C5b‐9 complement complex in autoimmune demyelination and multiple sclerosis: Dual role in neuroinflammation and neuroprotection

Abstract

Complement system activation plays an important role in innate and acquired immunity. Activation of complement leads to the formation of C5b-9 terminal complex. While C5b-9 can promote cell lysis, sublytic assembly of C5b-9 on plasma membranes induces cell cycle activation and survival. Multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE) are inflammatory demyelinating diseases of the central nervous system (CNS) mediated by activated lymphocytes, macrophages/microglia and the complement system. Complement activation may contribute to the pathogenesis of these diseases through its dual role: the ability of activated terminal complex C5b-9 to promote demyelination and the capacity of sublytic C5b-9 to protect oligodendrocytes (OLG) from apoptosis. By inducing EAE in C5-deficient mice, we showed that complement C5 promotes remyelination and protects oligodendrocytes from apoptotic cell death. These findings indicate that activation of complement C5b-9 plays a pro-inflammatory role in the acute phase of the disease, but may also be neuroprotective during the chronic phase of the disease.

Sublytic C5b-9 Complexes Induce Apoptosis of Glomerular Mesangial Cells in Rats with Thy-1 Nephritis through Role of Interferon Regulatory Factor-1-dependent Caspase 8 Activation

“…At a lower dose, C5b-9 can induce sublytic injury (i.e. cell apoptosis) (14), but some studies from mouse experimental allergic encephalomyelitis show that sublytic C5b-9 can protect oligodendrocytes from apoptosis and lead to survival (25,26), suggesting that the different roles in these cells may be due to different biochemical reactions, including cell states, upon sublytic C5b-9 attack (3,9,27).…”

Complement Plays an Important Role in Spinal Cord Injury and Represents a Therapeutic Target for Improving Recovery following Trauma

“…In rodent models of EAE, injury and myelin loss is attenuated in animals deficient in C5 and C6 and increased in animals deficient in CD59a, an inhibitor of MAC formation. [27][28][29][30][31] A contradictory finding was reported, however, in a rat model of immunological demyelination in which intraspinal infusions of IgG antibodies were administered in the presence of serum deficient in either C3, C4, C5, C6, or factor B.…”

Current Therapeutic Modalities, Enzyme Kinetics, and Redox Proteomics in Traumatic Brain Injury

“…At autopsy, TBI patients have reported Aβ peptides and neurofibrillary tangles of hyperphosphorylated tau proteins, thus leading to the hypothesis that AD can possibly be a secondary effect of TBI [25]. A past study showed that an increase of neuronal C5a receptors and C5b-9 terminal complex, a promoter of the cell cycle and cell lysis, in diffuse axonal injury (DAI) of TBI, could lead to possible secondary neuronal cell death [26,27]. New studies show that the C5a receptors and C5b-9 terminal complex should be used as targeted treatment areas, but are not necessarily a source of secondary axotomy in DAI [28].…”