Caspase-mediated oligodendrocyte cell death in the pathogenesis of autoimmune demyelination.
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. MS is believed to be an autoimmune disorder mediated by activated immune cells such as T- and B-lymphocytes and macrophages/microglia. Lymphocytes are primed in the peripheral tissues by antigens, and clonally expanded cells infiltrate the CNS. They produce large amounts of inflammatory and cytokines that lead to demyelination and axonal degeneration. Although several studies have shown that oligodendrocytes (OLGs), the myelin-forming glial cells in the CNS, are sensitive to cell death stimuli, such as cytotoxic cytokines, anti-myelin antibodies, nitric oxide, and oxidative stress, in vitro, the mechanisms underlying injury to the OLGs in MS/EAE remain unclear. Transgenic mice that express the anti-apoptotic protein specifically in OLGs and caspase-11-deficient mice are significantly resistant to EAE induction. Histopathological analyses show that the number of caspase-activated OLGs and dead OLGs are reduced in the CNS of these mice. The numbers of infiltrating immune cells and the amounts of cytokines are also markedly reduced in EAE lesions. Therefore, caspase-mediated OLG death leads to the exacerbation of demyelination and the deterioration of neurological manifestations by inducing local inflammatory events.
Hisahara
Shin
S
Department of Neurology, School of Medicine, Sapporo Medical University, South 1 West 17, Chuo-ku, Sapporo, Hokkaido 060-8556, Japan. hisahara@sapmed.ac.jp
Okano
Hideyuki
H
Miura
Masayuki
M
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000502:physiology*; D016923:Cell Death; D003583:Cytokinins / Q000502:physiology; D020278:Demyelinating Autoimmune Diseases, CNS / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D009836:Oligodendroglia / Q000473:pathology*
D003583:Cytokinins; D020169:Caspases