The "Just Ask!" column in 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 healthcare providers.

From Fall 2009 Forum

Q: I am confused. Can you clarify the relationship of CFIDS/ME to leukemia?

A: NCF (National CFIDS Foundation) research has provided us with a peek at the progression of CFIDS/ME. The easiest way to look at this is via the following drawing of the disease progression:

CFIDS/ME => Acquired Primary Immunodeficiency => Myelodysplasia => Leukemia

What we have observed is that some CFIDS/ME patients first develop an acquired primary immunodeficiency. Primary immunodeficiencies [1] seen in these patients include such things as common variable immunodeficiency, sometimes referred to as CVID; hypogammaglobulinemia and/or selective IgG subclass deficiencies; severe combined immunodeficiency (SCID) and/or adenosine deaminase deficiency; acquired angioedema; and C1-esterase inhibitor deficiency. As some CFIDS/ME patients progress from this point, they go on to develop myelodysplasia. Myelodysplasia, also known as "pre-leukemia," is a diverse collection of hematological conditions united by ineffective production or dysplasia of myeloid blood cells [2].

Myelodysplasia is a bone marrow stem cell disorder resulting in disorderly and ineffective hematopoiesis (blood production) manifested by irreversible quantitative and qualitative defects in hematopoietic (blood-forming) cells. Some of these CFIDS/ME patients have gone on to develop leukemias, typically acute myelogenous leukemia (AML) although we have seen other leukemias and lymphomas as well. The NCF utilized advanced flow cytometry and bone marrow cytology to form its opinion with the assistance of researchers in the field. I can tell you that the NCF has seen more primary immunodeficiencies than myelodysplasia and likewise, we have seen more cases of myelodysplasia than leukemia in patients. The important thing to remember is that CFIDS/ME is a disease process and we would expect a full spectrum of disease in this condition dependent upon its duration. This simple diagram represents this disease process from all our data to date. This is why the NCF chose to hand select several researchers in the leukemia and stem cell field, hopefully to assist us in answering key questions that we had put before them. We expect this research to fit with the current work that we have expedited regarding the ciguatera epitope and cyanobacterial toxins.

References:
1. Primary Immunodeficiency Association website at www.pia.org.uk
2. Wikipedia at http://en.wikipedia.org/wiki/Myelodysplastic_syndrome

Q: I see that the NCF will be doing research related to mitochondrial dysfunction. Could you please comment further?

A: Let me go back to an early discovery in CFIDS/ME. If you would like, you can find this on the NCF's website. Around 1991, Dr. Elaine DeFreitas and Dr. Brendan Hilliard, both from the Wistar Institute, made their discovery of a "CFIDS-associated virus" or CAV [1]. One of the key characteristics of this virus was that the virions were found in the mitochondria. In simple terms, the mitochondria were directly infected! This was very important because in super-sleuthing terminology, this was the scene of the crime! A novel virus that could infect the mitochondria would represent a totally new concept in infectious disease. Around this same time period, there was a paper by Behan, at the University of Glasgow in Scotland, that details the abnormal mitochondria found in CFIDS/ME [2]. Futher confirmation of mitochondrial abnormalites have been identified by Dr. Brad Chazotte at Campbell University [4]. In addition, Dr. Yoshitsugi Hokama recently published a paper on anticardiolipin antibodies in CFIDS/ME [4]. This relates to potential alterations of the mitochondrial inner membrane thus affecting mitochondial function and metabolism. These alterations are tied to Hokama's earlier work on ciguatera and CFIDS/ME. All of Hokama's work is of critical importance due to the fact that changes in mitochondrial cardiolipin are associated with mitochondrial encephalomyopathies [5].

Our newest grant is aimed at delineating the "cause-and-effect" scientific details that are applicable to CFIDS/ME regarding the ciguatera-epitope and its potential relationship to cyanobacteria, the production of BMAA and their direct effects on the mitochondria. The NCF strongly believes that the latest data points to the potential involvement of a toxic photosynthesizing bacteria in the pathogenesis of this disease. As such, this research should greatly help us to answer this important scientific question!

References:
1."Method and compositions for diagnosing and treating chronic fatigue immunodysfunction syndrome"; World Patent #WO/1992/005760; issued 4/16/92; DeFreitas E, Hilliard B -inventors; Wistar Institute
2. "Mitochondrial abnormalities in the postviral fatigue syndrome"; Behan WM, More IA, Behan PO; Acta Neuropathol. 1991;83(1):61-5
3. "Mitochondrial dysfunction in chronic fatigue syndrome"; Chazotte B; Mitochondria in Pathogenesis. Lemasters, J.J. and Nieminen, A.L., eds.) Plenum Press, N.Y. pp 393-410, 2001
4. "Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome"; Hokama Y, Campora CE, Hara C, Kuribayashi T, Le Huynh D, Yabusaki K; J Clin Lab Anal. 2009;23(4):210-2
5. "Mitochondrial encephalomyopathies: an update"; DiMauro S, Hirano M; Neuromuscul Disord. 2005 Apr;15(4):276-86

Q: Help me to understand the role of Parainfluenza Virus-5 (PIV-5) in the pathogenesis of CFIDS/ME?

A: The NCF's work with researchers at Northwestern University on the role of PIV-5 in CFIDS/ME has helped us to answer numerous questions. This work was completed with the kind assistance of Dr. Robert Lamb, Dr. Curt Horvath and Dr. Thomas Kraus. PIV-5 was considered to be involved with CFIDS/ME due to the fact that PIV-5 directly targets the Stat1 protein in lymphocytes and by the fact that PIV-5 had previously been found in patents with CFIDS/ME by Dr. Steven Robbins. By knocking out the Stat1 protein, interferon cannot translocate to the cell's nucleus and as a consequence, the cell is unable to effectively battle viral or bacterial infections. Therefore, Stat1 plays a critical role in this disease. This was echoed by Drs. deMeirleir and Suhadolnik. What we have learned is that there appears to be a functional hole created by Stat1 deficiency and this appears to be exploited by PIV-5. After numerous conversations with the Northwestern researchers, the NCF identified a critical link between oncogenic Ras and Stat1.

In other words, one has a direct impact on the other. More recently, the NCF has further identified an important role for Stat1 directly in mitochondrial function and metabolism. Because of these scientific inquiries and the research work involved, the NCF feels that PIV-5 infection exploits the cell in a somewhat similar fashion to that of Ras (molecular mimicry). Currently, the NCF feels that Ras activity is the primary reason as to why Stat1 has been found to be altered in CFIDS/ME patients. Furthermore, we feel that this Ras activity is directly related to the toxic component associated with the ciguatera epitope. As you can imagine, this is extremely difficult work that continues to evolve and fortunately for the patient community, it has been examined by some of the best minds in science today!