2001 Clinical and Scientific Meeting

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

Free University of Brussels and RED Laboratories, Belgium.

Chronic Fatigue Syndrome (CFS) and Multiple Sclerosis (MS) as Subsets of a Group of Cellular Immunity Disorders

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-?B). 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.

 

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