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IMMUNE ABNORMALITIES IN PATIENTS WITH CFIDS/ ME POINT DIRECTLY TO LEUKEMIC CELLS By Alan Cocchetto, Medical Director, National CFIDS Foundation © 2014 From Fall 2014 Forum In 2012, the National CFIDS Foundation (NCF) had penned an article that outlined the latest Natural Killer (NK) cell findings that were identified in patients with CFIDS/ME [1]. The Australian scientists had found a rather unique NK cell biomarker, known formally as CD56bright cells, to be abnormal in its patient cohort [2,3]. Both Dr. Daniel Peterson as well as Dr. Nancy Klimas participated with this medical group who sponsored this particular study. Long story short, the NCF had found a medical journal article that directly connected abnormalities in CD56bright cells to ionizing radiation exposure [4]. It appears that CD56bright cells can serve as a biodosimetry radiation exposure measurement tool according to this article. So does the NCF believe that these patients received internal radiation exposure? It seems highly likely that they did. These same Australian scientists have recently further identified additional cell markers that were also found to be abnormal in patients [5]. Interestingly, these patients fulfilled not only the 1994 Centers for Disease Control diagnostic criteria for the Chronic Fatigue Syndrome but also fulfilled the latest diagnostic criteria known as the International Consensus Criteria (ICC). Since these additional markers, identified in the journal article as killer immunoglobulin receptors (KIR) on patient NK cells, have a profound association with leukemia, the NCF wanted to alert the patient community to this important medical connection. The NCF has repeatedly pointed out the CFIDS/ME connection to leukemia/lymphoma development previously in numerous articles written for The National Forum patient newsletter. The one thing that is certain is that the impairment of NK cell activity has consistently been observed in patients. According to the logical conclusion from the authors of this current paper, “This suggests an inability of the NK cells in CFS/ ME patients to clear viral and other microbial infections and also a prevalence of recurring viral infections [5].” However, the NCF Medical Committee would remind these authors of the following: Stat1, a critical immunological protein, has been found to be abnormally non-existent in many patients with this disease. This was first discovered by Dr. Kenny DeMeirleir, from Belgium, then verified by a grant from the NCF to Dr. Konstance Knox and Dr. Donald Carrigan, from the Institute for Viral Pathogenesis, who reported this finding at an AACFS (now the IACFS) medical conference. Furthermore, the NCF had contacted Dr. Robert Suhadolnik, from Temple University, who utilized gene array technology to verify the lack of Stat1 protein in his patient samples he had received from the National Institutes for Health (NIH). Thus, without the Stat1 protein, interferon can’t translocate to the nucleus of the cell to fight infection. As a result, this subjects the host to innumerable bacterial and viral infections. There is a great deal of information in the medical literature regarding Stat1 depletion and the critical role it plays in infection. Stat1 protein activation, on the other hand, is associated with leukemic cell generation. In addition, the Stat1 protein had previously been identified as a direct target of ionizing radiation. The NCF believes that the Australian scientists should consider these additional facts since the lack of Stat1 may inherently be of greater importance than NK cell activity when considering overall infection potential Moving on, what about these latest NK cell KIR markers? In addition to abnormal NK cell activity, these scientists had identified two KIR markers that were found to be abnormal as well. These are known as KIR2DS4pos and KIR3DL1neg. Both of these markers were found to be highly statistically significant (p<0.001) according to the paper. In the medical literature, accumulating evidence suggests that natural killer cell immunoglobulin-like receptors (KIRs) contribute to the pathogenesis of diverse diseases such as leukemia [6]. It has been found that since the rate of activating KIR2DS4 was found to be much higher in patients with chronic myeloid leukemia (CML) than in healthy controls, the activating KIR2DS4 may serve as a CML susceptive gene to trigger leukemia development [6]. Other medical journal papers also suggest a strong association of KIR2DS4 with leukemia as well [7-9]. One of the best papers that I was able to find was “Identification of natural killer cell receptor phenotypes associated with leukemia [9].” The capacity of NK cells to kill tumor cells spontaneously and their potent antileukemic cytotoxic activity in-vitro suggest important functions for this cell type in the in-vivo antileukemia immune response. The functional activity of NK cells is regulated by distinct cell surface receptors integrating a balance between positive and negative signals that either trigger or block NK cell cytotoxicity. In this paper [9], the authors state that “… an important percentage of leukemia patients express a KIR phenotype in favor of escape from NK cell immunity.” The following KIR phenotypes are found in Table #1 from this paper. The two phenotypes are shown so as to highlight the importance of the findings for KIR2DS4 and KIR3DL1 abnormalities identified in CFIDS/ME patient samples: KIR Phenotype Phenotype frequency (%) in Leukemic Malignancies
Notes:
As you can see, this data identified a robust association between the KIR phenotypes found in CFIDS/ME patients (KIR2DS4 and KIR3DL1) and the frequencies of these phenotypes in various leukemias. This is of utmost importance because of the end-point implications in the CFIDS/ME disease process. Thus, if the NK cells in CFIDS/ME patients are unable to destroy leukemic cells, this may allow malignant cells to escape from the innate immune control. This may be why the NCF and other researchers have seen leukemias and lymphomas in patients. Looking back to 2008, Dr. Suzanne Vernon, the CFIDS Association’s Scientific Director, published a CFIDS/ME study with her colleagues [10]. These authors stated, “In this work we observe an increased expression of the NK cell gene set. Of the 4 genes used to capture NK cell function the expression of NKG2A/C was most increased.”Noting this finding from Vernon and her colleagues, the NCF revisited the paper associated with KIR phenotypes and leukemic malignancies [9]. From Table #1 KIR Phenotype Phenotype frequency (%) in Leukemic Malignancies
As you can see, the NKG2A/C phenotypes are highly associated with leukemic malignancies. These data further reinforce the above findings from the Australian group. In summation, this information greatly adds to the strength of the NCF’s previous arguments that leukemic cells generated from changes to the bone marrow, most likely at the stem cell level, are at the heart of the CFIDS/ME disease process itself which leads to the development of primary leukemias/ lymphomas and/or secondary tumor formation. Ionizing radiation greatly impacts the bone marrow and stem cell compartment and is known to directly cause leukemia. In 2010, the National CFIDS Foundation formally announced the link between internal radiation exposure and the development of CFIDS/ME [11]. Since then, the NCF has continued to pursue unequivocal scientific proof via radionuclide testing, identification of chromosomal abnormalities, pursuing chromosome biology and analysis, etc. As the NCF moves forward, our efforts are aimed towards finding an appropriate therapeutic solution to this menacing disease process. We are poised to achieve this via our continued commitment to fund appropriate research that directly connects these disease mechanisms to formally establish a disease model. Disease knowledge coupled with scientific understanding has led us towards the sincere commitment to pioneer an appropriate drug therapy. Additional grant announcements are around the corner. To date, the NCF has provided over $2 million dollars in selfdirected research grants to global scientists who share in our vision to beat this devastating disease. References
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