Downregulation of RNase L inhibitor correlates with upregulation of interferon-induced proteins (2-5A synthetase & RNase L) in patients with Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS)

Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) is a disorder

characterized by debilitating fatigue associated with

immunological abnormalities and cognitive impairments. The

recently cloned RNase L Inhibitor (RLI) gene encodes a

specific protein which is believed to regulate 2-5A synthetase

and RNase L activity via the formation of a latent

heterodimeric protein complex. In the present study, we

investigated the levels of 2-5A synthetase, RNase L and RLI in

patients with CFIDS as compared to healthy controls.

Quantitative Competitive PCR (Q/C PCR) analysis showed a

statistically significant decrease in RLI mRNA present in the

peripheral blood lymphocytes (PBL) of patients with CFIDS (n =

25, mean = 569, S.E = 154) as compared to RLI mRNA level

present in peripheral blood lymphocytes (PBL) of healthy

controls (n = 15, mean = 2296, S.E = 506; p < 0.0001). The

decrease in RLI mRNA in CFIDS individuals correlated directly

with RLI and RLI: RNase L protein ratio while showing an

inverse relationship to the 2-5A synthetase and RNase L

activity. This RLI mRNA and protein deficiency in CFIDS

patients may explain the increase in activity of RNase L found

in CFIDS patients. The unidirectional decrease in RLI message

and protein levels in CFIDS individuals may contribute to the

destabilization of the latent RLI:RNase L heterodimeric

protein complex, resulting in the excessive activation of

RNase L shown in this study. The increased activation of RNase

L may result in an increased cellular RNA turnover and

subsequent inhibition of protein synthesis; thus resulting in

general fatigue, myalgia muscle weakness and other

symptomatologies shown in CFIDS patients. Furthermore, this

data supports the hypothesis that the antiviral 2-5

oligoadenylate synthetase (2-5OAS) overexpression in

individuals with CFIDS correlates with an increase in RNase L

activity and with a decrease in RNase L inhibitor.

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