Subject: MED, RES: Colds and flus--Why do some PWCs not get them?MODERATOR NOTE: Do not hit reply, send comments to <Richvank###AOL.COM> NOTthe Moderators, thank you.Many persons with chronic fatigue syndrome (PWCs) report that during asignificant part of the time during their illness, they do not catchcolds and flus that are going around, which in some cases their otherfamily members or associates do catch. They also report that during theperiods when they are vulnerable to catching colds and flus, theyactually are experiencing less severe CFS symptoms than during the times whenthey are not vulnerable. How can this be explained?I don't think anyone fully understands this in detail, but I wouldlike to offer an hypothesis, based on the glutathione depletion model forCFS that I have previously described in an AACFS poster paper, whichcan be found at any of the following three urls:<http://www.personalconsult.com/articles/glutathioneandchronicfatigue.html>http://www.personalconsult.com/articles/glutathioneandchronicfatigue.html http://www.cfsresearch.org/cfs/research/treatment/26nf.htm
or<http://phoenix-cfs.org/GluAACFS04.htm>http://phoenix-cfs.org/GluAACFS04.htmBefore I discuss this pathogenesis hypothesis, I want to say that I amstrongly convinced that there is a genetic predisposition involved inCFS. I don't believe that enough is known yet to pinpoint it, but itmust be such as to be effective in the earlier stages of the pathogenesisin order to be relevant in increasing the likelihood of developing CFS.This genetic predisposition explains why not everyone develops CFS,though subjected to similar stressors, and it also explains the familialassociation often found in CFS.As can be seen in this poster paper, I have suggested that a state ofsevere long-term stress made up of various types (physical, chemical,biological and/or psychological/emotional) causes a long-term elevationof cortisol and epinephrine (adrenaline). ( Note that the decrease incortisol secretion occurs later in the pathogenesis.) Such hormonalelevations are normal responses to stress. However, the long-term natureof the stress state is significant.These in turn produce a depletion in glutathione and a suppression ofthe immune system, particularly the cell-mediated immune response andthe inflammatory response. The cell-mediated response includes the Th1response, involving helper-T cells and macrophages that is important forcombating intracellular bacterial infections, and the cytotoxic T-cellresponse involving cytoxic or "killer" T cells that is important forcombating viral infections. Both glutathione depletion and a shift awayfrom the Th1 immune response have been reported in CFS.I have further suggested that when glutathione becomes sufficientlydepleted in the particular cells that harbor the various latentherpes-family viruses, such as Epstein--Barr, cytomegalovirus, or HHV-6, thereactivation of one or more of these viruses is triggered by the formationof disulfide bonds in glycoprotein -B, as reported by Italianresearchers. This accounts for herpes-family viral infections being the mainviral infections found in PWCs.PWCs are also often found to be infected with intracellular bacteria,such as mycoplasma and Chlamydia. I suggest that both are allowed tooccur when the glutathione level becomes sufficiently depleted in thecells involved, by the following mechanisms:Mycoplasma
are known to produce superoxide and hydrogen peroxide. Itseems likely that they use these to attack human cell phospholipidsmembranes. Glutathione normally provides a defense against these reactiveoxygen species. Glutathione depletion might allow the mycoplasma entryto the cells.At one stage of the life cycle of Chlamydia, disulfide bonds must formin the protein coat. I suggest that glutathione depletion allows thesebonds to form, just as it allows the disulfide bonds to form inglycoprotein B in the proliferation of the herpes viruses.It thus appears that the viral and intracellular bacterial infectionsmost commonly found in PWCs result from the effect of glutathionedepletion on endogenous pathogens (those already present in the body). Thisexplains why these particular infections are found in CFS.I suggest that when the immune system detects the viral and/orintracellular bacterial infections, it attempts to respond by mounting acell-mediated immune response. In doing so, the lymphocytes import much ofthe scarce supply of glutathione from the blood plasma, leaving littlefor the skeletal muscles. This has already been hypothesized by Bounousand Molson. The depletion of muscle cell glutathione causes anincrease in the concentration of peroxynitrite in the skeletal muscle cells(as discussed by Prof. Martin Pall in several publications), whichinhibits oxidative metabolism and thus decreases the rate of production ofATP. This in turn causes the observed physical weakness and fatigue.Even though the lymphocytes absorb the glutathione that is available,because of the shortage they are still unable to get enough to mount avigorous cell-mediated immune response. They therefore carry on a sortof "guerrilla war" against the viral and intracellular bacterialinfections, but are not able to defeat them. This produces the ongoing"flu-like" symptoms experienced by PWCs.It is normal for cells also to mount a "holding action" against viralinfections by means of the secretion of interferons. These stimulategenes that are called ISGs (interferon stimulated genes). These includethe Mx gene and the genes involved in the PKR and the RNase-L pathways,as researched by Suhadolnik and De Meirleir's group in Belgium. Thesemechanisms interfere with replication of the viruses, but they alsoimpede the normal operations of the cells.These mechanisms ordinarily remain active only until the cell-mediatedimmune response has had time to ramp up and kill the infected cells.However, in CFS, the cell-mediated immune response never develops tofull strength (as Dr. Cheney has put it, "The cavalry never arrives,") andtherefore the interferon-stimulated processes continue. In addition,the normal RNase-L enzyme becomes cleaved and shortened to anunregulated form. I have suggested that the latter is due to the action ofcaspases, which are upregulated because of glutathione depletion. Thisaccounts for the presence of the low-molecular-weight version of RNase-Lfound in CFS, as discovered by Suhadolnik.Somewhat later in the pathogenesis, for reasons that are not yetunderstood but that may well be due to glutathione depletion, a dysfunctionof the hypothalamus-pituitary-adrenal (HPA) axis develops, as discussedby Demitrack and others. This often results in a decrease in totaldaily cortisol secretion below normal, as well as a disturbance in thedynamic response of the HPA axis. The drop in cortisol secretion removesthe earlier suppression of the inflammatory response, making the PWCvulnerable to inflammation, as observed by some PWCs.The above processes leave the PWCs immune system in a dysfunctionalstate. When a PWC in this condition is now exposed to influenza or commoncold viruses, what happens?I think the first thing I want to note is that the influenza and commoncold viruses are exogenous. That is, they come from the outside, ascontrasted with the latent viruses discussed above, which are alreadyinside human cells. They are thus subject to antibody defenses, whichthose inside the cells are not. Since the immune system is shifted to theTh2 mode in many PWCs, the antibody defenses may be stronger thannormal in these people. That is one possibility to explain the greaterresistance to colds and flus.Another possibility specifically for influenza, is that the Mx pathway(mentioned above) is activated by high ongoing levels of interferons inmany PWCs. The Mx proteins specifically suppress the transcription ofRNA viruses such as influenza A. It may be that influenza cannot get afoothold in the cells of these PWCs because of the constant activationof the Mx pathway. This pathway does not come into play for therhinoviruses that produce the common cold, however.Those are my best guesses at present to explain the phenomenon ofinvulnerability to flu and cold infections that many PWCs report. Commentswould be welcome. Send them to me at: <Richvank###AOL.COM>Rich Van Konynenburg, Ph.D.