Journal of IiME Volume 6 Issue 1 (June 2012) central nervous system (and) blood-brain barrier permeability and CNS inflammation is thought to be a key aspect in the pathogenesis of (ME)CFS” (Metzger K et al. Biochem Biophys Res Commun 2008:376(1):231-233). 2008 “Myalgic encephalomyelitis/chronic fatigue syndrome is a heterogeneous disease….The central problem in the management of patients with ME/CFS is the lack of biomarkers for patient stratification into subgroups according to distinct immune responses, virus infections and neurological abnormalities….Our data shows for the first time in ME/CFS a cytokine and chemokine profile, which suggests a Th17 shift in subgroups of our cohort. We conclude that cytokine and chemokine patterns in subgroups of ME/CFS can be used diagnostically, as serum biomarkers to stratify patients for appropriate anti-inflammatory, anti-microbial and anti-viral therapeutics” (Serum cytokine and chemokine profiles of individuals with myalgic encephalomyelitis (ME) reveal distinct pathogen associated signatures. Vincent C Lombardi, Kenny DeMeirleir, Judy A Mikovits et al. Cytokine 43 (2008):243-262: doi:10.1016/j.cyto2008.07.077). 2008 At the 6th International Conference on HHV-6 & 7 held in June 2008 at Baltimore, Maryland, Day 4 (23rd June 2008) included a presentation by Professor Nancy Klimas, then at the University of Miami, whose presentation was entitled “Immune markers in viral reactivation”. She is reported as having said: “Remember the immune, the autonomic and the neuroendocrine (systems) are over-lapping….the pathognomonic thing in (ME)CFS is this over-activated immune system…the immune system is antigen-driven. Look for the antigen when you have an activated system….There are only so many things that can activate and drive a system: a pathogen, or more than one pathogen; an allergen; sympathetic nervous system activation of the immune system…and autoimmunity, so – how many different ways might you turn on the button and leave it pushed on – well, maybe five different ways….And that’s what the clues are we have here….anything that overdrives a system can turn Invest in ME (Charity Nr. 1114035) on the pro-inflammatory cytokine cascade..(that) is turned on in the sickest group of (ME)CFS patients. Apoptosis is when a cell has been on so long it’s been driven into cell death. If you push the button on (for) so long and don’t release it, the cell will apoptose, and that’s been shown in many different cell lines, including T cells and neutrophils. Functional defects that we (and others) have shown (include) natural killer cell dysfunction; cytotoxic T-cell abnormalities; (abnormally low cell content of) perforin and granzyme, and macrophage antibody production abnormalities (very important in sustaining longterm inflammatory responses). We’ve shown NK cell function to be different in (ME)CFS, and significantly different – we think this is a useful biomarker. It’s certainly one that circles an important group in (ME)CFS….If you split the chronic fatigue patients into fairly normal NK-cell function versus abnormal NK-cell function, you find that the SF-36 (fatigue scale) is significantly different between these two groups, so again immune dysfunction is correlating with the severity of illness in this patient population. A different objective marker of severity is the PASAT (cognitive assessment tool) – how well your higher levels of thinking are working, and again (there is) a low NK and a normal NK split, and the more severely impaired NK-cell function people have more impaired cognitive function”. Looking at lymphocyte activation and at the percentage of CD2+CD26+ lymphocytes, Professor Klimas said: “This is probably the only study I know of in (ME)CFS that looked for surrogate cytotoxic T-cell function and..it’s not there….we see a significant difference across the board on the amount of CD26 expression on these cells. Now this is an important thing to see. There are more cells expressing this, there’s more activation, but on a per cell basis, the ability of these cells to actually put that marker where it is on the receptor – which is a very important functional marker – is quite a bit lower than the controls. So there’s more activation, but the functional ability of the cell to express that marker…is diminished, and it’s a very significant thing…we think this is a very good biomarker for circling the group that is (ME)CFS…..Neuropeptide Y is a very active substance that has many functions across brain and immune system, so we looked at this, thinking maybe this might be a biomarker (and) sure enough we find neuropeptide Y is elevated as compared to controls in a very significant www.investinme.org Page 83 of 108

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