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Chronic Fatigue Syndrome (CFS) and Multiple Sclerosis (MS) as Subsets

of a Group of Cellular Immunity Disorders

P. Englebienne, M. Frémont, V. Herst and K. De Meirleir

Free University of Brussels and RED Laboratories, Belgium.

Apoptosis (cell suicide) is a critical component of adaptative

cellular immunity. Upon infectious challenges, type I interferons

elicit apoptotic responses by inducing the expression of 2-5A

synthetase (2-5OAS), RNase L and the p68 RNA-dependent kinase (PKR).

Activated PKR induces apoptosis by inhibiting translation (through

eIF2? phosphorylation) and by a mechanism involving the activation of

caspase 8 mediated by the Fas-associated death domain. Activation of

2-5OAS results in the production of 2-5oligoadenylates which in turn

activate RNase L. Activated RNase L induces apoptosis by a mechanism

involving the caspases. Results from our laboratories point to an

improper activation of 2-5OAS both in CFS and MS monocytes. This

results in an inappropriate activation of RNase L. This process

ultimately leads to a blockade of the RNase L-mediated apoptotic

program. This supports the involvement of environmental factors and

cellular stress capable of generating small RNA fragments and/or

inducing the transcription of endogenous retrovirus or repetitive Alu

sequences. These " abnormal " RNA sequences are responsible for the

inappropriate activation of 2-5OAS and have been implied in the

etiology of both disorders. These RNA fragments, depending on their

origin and structure, are capable of either activating or down-

regulating PKR. This results in a differential effect not only on the

PKR/RNase L-mediated apoptotic programs but also on the activation by

PKR of the inducible NO synthetase (through NF-?. A release of NO

at either high (CFS) or low rates (chronic MS) by lymphocytes has

corrolary consequences: triggering the skeletal and cardiac muscle

ryanodine receptors (calcium channels), NK cell function, COX2

activation and glutamate release by activated T-cells in the brain.

Glutamate upregulation leads to oligodendrocyte excitotoxicity in MS

and downregulation in CFS impairs hypothalamic CRH secretion. Our

results suggest that CFS and chronic MS are the extremes of an array

of dysfunctions in the 2-5A/RNase L/PKR pathways where other

autoimmune diseases might fit.