Have we been missing a trick lately? While there are numerous (often conflicting) studies on various immune parameters, cytokines, chemokines etc, one consistent finding is that ME/CFS is characterised by high levels of oxidative stress. One aspect of oxidative stress and the body's response to it that hasn't had much attention is the influence of heat shocks proteins (HSPs). Perhaps they are a little too old school, but they are also a fundamental part of the body's response to 'stressors' of all types (heat, cold, exercise, infection, chemical, psychological stress etc). In fact, heat shock proteins should protect against any physiological stressor associated with day to day living and any dysfunction in the expression of HSPs would leave the body very exposed to ongoing oxidative stress leading to cell death and senescence (a reduction in HSP expression is associated with ageing). I'm not going to wax lyrical here. Just provide a few comments and links for anyone interested. On Heat shock Proteins generally http://en.wikipedia.org/wiki/Heat_shock_protein What should happen is that HSP expression remains at base levels until a potentially damaging stressor causes the rapid, massive and sustained release in order to prevent cellular damage from oxidative stress. HSPs in ME/CFS Three studies have found certain abnormalities in HSP production in ME/CFS patients compared to controls. HSP27 is chronically significantly raised in ME/CFS but, in response to exercise, production of HSPs (HSP27, 60 and 70) declines rapidly rather than remain elevated exposing cells to oxidative stress. Thambirajah et al, 2008 (full paper) : http://www.name-us.org/ResearchPage...idativeArticles/2008ChowHeatShockProteins.pdf Jammes et al, 2009 (full paper) : http://www.co-cure.org/Jammes.pdf Jammes et al, 2011 (abstract only) http://www.ncbi.nlm.nih.gov/pubmed/22112145 Interestingly, in this paper, they find this dysfunction most strongly associated with those reporting a prior viral illness of high intensity exercise. Here's the description of the function of the relevant HSPs from Thambirajah et al : In a nice piece of symmetry, normally HSP production peaks at 48 hours after exercise, at the time that markers of PEM appear to be most pronounced. http://jap.physiology.org/content/101/1/176.full.pdf The consequences of ongoing inadequate protection against oxidative stress are easy to imagine and this lack of protection negates the need to look for pathogens that cross the blood brain barrier. The absence of the protective effects of HSPs against oxidative stress can explain neurodegeneration. Far from being a 'complex' or 'mysterious' disease, a deficient HSP response to stressors suggests a very fundamental systemic pathology with many downstream effects.