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By Medical Research Committee, National CFIDS Foundation, Inc. © 2008
No parts of document may be reproduced without the written consent from the Foundation.

Dr. Byron Hyde, founder of the Nightingale Research Foundation in Canada, had previously stated that "ME (Myalgic Encephalomyelitis) has the attributes of a disease process, whereas CFS (Chronic Fatigue Syndrome) is clearly a syndrome

[1]." This statement is clearly in-line with the latest research from the National CFIDS Foundation (NCF). Furthermore, Dr. Hyde is one of the first CFIDS/ME physicians worldwide to embrace the neoplastic/malignancy component of this disease as is evidenced by his work on thyroid cancer in patients. For us to explain to you some of the latest research, allow us first to highlight a significant CFIDS/ME medical breakthrough from years ago that had dramatically led to increasing the NCF's on-going knowledge about this disease. This initial information proved to ultimately provide a "compass setting" to guide the NCF to establish its own critical research agenda in the CFIDS/ME scientific community at large. No other patient, physician or medical research group, either here in the U.S. or elsewhere worldwide, has ever followed up on this important initial medical discovery. In this article, new scientific links to a neoplastic disease process now begin to emerge. A key scientific break came from W. John Martin, MD, PhD, in 1991, regarding what he referred to as the "Stealth Virus" that he was finding in patients with this disease. Dr. Martin, who is currently listed as a Professor at the Keck School of Medicine at the University of Southern California, coined this phrase after isolation of a novel virus in patients. For those who are interested or need a refresher, there is an excellent description in the book Osler's Web

[2]. According to Hillary Johnson's book in 1991, "In a late-night conversation with Marc Iverson (then Chairman of the Board of the CFIDS Association of America), the scientist expressed his view that the novel agent he was studying was responsible for a panoply of illness in the population, much of it being written off as idiopathic, or atypical, in the case of the acute, devastating encephalopathies cropping up at L.A. County Hospital and elsewhere, or psychiatric, in the cases of CFS. "The public health ramifications of this are horrendous," Martin told Iverson. "CFS is the tip of the iceberg. There are all kinds of misdiagnoses going on...." Fortunately for the NCF, Dr. Martin had filed for a World Patent to protect his intellectual property rights regarding his stealth virus

[3]. Martin's patent was filed in 1991. Though Martin has several patents, this is his only patent that discusses the role of ciguatoxin reactivity in CFIDS/ME patients. On page 93 of his patent, Martin described the "Detection of a product in stealth virus infected cultures using an immunoassay for ciguatera toxin." Here Martin outlined his contact with Dr. Douglas Park, who currently is the Director of the Division of Natural Products at the Center for Food Safety and Applied Nutrition at the FDA. Dr. Park also has a patent that outlines ciguatoxin reactivity in patients with CFIDS/ME

[4]. Park assisted Martin by testing for ciguatoxin reactivity in patient samples obtained by Martin himself. A decade later, in 2002, the NCF found Martin's patent in the world patent database. Within days of this discovery, the NCF had contacted world reknown ciguatoxin expert Dr. Yoshitsugi Hokama at the pathology department at the University of Hawaii. All the information was shared and Hokama began working with his colleagues on the ciguatoxin reactivity in CFIDS/ME patient blood. This led to the NCF's first ever official newswire announcement regarding the initial scientific findings which were discussed publicly at a conference in Okinawa Japan in late 2002

[5]. Hokama, along with fellow pathologists, had initially examined 26 CFIDS/ME blood samples along with 33 controls and found higher levels of ciguatoxin reactivity relative to controls. Ironically, to this very day Dr. Martin has never mentioned ciguatoxin reactivity in patient blood samples! In 2003, another study was published that had greatly expanded both the numbers of patients tested as well as to broaden the scope of the study by testing additional patients with other well defined illnesses

[6]. Determined to discover what the ciguatera epitope was, the NCF funded additional research at the University of Hawaii that yielded another publication in 2008

[7]. After extensive testing and spectroscopy studies had been completed, it was determined that the ciguatera epitope, that was reacting with Hokama's ciguatoxin monoclonal antibody, was a lipid that included cardiolipin and other phospholipids along with specific anticardiolipin antibodies. The newest research from the University of Hawaii indicates that these anticardiolipin antibodies have a 95% specificity for the IgM isotype. In addition to other test results, we were now detecting high levels of IgM anticardiolipin antibodies in CFIDS/ME patient blood. B-cell lymphocytes express the cell marker CD5

[8]. This is important because CD5 B-cells produce autoantibodies that play a key role in antigen presentation, tolerance induction and immunity. Specific CD5+ B-cells, referred to as B1a cells, have been found to be directly associated with the production of IgM anticardiolipin antibodies

[9]. Furthermore, research completed by Italian scientists over a decade ago on 265 CFS patients found an increase and expansion in CD5+ B-cells in these patients

[10]. This expansion of CD5+ B-cells was connected to a reduction and therefore decreased levels of CD4+CD45RA+ T-cells (naive T-cells). Not only is an expansion of CD5+ B-cells associated with CLL or chronic lymphocytic leukemia but a reduction in CD4+CD45RA+ T-cells has been associated with CLL as well thus suggesting a potential role for naive T-cells in the immunoregulatory control of B-cell responses

[11,12,13]. Since high levels of IgM anticardiolipin antibodies have now been identified in CFIDS/ME patients, the NCF has been able to find an interesting scientific paper that correlates high levels of IgM anticardiolipin antibodies with chronic lymphocytic leukemia (CLL)

[14]. In this paper, the authors point out that CLL is a clonal B-cell malignancy expressing the CD5 antigen and that these leukemic cells were found to secrete a pathogenic IgM anticardiolipin antibody that was associated with clinical symptoms. The NCF firmly believes that this discovery moves us closer to a neoplastic disease process in CFIDS/ME.

[ Editor's notes: * Cardiolipin is a phospholipid that is uniquely localized in the inner mitochondrial membrane and that is of vital importance for the function of the mitochondrial respiratory chain. Mitochondria are sometimes described as "cellular power plants" because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy. Phospholipids are lipids (fat soluble molecules) that contain a phosphate group. Phospholipids are a major component of all biological membranes. Anticardiolipin antibodies are antibodies that are directed against cardiolipin. * Dr. Byron Hyde's paper on thyroid cancer in patients, Dr. W. John Martin's World Patent, Dr. Umberto Tirelli's paper on immunological abnormalities in CFS and the scientific paper on CLL production of IgM anticardiolipin antibodies will all be available on the NCF's website.]

1. Thyroid Malignancy Association with Cortical & Subcortical Brain SPECT Changes In Patients Presenting with a Myalgic Encephalomyelitis / Chronic Fatigue Syndrome; Hyde B, Leveille J, Baudrey S, Green T; Alasbimn Journal 10 (38):Oct 2007

2. Osler's Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic; Johnson H; Chapter titled: 1991: Black Diamonds - A Conspiracy of Dunces, pgs 466-469. Crown Publishers, 1996

3. Stealth Virus Detection in the Chronic Fatigue Syndrome; World Patent # WO9220787; issued November 26, 1992; filed May 22, 1992; continuation in patent filed September 20, 1991; Inventor: William John Martin; Applicant: William John Martin

4. Rapid Extraction of Ciguatoxin from Contaminated Tissues; World Patent # WO9322672; issued November 11, 1993; filed May 1, 1992; Inventors: Douglas L Park, Pedro M Gamboa; Applicant: Hawaii Chemtect Inc.

5. "Acute Phase Lipids" in Sera of Various Diseases: Chronic Fatigue Syndrome, Ciguatera, Hepatitis, and Various Cancer with Antigenic Epitope Resembling Ciguatoxin as Determined with MAB-CTX; Hokama Y, Shirai BK, Whang C, Chun KF, Higa N, Suma C, Uto GA, Enlander D, Cocchetto A; International Symposium on Toxins and Natural Products; Okinawa, Japan; November 17-19, 2002

6. Chronic Phase Lipids in Sera of Chronic Fatigue Syndrome (CFS), Chronic Ciguatera Fish Poisoning (CCFP), Hepatitis B, and Cancer with Antigenic Epitope Resembling Ciguatoxin, as Assessed with MAb-CTX; Hokama Y, Uto GA, Palafox NA, Enlander D, Jordan E, Cocchetto A; J Clin Lab Anal. 2003;17(4):132-9

7. Acute Phase Phospholipids Related to the Cardiolipin of Mitochondria in the Sera of Patients with Chronic Fatigue Syndrome (CFS), Chronic Ciguatera Fish Poisoning (CCFP), and Other Diseases Attributed to Chemicals, Gulf War, and Marine Toxins; Hokama Y, Empey-Campora C, Hara C, Higa N, Siu N, Lau R, Kuribayashi T, Yabusaki K; J Clin Lab Anal. 2008;22(2):99-105.

8. CD5 Expression by B Lymphocytes and its Regulation upon Epstein-Barr Virus Transformation; Kaplan D, Smith D, Meyerson H, Pecora N, Lewandowska K; Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13850-3.

9. Changes in Peripheral Blood CD5 (Bla) B-Cell Populations and Autoantibodies Following Blood Transfusion; Paglieroni TG, Ward J, Holland PV; Transfusion. 1995 Mar;35(3):189-98.

10. Immunological Abnormalities in Patients with Chronic Fatigue Syndrome; Tirelli U, Marotta G, Improta S, Pinto A; Scand J Immunol. 1994 Dec;40(6):601-8.

11. T-Cell Activation and Subset Pattern are Altered in B-CLL and Correlate with the Stage of the Disease; Totterman TH, Carlsson M, Simonsson B, Bengtsson M, Nilsson K; Blood 1989; 74:786792.

12. Decreased CD45RA T-Cells in B-Cell Chronic Lymphatic Leukemia Patients:Correlation with Disease Stage; Peller S, Kaufman S; Blood 1991;78:15691573.

13. Expression of CD4+/CD45RA+ (naive) and CD4+/CD45RO+ (memory) T-Cell Subsets is Different in B-Cell Chronic Lymphocytic Leukemia (B-CLL) and Hairy Cell Leukemia (HCL); Raspadori D, Marotta G, Ventura MA, Birtolo S, Bucalossi A, Forconi F, Galieni P, Lauria F, Tura S; Haematologica 1996;81(suppl 5):208.

14. Characterization of a Human Monoclonal Autoantibody Directed to Cardiolipin/Beta 2 Glycoprotein I Produced by Chronic Lymphocytic Leukaemia B Cells; Mariette X, Levy Y, Dubreuil ML, Intrator L, Danon F, Brouet JC; Clin Exp Immunol. 1993 Nov;94(2):385-90.

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