injury, multiple sclerosis, and Alzheimer’s disease (AD), complement proteins, including C3, are linked to impaired cognitive functions ( Carpanini et al, 2019 ; Schartz and Tenner, 2020 ; Bourel et al, 2021 ; Saez-Calveras et al, 2022 ). In this study, we found SE-induced impairments in recognition memory in WT mice but not in C3 KO mice ( Figure 4 ).…”

The complement system in neurodegenerative and inflammatory diseases of the central nervous system

“…Finally, animal models involving complement deficiencies have been immensely helpful in dissecting complement-mediated pathological contributions to neurodegenerative and neuroinflammatory diseases and have served as pioneering platform for in vivo testing of complement inhibitors ( 240 ). However, most studies on complement in CNS pathologies have been performed using mice with global deficiencies in complement components of interest.…”

Association of Complement Factors With Disability Progression in Primary Progressive Multiple Sclerosis

“…Immunohistochemical studies of postmortem MS brains have shown immunoreactivity for CCs, activation products, and complement regulators not only in plaque and periplaque areas but also in normalappearing white matter and cortical regions. 10,11 Several studies have also reported differences in the blood and CSF levels of CCs between patients with MS and healthy controls and between patients with different clinical forms of MS. [12][13][14] However, few of these studies were performed in patients with progressive MS and none of them evaluated long-term outcomes. Of interest, immunoreactivity for CCs has been observed in chronic active and inactive plaques of patients with progressive MS in the absence of other inflammation markers such as blood immune cells, indicating that progression of inflammation in MS does not depend on infiltrating cells and can be driven by innate immune mechanisms including complement activation.…”