Abstract
Reactivity to myelin associated proteins is the hallmark of human multiple sclerosis (M.S) and its experimental counterparts. However, the nature of such reactivity has not been described fully. Herein, we report that myelin basic protein (MBP) reactivity accumulates in a rat model for M.S. over a period of time and sensitizes TRAIL mediated progressive oligodendrocyte apoptosis. We used active immunization by Myelin Oligodendrocyte Glycoprotein (MOG, 50 μg) to study chronic remitting relapsing encephalomyelitis in rats. A time point analysis of the progressive disease revealed cumulative accumulation of anti myelin basic protein antibodies during the disease progression with minimal change in the anti-MOG antibodies. Increased reactivity to MBP was studied to sensitize TNF related apoptosis-inducing ligand (TRAIL) and other proinflammatory cytokines in a cumulative fashion leading to the Caspase dependent apoptosis of oligodendrocytes and myelin loss. In a rescue experiment, we could limit the demyelination and prevent disease progression by neutralizing the effector, TRAIL in an early stage of the disease. This is the first study to identify the accumulation of MBP antibodies in MOG induced EAE which possibly leads to TRAIL sensitized oligodendrocyte apoptosis in the white mater of EAE rats. This finding stresses on the need to study MBP antibody titers in M.S. patients and therefore might serve as an alternate marker for progressive demyelination.
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Acknowledgments
Authors are thankful to Dr. G.N Qazi (Vice Chancellor, Jamia Hamdard) for the moral support during the course of the study. Mir Sajad was Postdoctoral Research Associate (Grant no-81/4/2009-BM-Stem Cell), Indian Council of Medical Research (ICMR) Govt. of India, New Delhi.
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Mir, S., Ali, F., Chauhan, D. et al. Accumulation of reactivity to MBP sensitizes TRAIL mediated oligodendrocyte apoptosis in adult sub cortical white matter in a model for human multiple sclerosis. Metab Brain Dis 31, 299–309 (2016). https://doi.org/10.1007/s11011-015-9750-5
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DOI: https://doi.org/10.1007/s11011-015-9750-5