# CFS and the immune system



## trbell (Nov 1, 2000)

I will try to post some messages describing what seemed to me to bethe most significant things that came up at the National Institutesof Health (NIH) workshop on Neuro-Immune Mechanisms and CFS, held atBethesda, MD on June 12 and 13, 2003. This is the first of thoseposts.I think that one of the most significant talks at the workshop wasgiven by Suzanne Vernon from the Centers for Disease Control andPrevention (CDC). She gave a summary of the ongoing work on CFS atthe CDC, and focused particularly on their gene expression work. Asyou may know, they have been working on gene expression in CFS forabout 5 years. In this type of analysis, they are able to query alarge number of genes from cells of PWCs at the same time, to seewhich ones are being expressed to a greater or lesser degree than innormal, healthy people. (Gene expression means that the cell istranscribing the DNA of the gene into messenger RNA, and what ismeasured in this analysis technique is the amount of this RNA foreach of the genes. In the cells, the RNA is normally used as thecoded instruction for assembling an enzyme or other protein, onecorresponding to each gene, so that in a normally operating cell,the amount of gene expression into messenger RNA would correspondmore or less to the amount of each protein being produced. Sincethe proteins carry on the "business" of the cell, gene expressionmeasurements can give clues about how the cell's operation isperturbed from normal.)The reason for studying gene expression is to get clues about whatis different in the cells of a PWC from those in a normal person.It is considered a "hypothesis-generating" activity. As I've saidpreviously, I think it has powerful potential for helping us tounderstand CFS, as it is also doing with many other disorders.There are I think 3 or 4 other groups working in this area now,also. The Glasgow group is looking at gene expression in musclecells. Ben Natelson reported that his group is looking atcerebrospinal fluid.The CDC group has chosen to study genes from peripheral bloodmononuclear cells (PBMCs), which are certain white cells from bloodsamples, including lymphocytes and monocytes, because of therelative convenience and low cost of taking blood samples ascompared with other types of tissue. They, like most of the CFSresearch "establishment," believe that the answers to CFS lie in thebrain, so they are hoping that since the white cells circulate inand out of the brain, they will be good guides as to what is goingon in the brain.As you may know, in the past Suzanne and the group at the CDC havereported that they have found gene expression to be consistent andreproducible over time in a given individual, making it a stable,reliable indicator of what's going on in the cells of anindividual. They have also found that they are able to distinguishbetween PWCs and normal, healthy people on the basis of their geneexpression. Up to now, they hadn't gotten into which genes areexpressed differently in PWCs, and what enzymes those genes codefor.The new work that Suzanne reported involved a larger study of PWCs(from the ongoing CDC Wichita study) and controls, looking at 4,000genes. (Note that there are a total of around 40,000 genes in thehuman genome, and the earlier CDC work looked at "only" about1,000.) In this recent work, they found that 112 out of the 4,000genes were either up- or down-regulated in terms of gene expressionin the PWCs relative to the normal, healthy people. They also foundthat most of these genes code for enzymes involved in intermediarymetabolism, not those associated with cytokines or receptors. Thiswas a surprise to them.They tried to see if they could separate the PWCs into differentgene expression behavior based on their symptoms, and they foundthat this did not work. That is, symptoms do not correlate withgene expression differences. What they did find was that they couldseparate the PWCs into a rapid onset group (less than one month) anda gradual onset group (more than one month) based on gene expressiondifferences. Furthermore, they found that the majority of the genesthat were upregulated in the rapid onset group were also genesassociated with metabolism. They also tried to see if they couldpredict which PWCs would recover, based on their gene expression,and they found that they could, using primarily metabolic genesagain mitochondrial transport genes and lipid metabolism genes.They did not see any genes for novel proteins being expressed in thePWC cells, only either higher or lower expression of those normallyexpressed.Those are about all the details she gave, but I think this is amajor development. What I think it suggests is that the reason theimmune cells are not able to function correctly in CFS is that thereis something wrong with their intermediary metabolism, i.e. theirability to burn fuel and generate ATP to power the activities of thecells. I think this supports focusing research on the metabolism ofthe cells rather than the cytokines and receptors. I think thismust have been a little chagrinning to the organizers of theworkshop, if they caught the full significance of it, since theworkshop was focused on things like cytokines and how they are usedto communicate between the brain, the immune system and theendocrine system. Not that these things aren't important, but inthe light of this new research, they don't seem to represent thecore of the pathogenesis of CFS. It will be interesting to see ifthe action shifts to metabolism now. Except for a few researchers,such as Marty Pall, most of the formal CFS research in the past hasfocused elsewhere. Among clinicians, R. Paul St. Amand and PaulCheney, though they have very different views, have also bothfocused to a large degree on metabolism. And, as you probably areaware, I have also focused there. But the bulk of the funded CFSresearchers have been looking at immunology, endocrinology,cytokines and a "central" mechanism for the cause of CFS, i.e. acause located in the brain. I have thought, based on reports fromPWCs, that the brain-related symptoms show up later in thepathogenesis, and that the metabolism in the immune cells and theskeletal muscle cells shows up as having problems right at the timeof onset of CFS, in those with sudden onset at least.I think it is possible that there are partial blockades in themetabolism of the mononuclear cells, just as I believe there are inthe Type 1 skeletal muscle cells and probably also the neurons.And, I think that glutathione depletion could be the cause of thepartial blockades, giving rise to elevated peroxynitrite. The cellsmay also be short of cysteine because of the glutathione depletion,and may be unable to make the proteins that contain cysteine. Inthis situation, the cells may be expressing the genes for theseproteins at an elevated level, because of feedback indicating thatthere still aren't enough of them. Just because the gene that codesfor a protein is overexpressed, that doesn't necessarily mean thatthe corresponding protein is being produced in higher than normalquantity, because there may be a shortage of raw material that isblocking the translation into proteins. I e-mailed Suzanne andsuggested that she consider this possibility, but haven't heardanything back so far.I also had more conversations with Nancy Klimas at the meeting, andagain urged her in the light of these new results to look at themetabolism of the immune cells, not just at their immunologyfunctions, and to pay particular attention to glutathione andcysteine.(I'm not sure I got her wholehearted agreement on that, but I gaveit another shot, anyway!)To me, this was the biggest development that came to light at theworkshop. I will try to summarize some the rest of the workshop inlater messages.Rich Van Konynenburg --------------------------------------------- Too much mail? Try a digest version. See http://www.co-cure.org/digest.htm Send posts to mailto:CO-CURE###listserv.nodak.edu Join or leave the list at http://www.co-cure.org/sub.htm ---------------------------------------------


----------

