25. august 2003 EDITORIAL Journal of Chronic Fatigue Syndrome, Vol. 11(2) 2003, 1-5 This issue of the journal has a group of articles on the 2',5'-oligoadenylate-dependent ribonuclease L system in ME/CFS and a review of the pathways and its activities as well as the prevalence of potentially important pathogens in the morbidity of ME/CFS. A pilot study is also presented which assesses the use of Isoprinosine® in a single blinded placebo controlled study on immune cell and cytokines levels. 2',5' -OLIGOADENYLATE-DEPENDENT RIBONUCLEASE L (RNASE-L) SYSTEM In 1993 and subsequently in 1994 Suhadolnik et al. (1-3) published three ground breaking papers on anomalies in the interferon based 2',5'-oligoadenylate-dependent ribonuclease L (RNase-L) system in patients with ME/CFS. Since then many papers have been published on these changes in ME/CFS patients (4-9) including evidence that the pathway can be upregulated by various chemical agents (10). The pathway is not upregulated in the manner seen in an acute viral infection (11-16) or with interferon associated carcinomas (17) but deregulated. Dr. P. Englebienne presents a review of the activity of the 2',5'- oligoadenylate-dependent ribonuclease L (RNase-L) system in health and disease and reviews the cellular defense mechanisms induced by type I interferons during intracellular infection, cell differentiation, immune activation, and as a tumor-suppressor. He also discusses the changes seen in ME/CFS patients and the potential new targets for therapeutic development. MYCOPLASMA SP., CHLAMYDIA SP., HHV-6 IN ME/CFS Mycoplasma species have been suggested to have an increased prevalence in patients with ME/CFS (18-20) as assessed by Polymerase Chain Reaction (PCR) although there is no evidence of an increased prevalence in exposure to Mycoplasma sp. as assessed by serological methods (21). The claims have been made that Mycoplasma sp. such as Mycoplasma fermentans are involved in the development of fatigue. Nicolson et al. have presented evidence in an appropriately powered study that ME/CFS patients were ~14 fold more likely to have evidence of a positive PCR test for Mycoplasma sp. and ~8 fold more likely to be PCR positive for Chlamydia sp. and ~5 fold more likely to be PCR positive for HHV-6. The study by Nijs et al. (Deregulation of the 2,5A synthetase RNase L antiviral pathway by Mycoplasma sp. in subsets of Chronic Fatigue Syndrome) and a previous paper (22) also showed the same prevalence of Mycoplasma sp. although the European and the US Mycoplasma species differed in their subspecies. They also found that this was associated with an alteration in the 2',5'-oligoadenylate-dependent ribonuclease L (RNase-L) system involving the increase in fragmented 37kDa RNase-L. Whilst these papers show some compelling evidence associating pathogens and the altered RNase-L pathway they do not as yet give sufficient evidence of cause and effect. Whilst viral infections in particular are associated with increases in RNase-L, certain bacterial infection have been shown to be associated with increases in RNase-L activity (23-26). Conflicting evidence from other studies have shown the certain bacterial infections are not associated with increased RNase-L activity - one suggesting that a c-reactive protein: 2',5'-oligoadenylate synthetase activity may allow differentiation between bacterial and viral infections (27-29). Obviously further studies are required to evaluate these relationships and their importance in ME/CFS. Nijs et al. (Immunophenotyping predictive of mycoplasma infection in patients with chronic fatigue syndrome) in a preliminary study used a novel decision (classification) tree method to assess the association between immune cell changes and the carriage of Mycoplasma sp. in ME/CFS patients. This preliminary study requires that it be reproduced with much larger numbers and with a large selection of possible pathogens to assess whether this may be a method that could be used to assist in separating the subsets of ME/CFS patients covered by the current definitions (30,31) MYCOPLASMA SP. IN GULF WAR ILLNESS PATIENTS AND THEIR FAMILIES Nicolson et al. present data in an appropriately powered study on the prevalence of Mycoplasma sp. infections detected by PCR in Gulf War Illness (GWI) patients and their families. Consistent with previous results and those of ME/CFS patients listed above there was a high Mycoplasma sp. PCR positive rate. The GWI patients were 9 fold more likely to have a PCR positive response and ~18 fold more likely to have a positive PCR for M. fermentans. Fifty-three percent of the family members of the PCR positive GWI patients were also PCR positive suggesting a transmission of the Mycoplasma sp. within the family environment. These PCR positive family members were predominately diagnosed to have ME/CFS or fibromyalgia. How the veterans contracted the Mycoplasma sp. infections is not known and will require further studies to evaluate the possibilities. THE JOURNAL The Journal of Chronic Fatigue Syndrome is the only specialist journal for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and unfortunately is not currently listed on the medical search engines such as Medline or similar. That fact that it is not listed results in a restriction of the availability of important papers in this journal to the standardized searches but also results in researchers not wishing to publish in the journal. A simple search on PubMed® from 1st January 2002 to 30th June 2002 (see in this issue) shows that there were 68 papers published on CFS or highly related matters and clearly shows that the journal has not attracted the important papers on ME/CFS. To address these issues the editors have introduced an improved system of manuscript evaluation and review and new standards for the manuscripts. We hope that these improvements will attract the manuscripts that will allow us to obtain listing. P.S. For those who use Reference Manager™ we have developed a style template which can be obtained by contacting us at . Kenny De Meirleir Neil McGregor Editors REFERENCES I. Suhadolnik RJ, Reichenbach NL, Hitzges P et al. Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin 11lject Dis 1994; 18 Suppl I :S96-1 04. 2. Suhadolnik RJ, Reichenbach NL, Hitzges Pet al. Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C 12U) in chronic fatigue syndrome. In Vivo 1994; 8:599-604. 3. Suhadolnik RJ, Reichenbach NL, Hitzges PM et al. RNA drug therapy acting via the 2-5A synthetase/RNase L pathway. Ann N Y Acad Sci 1993; 685:756-757. 4. Demettre E, Bastide L, D'Haese A et al. Ribonuclease L proteolysis in peripheral blood mononuclear cells of chronic fatigue syndrome patients. J Bioi Chern 2002; 277:35746-35751. 5. Suhadolnik RJ, Peterson DL, O'Brien K et al. Biochemical evidence for a novel low molecular weight 2-5A-dependent RNase'L in chronic fatigue syndrome. J Interferon Cytokine Res 1997; 17:377-385. 6. Vojdani A, Choppa PC, Lapp CW. Downregulation of RNase L inhibitor corre- lates with upregulation of interferon-induced proteins (2-5A synthetase and RNase L) in patients with chronic fatigue immune dysfunction syndrome. J Clin Lab Immunol 1998; 50:1-16. 7. Vojdani A, Lapp CWo Interferon-induced proteins are elevated in blood sam- ples of patients with chemically or virally induced chronic fatigue syndrome. Immuno-pharmacollmmunotoxicol 1999; 21: 175-202. 8. De Meirleir K, Bisbal C, Campine I et al. A 37 kDa 2-5A binding protein as a potential biochemical marker for chronic fatigue syndrome. Am J Med 2000; 108:99-105. 9. Shetzline SE, Martinand-Mari C, Reichenbach NL et al. Structural and functional features of the 37-kDa 2-5A-dependent RNase L in chronic fatigue syndrome. J Interferon Cytokine Res 2002; 22:443-456. 10. Vojdani A, Lapp CWo Interferon-induced proteins are elevated in blood sam- ples of patients with chemically or virally induced chronic fatigue syndrome.lmmuno-pharmacollmmunotoxicol 1999; 21: 175-202. 11. Gow JW, Simpson K, Behan PO et al. Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection. Clin Infect Dis 2001; 33:2080-2081. 12. Huppertz HI, Becker K, Kreth HW. Clinical value of measuring the interferon-induced enzyme 2'-5'-oligoadenylate synthetase in children. Acta Paediatr 1992; 81 :329-334. 13. Brewster FE, Byron KS, Sullivan JL. Immunoregulation during acute infection with Epstein-Barr virus: dynamics of interferon and 2',5'-oligoadenylate synthetase activity. J Infect Dis 1985; 151:1109-1115. 14. Heathcote J, Kim YI, Yim CK et al. Interferon-associated lymphocyte 2',5'- oligoadenylate synthetase in acute and chronic viral hepatitis. Hepatology 1989; 9:105-109. 15. Okuno T, Shindo M, Arai K et al. Detection of 2',5' oligoadenylate synthetase activity in acute viral hepatitis with special reference to histologic features in tire acute stage. Gastroenterol Jpn 1991; 26:162-169. 16. Schattner A, Wallach D, Merlin G et al. Assay of an interferon-induced enzyme in white blood cells as a diagnostic aid in viral diseases. Lancet 1981; 2:497-500. 17. Vonderheid EC, Suhadolnik RJ, Sobel EL et al. Increased 2',5'-oligoadenylate synthetase activity in blood mononuclear leukocytes from patients with advanced cutaneous T-cell lymphoma. Clin Immunollmmunopathol1984; 31: 138-150. 18. Choppa PC, Vojdani A, Tagle C et al. Multiplex PCR for the detection of Mycoplasma fermentans, M. hominis and M. penetrans in cell cultures and blood samples of patients with chronic fatigue syndrome. Mol Cell Probes 1998; 12:301-308. 19. Nasralla M, Haier J, Nicolson GL. Multiple mycoplasmal infections detected in blood of patients with chronic fatigue syndrome and/or fibromyalgia syndrome. Eur J Clin Microbiol Infect Dis 1999; 18:859-865. 20. Vojdani A, Choppa PC, Tagle C et al. Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with Chronic Fatigue Syndrome. FEMS lmmunol Med Microbiol 1998; 22:355-365. 21. Komaroff AL, Bell DS, Cheney PR, Lo SC. Absence of antibody to Myco-plasma fermentans in patients with chronic fatigue syndrome. Clin Infect Dis 1993; 17:1074-1075. 22. Nijs J, Nicolson GL, De Becker P et al. High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients. FEMS Immunol Med MicrobioI2002; 34:209-214. 23. Buffet-Janvresse C, Magard H, Robert N, Hovanessian AG. Assay and the levels of 2-5A-synthetase in lymphocytes of patients with viral, bacterial and autoimmune diseases. Ann Immunol (Paris) 1983; 134D:247-258. 24. Buffet-Janvresse C, Hovanessian AG. Enzyme markers for the presence of circulating interferon: 2-5A synthetase in blood lymphocytes and protein kinase in platelet-rich plasma. Proc Sac Exp Bioi Med 1984; 175: 169-175. 25. Chousterman S, Chousterman M, Reinert P, Thang MN. Clinical value of the determination of an interferon-induced enzyme activity: studies of the 2'5'-oligoadenylate synthetase activity in peripheral blood lymphocytes of patients. Biomed Pharmacother 1983; 37:176-180. 26. Pereyra BS, Falcoff R, Falcoff E, Lemonnier D. Interferon induction by Lactobacillus bulgaricus and Streptococcus thermophilus in mice. Eur Cytokine Netw 1991; 2:299-303. 27. Sasaki K, Fujita I, Hamasaki Y, Miyazaki S. Differentiating between bacterial and viral infection by measuring both C-reactive protein and 2'-5'-oligoadenylate synthetase as inflammatory markers. J Infect Chemother 2002; 8:76-80. 28. Schattner A, Wallach D, Merlin G et al. Variation of (2'-5') oligo A synthetase level in lymphocytes and granulocytes of patients with viral infections and leukemia. J Interferon Res 1982; 2:355-361. 29. Schattner A, Merlin G, Bregman V et al. (2'-5') Oligo A synthetase in human polymorphonuclear cells increased activity in interferon treatment and in viral infec- tions. Clin Exp Immunol1984; 57:265-270. 30. Holmes GP, Kaplan JE, Gantz NM et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988; 108:387-389. 31. Fukuda K, Straus SE, Hickie I et al. The chronic fatigue syndrome: a compre- hensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994; 121 :953-959. © 2003 by The Haworth Press, Inc. All rights reserved. ________________________________________________ ABOUT THE EDITORS Kenny De Meirleir, MD, PhD, is Professor of Physiology and Medicine at the Vrije Universiteit Brussel, where he is Director of the Human Performance Laboratory (BLITS) and member of the "the Vakgroep" Internal Medicine group. His interest in chronic fatigue syndrome dates back to 1989. Dr. De Meirleir serves on the board of directors of several nonprofit scientific organizations and is a co-editor (With Roberto Patarca-Montero) of Chronic Fatigue Syndrome: Critical Reviews and Clinical Advances. Dr. De Meirleir has co-authored numerous journal articles and book chapters on different subjects. Through lectures and support of patients' groups, his efforts focus upon increasing awareness of CFS in Europe. Neil R. McGregor, BDS, MDSc, PhD, is a member of several professional associations, including the Australian Dental Association, Australian and New Zealand Academy of Periodontists, Royal Australian College of Dental Surgeons and International Association of Dental Researchers, and has a large number of published papers, conference presentations, and conference abstracts on chronic pain, chronic fatigue and chronic neurological diseases to his credit. His efforts are directed to increasing the understanding of the etiology and biochemistry of CFS.