Environmental risk factorsThursday, October 03, 2013, 15:45 - 17:00
Modeling the nascent multiple sclerosis lesion in cerebellar slice explants with Clostridium perfringens epsilon toxinY. Ma, R. Rumah, J. Linden, M. Oo, T. Vartanian (New York, US)
Background: Nascent MS lesions are characterized by blood-brain barrier breakdown, oligodendrocyte apoptosis, relative preservation of myelin and an absence of adaptive immune infiltrates. We propose Clostridium perfringens epsilon toxin (ETX) as a candidate toxin responsible for new lesion formation in MS since ETX targets CNS endothelial cells and oligodendrocytes. In this study we sought to model features of oligodendrocyte death in the earliest MS lesions.
Methods: Cerebellar slice cultures were generated from P6 mice. Cultures were grown for 21 days leading to robust myelination. At 21 days cultures were treated briefly with either lysolecithin or ETX. Slices were then fixed and stained for oligodendrocytes (olig2), microglia (IB4), Purkinje cells (calbindin), axons (neurofilament) and myelin (MBP), and visualized by confocal and conventional epi-fluorescence microscopy.
Results: C. perfringens epsilon toxin induced rapid and nearly complete (>98%) death of oligodendrocytes. At early time points, ETX induced oligodendrocyte apoptosis was accompanied by preservation of myelin (>90%). At later time points, demyelination followed ETX induced oligodendrocyte apoptosis as predicted. In contrast, lysolecithin treated cerebellar slices showed a decrement in oligodendrocyte numbers and marked reduction of myelin even by 22 hours after treatment.
Conclusions: The environmental trigger for MS is unknown. Since the earliest MS lesions show oligodendrocyte apoptosis with preservation of myelin, we reasoned that the environmental trigger for MS would target oligodendrocytes and that demyelination follows as a dying-back phenomenon. C. perfringens epsilon toxin fits conceptually with new lesion formation by inducing primary oligodendrocyte cell death with secondary demyelination. Our model recapitulates the features of oligodendrocyte death in nascent lesion formation.
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