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Friday, January 15, 2016

Multiple Causes for Systemic Exertion Intolerance Disease - SEID (formerly Chronic Fatigue Syndrome)

Patients who present with severe, apparently idiopathic fatigue, together with profound levels of physical and or cognitive disability, present a considerable therapeutic challenge. The effects of psychological approaches are limited. In an open label study, counseling achieved a statistically significant but very slight reduction in self-perceived psychometric measures of fatigue and disability, compared with intermittent psychiatrist consultations, but produced no ameliorative effect on objective measures of disability [1]. The same pattern is observed in studies using differing exercise regimes. These approaches can once again produce significant, but very slight, improvements in self-perceived psychometric parameters, but either produce significant, but clinically unimportant improvements in scientific measures of disability [1] or even potential harm [2]. Many such patients are afforded the exclusionary, non-specific, diagnosis of chronic fatigue syndrome (CFS), according to a plethora of different selection criteria [3], if rudimentary testing does not reveal the cause of their symptoms.

Sophisticated tests, however, often reveal profound immunological abnormalities in such patients and evidence of active pathogen activity [4, 5]. A study of 375 patients with apparently idiopathic disabling fatigue revealed pathological stimulation of lymphocytes together with abnormally elevated and distributed pattern of CD4+, CD8+, and CD19+ leucocytes in 53 % of patients and depleted levels of IgG3 in 59 % of the study population. More than half had circulating immune complexes and many tested positive for anti-nuclear antibodies [6]. Moreover, greater than 70 % of patients also displayed objective signs of active pathogen invasion [6]. These results support earlier work by a team led by the same author, with patients once again suffering from apparently idiopathic fatigue of an infectious onset where 50 % of the patients displayed lymphadenopathy and 73 % had objective evidence of persistent Herpes virus activity [7]. These findings are by no means atypical, as we shall discuss; however, not everyone with apparently idiopathic fatigue has evidence of chronic pathogen activity, although many have a documented infectious history to their illness [8]. Moreover, many of the viruses and other pathogens shown to be active in many of these patients are normally latent and or asymptomatic in the general population.

How do we reconcile these observations and explain how some people display evidence of active pathogen activity, while others who are infected with the same pathogens do not, and why do some people develop a phenotype of severe intractable fatigue following an infection while, thankfully, the vast majority of the population do not? Variations in strain or tissue tropism are obvious potential causes, and this will be discussed later. However, the work of numerous researchers investigating the occurrence of polymorphisms in populations of people with apparently idiopathic fatigue may well shed some light on other potential variables. In a cohort of 80 people afforded a diagnosis of CFS, Carlo-Stella and fellow workers reported a pattern of cytokine polymorphisms, which would render the bearer highly susceptible to a prolonged or severe inflammatory response [9]. A similar pattern was seen in a recent study where the authors also noted that the pattern of cytokine polymorphisms in their “CFS” patients differed from those with a diagnosis of major depression [10]. The authors of another recent study examining the effect of cytokine polymorphisms on the severity of fatigue experienced by patients with HIV reported that the severity of fatigue was associated with polymorphisms in tumor necrosis factor (TNF)α, interleukin (IL)-1β, and nuclear factor (NF)-ΚB, providing further evidence of an association between inflammation and fatigue [11].

Quite subtle variation in the base sequences of genes governing the innate immune response can alter an individual’s susceptibility to infection and the consequent development of diseases in quite profound and specific ways [12, 13]. Functional polymorphisms in genes effecting or regulating the immune response are also a major factor in determining the trajectory and prognosis of infectious illnesses and are also predictive of enduring pathology [14]. Moreover, polymorphisms in TNF, IL-1β, interferons (IFNs), IL-6, and IL-10, acting individually or synergistically, can amplify the severity and duration of the immune response to acute pathogen invasion [14]. Helbig et al. reported that patients with polymorphisms in TNFα, IFNγ, and HLA-DRB alone, or in combination, developed long-term fatigue and disability following acute pathogen invasion, whereas patients free of such polymorphisms recovered normally [15, 16]. On a more generic level, the severity of acute illness and the level of pro-inflammatory cytokine production is deterministic of symptom severity and duration [17, 18]. Honsettre et al. [19] determined that patients who experienced abnormally elevated cytokine production during initial infection went on to develop chronic long-term pathology, while the patients with expected levels of cytokine production did not. It is also noteworthy that a prolonged and or severe infection can leave an individual with chronically activated microglia [20]. This effect can also be achieved via sequential lesser infections as the result of the development of microglial priming [21].

The question arises as to how this long-term pathology is achieved and maintained, and why severe or prolonged immune activity and inflammation can sometimes produce serious long-term sequelae, both in terms of immune dysregulation and incapacitating fatigue. Engagement of Toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) leads to the initiation of the innate immune response [22]. Activation of the TLR2/4 complex induces the expression of intracellular signaling networks, such as NF-κB and mitogen-activated protein kinases (MAPK) with subsequent up-regulation of pro-inflammatory cytokines, reactive oxygen (ROS), and reactive nitrogen species (RNS) [22–24]. In genetically susceptible individuals, with the polymorphisms discussed above, an excessive or prolonged inflammatory response can lead to a massive cytokine surge, which in turn can lead to abnormally high production of reactive oxygen and nitrogen species including the very toxic peroxynitrie [20]. Elevated levels of ROS and RNS generated by TLR2/4 activation can attack an array of cellular molecules, including unsaturated membrane fatty acids, generating a range of damaged molecules, including protein carbonyls, 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and nitroso-protein adducts, and oxidized and degraded DNA. These can function as redox-derived damage-associated patterns or DAMPS [25, 26] exacerbating TLR2 and or TLR4 activity, thus provoking even greater synthesis of RNS, ROS, and pro-inflammatory cytokines in a self-sustaining, self-amplifying feed forward loop, called the “TLR-radical cycle” [22].

Degraded mitochondrial DNA is also known to act as a DAMP and activates TLR2 and TLR4 receptors [27, 28]. The TLR-radical cycle, once further activated by redox-derived DAMPs, may rapidly become self-sustaining and self-amplifying and may well underlie the excessive levels of nitro-oxidative stress and chronic immune activation seen in patients with neuroinflammatory, neurodegenerative, and autoimmune diseases [22]. It is also noteworthy that initial inhibition of mitochondrial function by ROS/RNS provokes the production of even higher levels of these entities creating a spiral of self-amplifying and self-sustaining mitochondrial dysfunction and bioenergetic failure [20, 29]. Microglia, once activated, provoke the activation of astrocytes, and this “dance” can also develop into self-sustaining and self-amplifying pathology [20]. The chronic dysregulation to the immune system, following an initial infection, could explain abnormal pathogen activity in certain individuals, and we now turn to a review of a number of pathogens seen active in people with apparently idiopathic fatigue, with an emphasis on the mechanisms by which they could produce chronic intractable fatigue accompanied by profound physical and cognitive disability. We shall comment on the role of polymorphisms in individual susceptibility to infection and disease trajectory in each case where data exists. We shall also comment on the capacity of each organism to affect the function of p53, given that interference with this transcription factor is a common replicative strategy, and that p53 plays a major role in the regulation of energy production at the basal level and in situations of increased energy demand [30]. The reader is referred to the work of Morris and Maes (2012) for a detailed explanation of the mechanisms underpinning the role of p53 in the generation and regulation of energy production [31].




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