Presentation Start Time:
1/28/2014 3:15:00 PM
Epsilon Toxin: An Environmental Cause of Multiple Sclerosis?
J. R. Linden
, Y. Ma, B. Zhao, K. R. Rumah, T. Vartanian;
The Brain and Mind Res. Inst. and the Dept. of Neurology, Weill Cornell Med. Coll., New York, NY.
Epsilon toxin (ETX) is a lethal, pore-forming toxin produced by Clostridium perfringens (C. perfringens) type B and D. Because of its potency, the CDC considers ETX a category B toxin. Recently, we demonstrated that sera and cerebral spinal fluid from patients with active multiple sclerosis (MS) show a ten fold increase in immunoreactivity to ETX compared to healthy controls. We also isolated a C. perfringens type B strain from a woman with early and active MS; no ETX producing strains were detected in healthy controls. MS is an inflammatory disease of the central nervous system (CNS) characterized by blood brain barrier (BBB) permeability and demyelination, a process in which the insulating myelin sheaths of neurons are damaged, inhibiting electrical impulse transmission. The environmental trigger of MS is still unknown, however previous observations that: 1) ETX induces BBB permeability 2) that ETX binds to myelin and 3) MS patients are immunoreactive to ETX and can carry the toxin producing bacteria make ETX an excellent candidate for initiating nascent MS lesion formation. In this study we prove that acute ETX exposure kills oligodendrocytes, the myelin-producing cells of the CNS, and that long-term ETX exposure reduces the total number of oligodendrocytes and the amount of myelin-associated proteins. Neutralizing antibodies against ETX inhibit cell death and myelin loss. We provide evidence supporting the ability of ETX to disrupt BBB permeability and enter the CNS parenchyma and also show that ETX binds to retinal vascular and meningeal cells, additional sites of MS-related inflammation. 37 food samples from grocery stores were screened for the presence of ETX or C. perfringens type B and D. C. perfringens was detected in 13.5% of samples and the ETX gene in 2.7%. In conclusion, ETX is mechanistically compatible with new MS lesion formation. In addition, infection by the ETX producing bacteria may be acquired from contaminated food. More studies are needed to determine human susceptibility to both the toxin and toxin-producing bacteria so methods of prevention and treatment can be developed.
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