A Guide To RNase L in Chronic Fatigue Syndrome (ME/CFS): Testing RNase L – A Biomarker?

The great goal in any newly emerging or poorly understood disease is to find a biomarker; a test that distinguishes the people with that disease from all others. Not only does a biomarker indicate the presence of a discrete disease process, it also provides researchers a pathway to the diseases origin. Once a biomarker is found, if the appropriate technology and resources are available then a resolution of a diseases origin is inevitable. Finding a biomarker for CFS will very likely, however, be difficult. The heterogeneity of the patient population, the different subsets that are emerging and the different triggers that spark the disease make it difficult for researchers to form the homogeneous sets of patients.

RNase L fragmentation has, however, been proclaimed to be a biomarker for CFS. Is it? Information provided in the last chapter of Chronic Fatigue Syndrome, A Biological Approach, a book examining RNase L dysfunction in CFS, indicates that the RNase L test fails a test of exclusivity; the 37-kDa fragment is also found in high levels in the acute stages of patients with multiple sclerosis.

A biomarkers efficacy in a clinical setting is not necessarily determined, however, by its exclusivity. Even if increased RNase L fragmentation is found in MS patients at some times, its usefulness as a biomarker for CFS is not diminished if clinicians can still distinguish CFS from MS based on other factors. The results given below indicate the degree of RNase fragmentation present mostly does distinguish CFS patients from others. To find more about RNase L visit the research section on this website.

Study  # of CFS Patients  # of Controls  % CFS Patients > .5 37/83-kDa %Controls> .5 37/83-kDa Significance % CFS patientsw/37-kDa Fragment % of Controlsw/37-kDa Fragment Quantity of 37-kDa CFS vs Controls
De MeirLeir et. al. 2000 57 58 72 11 p< .05* 88 28 p<.0001
Snell et. al. 2002 73 46 63 ? x x p<.001
Nijs et. al. 2003 155 X 83.3 x*** p< .05 x x x
Tiev et. al. 2003 11 14 90** 10** x x x x
Suhadolnik et. al. 2004. 66 113 x x x x x p<.001
Total 362 231 all p<.05 all p<.001 or 

Multiple studies from independent laboratories indicate from 63 to 90% of CFS patients display very high levels of RNase L fragmentation while 10% or less of controls do. Studies have consistently shown that CFS patients overall have significantly greater levels of RNase L fragmentation than do controls. Levels of RNase L fragmentation have been shown thus far to effectively differentiate CFS patients from fibromyalgia patients, depressed patients and healthy controls.

Several factors suggest RNase L fragmentation plays a central role in CFS. Levels of RNase L fragmentation have been found to be correlated with symptom expression (see CFS ABA Chapter VII), reduced aerobic capacity (VO2 max) and cognitive difficulties in CFS.

The RNase L enzyme is part of the interferon mediated immune response. Research is revealing significant problems in this response are seen in CFS patients. Dr. De Meirleir has found CFS patients display three different types of IFN mediated immune dysfunction;.

increased RNase fragmentation and dysfunctional protein kinase R (PKR)
increased RNase L fragmentation and (almost) normal PKR
normal RNase L and dysfunctional PKR (click here).
Thus while not all CFS patients exhibit increased RNase L fragmentation it appears that most do and that almost all CFS patients display some sort of disruption in the interferon mediated immune response. It appears further research into this response in general and in RNase L and PKR activity, in particular, should play an important role in elucidating the pathophysiology present in many CFS patients.

For much more information on the role this fascinating enzyme may play in CFS click here.

_________________________

* The acceptance of a research finding hinges hinges on the probability (p) of its being accurate. The probability finding (p < x) indicates the probability that a finding is a random result. In most research efforts a finding is considered ‘significant’ (i.e. is accepted) when statistical tests indicate there is a less than 5% probability (p < .05) that it is due to a random occurrence. Anything less than that is essentially unacceptable. Researchers typically either do not note such findings in their papers (except to say they are insignificant) or they may state they suggest a ‘trend’. The higher the p number the more robust the finding. The probability found in De Meirleir’s 2001 study, for instance, (p

**used cutoff point of .4 instead of .5 37/83-kDa RNase L

***x indicates information not available.

_____________________________

De Meirleir, K., Bisbal, C., Campine, I., De Becker, P., Salehzada, T., Demettre, E. and B. Lebleu. 2000. A 37-kDa 2-5A Binding Protein as a Potential Biochemical Marker for Chronic Fatigue Syndrome. American Journal of Medicine 108, 99-105.

Nijs, J, Kenny De Meirleir, Danny Coomans, D., De Becker1, Pascale and Garth Nicolson. 2003. Deregulation of the 2.5A synthetase RNase L antiviral pathway by Mycoplasma spp. in subsets of Chronic Fatigue Syndrome. Journal of Chronic Fatigue Syndrome 2003; 11(2): 37-50.

Snell, C., Van Ness J., Strayer, D. and S. Stevens. 2002. Physical performance and prediction of 2-5A synthetase/RNase L antiviral pathway activity in patients with chronic fatigue syndrome. In Vivo 16: 107-110.

Suhadolnik, R. A., Peterson, D., Reichenbach, N., Roen, G., Metzger, M., McCahan, J., O’Brien, K., Welsch, S., Gabriel, J., Gaughan, J. and N. McGregor. 2004. Clinical and biochemical characteristics differentiating chronic fatigue syndrome from major depression and healthy control populations: relation to dysfunction of the RNase L pathway. Journal of Chronic Fatigue Syndrome 12: 5-35.

Tiev, K. P., Demettre, E., Ercolano, P., Bastide, L., Lebleu, B. and J. Cabane. 2003. RNase L Levels in Peripheral Blood Mononuclear Cells: 37-kildalton/83 kilodalton Isoform Ration is a Potential Test for Chronic Fatigue Syndrome. Clinical and Diagnostic Laboratory Immunology. March 315-16.

1 comment

{ 1 comment… read it below or add one }

satoshikasumi November 24, 2012 at 5:33 pm

Thank you thank you thank you for posting this, Cort! This is an example of a frequent phenomenon in ME/CFS research called “ignoring the evidence”. Promising lines of research simply get dropped with, no follow up or attempts to falsify the hypothesis. XMRV was a rare counterexample where there was thorough scientific investigation of a hypothesis in this disease.

Large portions of the research community continue to purport that there is no biomarker and they talk as if the syndrome can only be defined by subjective complaints. This disease is held up to an incredibly high standard– no other disease of similar complexity has a single biomarker with 100% specificity and sensitivity.

The fact is, the biomarkers we already have discovered are looking pretty good. They just aren’t talked about.

Reply

Leave a Comment