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Just Ask!

An NCF Column for Inquiring Patients

By Prof. Alan Cocchetto

The "Just Ask!" column is intended to act as a means for patients to inquire about issues related to the NCF's research activities.  This column is NOT intended to act as medical advice in any way, shape or form!  The National CFIDS Foundation assumes no responsibilities for any action or treatment undertaken by readers.  For medical advice, please consult with your own personal providers.
Q: Dear NCF, I have had my RNaseL tested by a lab and it was found to be highly activated. The NCF has proposed that parainfluenza virus-5 (PIV-5) is the primary infection responsible for CFS/ME. Can you explain the relationship between PIV-5 infection and the RNaseL lab results? (Internet question)
A: Yes. The NCF does believe that the primary causative factor of CFIDS is PIV-5 and this is because of the research observations which have been previously mentioned in other Forums. In taxonomy terms (the characterization of a virus), PIV-5 is characterized by its negative-strand ssRNA (single-stranded RNA)  genome. To understand the relationship to RNaseL, let me provide you with the following comments.  The cellular responses induced by interferon (IFN) constitute an organism's primary defense against viral infection. Thus, upon infection, IFN gene expression is induced, IFN-encoding RNA transcripts are translated and IFN proteins are rapidly secreted from the cell. These IFN's may then exert a variety of effects on surrounding cells, the goal of which is to protect those cells from secondary viral infection. A number of different IFN molecules may be produced depending on the type of cell infected. For example, the type-I IFN's (IFN-alpha and IFN-beta) are released from infected leukocytes and fibroblasts respectively.    Type-I IFN's interact with specific receptors on the cell surface, activating a signaling cascade pathway that leads to the transcriptional induction of at least 30 genes [1]. Two of these IFN-induced genes encode the enzymes 2'-5'-oligoadenylate synthase (OAS) and protein kinase R (PKR). Both of these enzymes are activated by the binding of dsRNA (double-stranded RNA) molecules including those present in the cell cytoplasm following the infection of the cell by certain viruses. The activation of OAS by dsRNA increases the synthesis of 2'-5' oligoadenylates, which in turn activate RNaseL. Phew!

What should be noted here is that activated RNaseL nonspecifically degrades single-stranded RNA's and thus limits the replication of viruses with single-stranded RNA genomes or for which single-stranded RNA molecules are formed as intermediates during replication of the virus genome [2]. In fact, Dr. Kenny DeMeirleir commented in his book [3] that "The system of ssRNA cleavage by activated RNaseL has been claimed to be specific for the RNA of viral origin"which reinforces the primary function of RNaseL - to degrade ssRNA's to limit viral replication.  This basic understanding of what RNaseL does is important because it acts to degrade single-stranded RNA's of which PIV-5 itself has a single-stranded RNA genome. Thus RNaseL is attempting to shut-off the viability of PIV-5 by degrading its RNA genome, thus limiting its replication. It does this in conjunction with the action of OAS.

[1] Interferon-induced antiviral actions and their
regulation; Sen GC, Ransohoff RM; Adv Virus Res.

[2] The 2-5A system: modulation of viral and cellular
processes through acceleration of RNA degradation;
Player MR, Torrence PF; Pharmacol Ther. 1998

[3] Chronic Fatigue Syndrome: A Biological Approach;
Englebienne P, DeMeirleir K; CRC Press, 2002


Q: My doctor told me that the reason why I get terrible fungal infections is because my immune system has gone awry. Is there anything you can recommend to combat these horrible fungal infections as they are driving me crazy? (Phone question)
A: Pfizer Pharmaceuticals has a newer generation fungal drug called Vfend (Voriconazole) that helps to fight life threatening fungal infections. According to the Pfizer website, "Usually, only people who have a weak immune system get these infections. This includes patients with cancer or patients who have received an organ or bone marrow transplant." Voriconazole has been found to be effective against a variety of fungal species. As such, I highly recommend that you talk to your physician about this since fungal infections create a great deal of misery to patients.

Q: What, if any, blood tests does the NCF currently recommend for patients? (Internet/phone)
A: The NCF really recommends the following blood tests for patients:

1. Immune/Lymphocyte profile via flow cytometry - Absolute and percentage for each of the following cell markers:
CD3 - Total Lymphocytes
CD4 - Helper T-cells
CD8 - Cytotoxic/Suppressor T-cells
CD19 - Mature B-cells
CD4/CD8 Ratio Lymphocyte profiles are used by immunologists to get a captured view for the current state of the patient's immune system. Alterations to the cellular arm of the immune system can be readily recognized by the CD3, CD4, CD8 and CD4/CD8 ratios while the humoral arm is represented by the CD19 marker. These are basic immune profile tests. Lymphopenias (the loss of lymphocytes) have been seen in CFIDS patients for each of these different cell types and are representative of the immune dysfunction characteristic of this disease.

2. Kappa/Lambda Light Chains (Monoclonality and aberrant clonal excess evaluation)

3. Soluble IL-2R (Cellular activation is directly proportional to Karnofsky or disability score)

4. Ciguatera Epitope (As discussed in previous Forums)
The NCF encourages every patient to thoroughly discuss these important blood tests with their physicians. Be as proactive about your health as you can be! 

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