Oligodendrocyte cell death in pathogenesis of multiple sclerosis: Protection of oligodendrocytes from apoptosis by complement

Abstract

Abstract-Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. It is mediated by activated lymphocytes, macrophages, microglia, and complement. In MS, myelin-forming oligodendrocytes (OLGs) are the targets of inflammatory and immune attacks. OLG death by apoptosis or necrosis causes the cell loss seen in MS plaques. Studies of experimental allergic encephalomyelitis (EAE) in caspase 11-deficient mice show that caspasemediated death of OLGs is critical to demyelination. Complement activation may affect MS pathogenesis through activated terminal complex C5b-9, which promotes demyelination, and through sublytic C5b-9, which protects OLGs from apoptosis. By inducing EAE in C5-deficient mice, we showed that complement C5 promotes axon preservation and new myelin formation, which protect OLGs from apoptosis. These findings indicate that activated complement C5b-9 plays a proinflammatory role in acute MS but may also protect OLGs from death in chronic MS.

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

“…It has been suggested that the demyelination of axons is due to the death of myelin-forming oligodendrocytes, which in part may be caused by detrimental inflammatory and immune responses targeted to these cells [139]. The involvement of TNF-α in MS has been explored in several studies [103] (also see Table 1).…”

Understanding Multiple Sclerosis by Examination of Theories in Medical Literature

“…and inflammatory cell infiltrates, including T cells, B cells, macrophages, and activated microglia" [4]. A study published in 2001 by the Journal of Neuroscience Research showed the presence of myelin-reactive T cells in the blood and cerebrospinal fluid (CSF) of MS patients [5].…”

“…A study published in 2001 by the Journal of Neuroscience Research showed the presence of myelin-reactive T cells in the blood and cerebrospinal fluid (CSF) of MS patients [5]. It has also been reported that "demyelination primarily results from a T-cell-mediated immune response to various myelin antigens [4]. The theory adopted by Cadirci and others is that MS is associated with the up-regulation of TNF, TNF-β, IFN-g, and IL-12 pro-inflammatory cytokines.…”

The Role of Death Domains Superfamily in Multiple Sclerosis Pathogenesis

“…matory diseases of the central nervous system (CNS), considered as a multi-factorial disease depending on genetic and non-genetic factors [1], mediated by activated lymphocytes, macrophages, microglia, and complement [2], characterized by localized areas of demyelination, and being the leading cause of non-traumatic neurological disability in young adults [3]. In both MS and EAE, the myelin and the myelin-producing cells, the oligodendrocytes (OLGs), are targets of the autoimmune attack, and their loss is directly associated with neuronal dysfunction and damage leading to the clinical manifestations of the disease [4].…”

“…Apoptosis contributes to OLGs depletion in MS lesions and ultimately, increases demyelination. OLGs depletion increases potential for axonal injury and lack of remyelination [2]. Apoptosis is a coordinated and often energy-dependent process that involves the activation of a group of cysteine proteases called "caspases" and a complex cascade of events that link the initiating stimuli to the final death of the cell [8].…”