K.De Meirleir, P.De Becker, J.Nijs, D.Peterson, G.Nicolson, R.Patarca and P.Englebienne
Free University of Brussels,
Institute for Molecular Medicine
Huntington Beach, California
Sierra Internal Medicine
Incline Village, Nevada
University of Miami
Pathophysiological Mechanisms in CFS
It seems clear today that no single etiologic agent is responsible for the development of CFS. Instead, in this disorder there are a number of onset and predisposing factors that compromise immunity (changes in cytokine balance, T cell activation, poor cellular immunity). Intracellular & opportunistic infections and viral reactivation will result in increase of the protein kinase R and ribonuclease L activity and poor ds(or ss)-RNA inducers will augment RNase L monomers that are prone to proteolytic cleavage. Pathological cleavage of native RNase L is accompanied by the release of small ankyrin fragments which contain the site of interaction with the RNase L inhibitor. As RLI is a member of the ABC transporter family, the ankyrin fragments are capable of interacting with the ABC transporters. The result is a dysfunction of these transporters because of competitive interaction with their natural ankyrin protein. All the ABC transporters that are analogous to RLI play a role in physiology of which dysfunction can be related to various symptoms in CFS. Thus several symptoms observed in CFS patients could be the result of an acquired channelopathy.
In a group of 206 CFS patients, using PCR with nucleoprotein gene tracking, we found that approximately 70% showed mycoplasmal infection; compared to the patients who were mycoplasma spp negative, the mycoplasma positive patients had significantly more cleavage fragments of RNase L. The following mechanism is proposed: mycoplasmas have been shown to overexpress an apoptotic-like endonuclease, which acts on the nuclear fraction of the host cells. Small base pair fragments (< 25 base pairs) will induce bad activation of the 2'-5' A synthetase and leaves the monomeric RNase L unprotected to cleavage by calpain, elastase and cathapsin G. Mycoplasmas are probably also able to induce direct proteolytic cleavage of RNase L.
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