PHOENIX RISING: A CFS/ME Newsletter By Cort Johnson (December, 2005)
PHOENIX RISING: A CFS/ME Newsletter By Cort Johnson (December, 2005)
(Please send submissions, comments and/or clarifications to Phoenixcfs@yahoo.com)
Phoenix Rising is a monthly newsletter committed to elucidating CFS research, describing important events, telling patient stories, suggesting alternate treatments for CFS patients, etc. Please contribute to Phoenix Rising.
NEWS - Spence Lecture on CFS / ME Conference in London announced / Brain Phospholipid Conference in U.K. /Maximize Your Contribution to CFS Research / REDLABUSA opens new website / New MCS website launched / Wessely Shows up in Wikipedia and elsewhere
RESEARCH - Protein Study of Cerebral Spinal Fluid Finds Biomarker? / Novel Enterovirus Theory Explicated by Chia / Exercise Induces Immune Activation in CFS
SPECIAL REPORT: Making the Breakthrough or More or the Same? The Neuroimmune NIH Grant for CFS: Part I
‘Making the Breakthrough’ in CFS, Vance Spence Lecture available online - this is the kind of thing MERGE does so well In this illuminating lecture, Vance Spence, a physician and person with CFS, gives us an on the ground view of the pitfalls and promises facing CFS researchers. He outlines four problems in particular that plague CFS researchers; disease heterogeneity, poor funding, lack of recognition and the prevailing psychological paradigm and largely prevent them from ‘making the breakthrough’ in CFS. Everyone interested in CFS research should read this lecture (click here).
Myalgic Encephalitis 2006 Conference in London announced -The ME Conference of 2006 – An Update on Clinical Diagnosis, Research Trends and Educational Support on myalgic encephalitis (CFS) will be held on the 12th May in London, ME Awareness Day.
Some of the giants of the ME world, including Professor Malcolm Hooper, Professor Basant Puri, Dr. Byron Hyde, Dr. Bruce Caruthers, Jane Colby and Dr. Ian Gibson MP, will be speaking. For more information and an application form for this conference please contact firstname.lastname@example.org or see
Phoenix Rising desperately wants someone to report back to us on how the conference went. If you’re going please e-mail me at email@example.com.
BRAIN Phospholipid Conference in Scotland - This conferences features several CFS Researchers and has a Section Devoted to CFS. Brain phospholipids are fatty acids that are involved in many important processes including inflammation, oxidative stress, cell signaling. S Evidence suggests disrupted phospholipid metabolism may be at the heart of the neurological abnormalities in CFS and other diseases.
Several CFS researchers including Dr. Puri, Dr. Hooper and Dr. Kerr will be speakers. Dr. Kerr will do a talk on the Genetics of CFS. Dr. Hooper will give a talk on Multi-chemical sensitivity, Gulf War syndrome and chronic fatigue syndrome.
http://www.bp-conference.com/ Once again Phoenix Rising is looking for a reporter for this event. If you're going please e-mail me at firstname.lastname@example.org.
NJCFSA CFS Conference DVD Available Now - The Fall NJCFSA Conference that featured Dr. Paul Cheney, Dr. Susan Levine, Dr. Sanjay Mathew, and author Shanon McQuown is now available on DVD for the price of $15.00. To order contact the NJCFSA librarian, Betty McConnell at the following: Bettymc28@comcast.net. e-mailto:Bettymc28@comcast.net
Chia DVD Available - a DVD of Dr. John Chia’s recent talk of enteroviruses and CFS is now available for $15 from the Health Conference Center at Torrance Memorial Hospital (310) 517-4711. Dr. Chia’s recent paper is summarized in the Research of this newsletter.
Maximize Your Support of CFS Research - We all want our charitable dollars to go as far as possible. As CFS patients we in fact need to be able to maximize our contributions. Three CFS patients in the U.K. have just made it easier to do so. These three individuals will donate money every time someone sets up a ‘standing order’ (monthly contribution) to MERGE, the outstanding CFS research group in the U. K., from February through the end of May. MERGE, which receives no governmental funding, relies completely on charitable donations to continue its work. The way I see it – the more work MERGE does, the better I chance I have of getting well before I hit the grave. You can access their announcement by clicking on the below url , and download the standing order for MERGE by clicking on the URL’s below.
and access MERGE’s standing order form by clicking below
REDLABS USA Opens New Website - Yes, REDLABS, the Belgium laboratory that has done most of the work on RNase L and CFS in the last five years, has opened a branch in the U.S. Where is it? Why right next to the new CFS research center in Reno, Nevada. This new lab appears to offer a number of RNase L tests that I don’t believe were formerly available in the U.S. Plus if you want to ‘get the goods’ on RNase L and CFS check out a fantastic powerpoint slide presentation by Drs. De Meirleir and Englebienne. It’s nice to have REDLABS in the U.S. where RNase L fragmentation in CFS was discovered.
Dr. Wessely Shows up in Wikipedia (and Brazil and the US…..this guy is everywhere) – Last month Wessely got his foot in the door with Braziilian researchers by co-authoring another psychologically oriented review of CFS in a Brazilian journal. He’s also showed up in the U.S. working with survivors of Hurricane Katrina. This month he or someone associated with him decided someone of his stature needed to be in Wikipedia, the online encyclopedia. The authors of this piece are obviously keeping a close watch on it, despite writing what I thought was a rather dispassionate and well referenced rebuttal to the piece my contribution disappeared within a day.
The need for Dr. Wessely or his cohorts to put him onto Wikipedia is not particularly noteworthy or even surprising; this doctor does after all love the spotlight. What is noteworthy is the beginnings of a retreat from the positions he’s held. In fact most of the article concerns the physical abnormalities he’s found in CFS, not his psychological interpretation of it. Check out this from at the end of the article. “Wessely counters that few deny a physical cause, and research conducted under his direction has detected markers of physical abnormalities in CFS.” As evidence continues to build that CFS is real this man may slowly be starting to back away from his own past.
RESEARCH - Unless otherwise noted the research summaries are by Cort Johnson, a CFS patient, whose ‘expertise’ such as it is, extends mostly to subjects of CFS pathophysiology. Submissions from others with knowledge of other fields (psychology, epidemiology, etc). or of any aspect of CFS pathophysiology are gratefully accepted. Comments, suggestions, clarifications, etc, negative or positive, only add to the editors and others understanding of CFS. Please send them to Phoenixcfs@yahoo.com).
Rating The Months Research - The thesis of this newsletter is that the most important studies deal with the pathophysiology of CFS. Each month is graded according to the following criteria;
A - several difference making papers on CFS pathophysiology
B – a difference making paper on CFS pathophysiology plus several important ones
C - several important papers on CFS pathophysiology
D - 1 or no important papers on CFS pathophysiology but several on other aspects of CFS
F - no important papers on CFS
December Research Rating – B - For this month we have a stunning view of protein production in the brains of CFS patients, an interesting theory on enterovirus production in CFS and a study finding immune activation during exercise.
Paper of the Month - every month the editor picks out what he, based on his admittedly limited understanding of CFS, believes to be the most important paper published that month for an in-depth examination. This looks like a fantastic paper that had the ability to re-orient researchers thinking on CFS.
A BIOMARKER IN THE BRAIN?
Baraniuk, J., Casado, B., Maibach, H., Clauw, D., Pannell, L. and S. Hess. 2005. A Chronic Fatigue Syndrome related proteome in human cerebrospinal fluid. BMC Neurology 22,
This paper is a breakthrough in CFS research in a number of ways. First it is the first paper to utilize proteomics, a sister technology to genomics that has much discussed but little used to date. While genomics research measures patterns of gene expression, proteomics measures patterns of protein expression. Since genes code for proteins and it is proteins that actually do the work of the cell, measuring the proteins present is a logical extension of the gene expression program. Since not all gene mRNA is actually translated into proteins one could argue that protein expression is a more primary and important measure than gene expression.
(This definition comes from Wikipedia)
Proteomics is the large-scale study of proteins, particularly their structures and functions. This term was coined to make an analogy with genomics, and while it is often viewed as the “next step”, proteomics is much more complicated than genomics. Most importantly, while the genome is a rather constant entity, the proteome differs from cell to cell and is constantly changing through its biochemical interactions with the genome and the environment. One organism will have radically different protein expression in different parts of its body, in different stages of its life cycle and in different environmental conditions. This technology is instrumental in biomarker discovery.
With completion of a rough draft of the human genome, many researchers are now looking at how genes and proteins interact to form other proteins. A surprising finding of the Human Genome Project is that there are far fewer protein-coding genes in the human genome than there are proteins in the human proteome (~22,000 genes vs. ~400,000 proteins). The large increase in protein diversity is thought to be due to alternative splicing and post-translational modification of proteins. This discrepancy implies that protein diversity cannot be fully characterized by gene expression analysis alone, making proteomics a useful tool for characterizing cells and tissues of interest.
The term proteome was coined by Mark Wilkins in 1995 and is used to describe the entire complement of proteins in a given biological organism or system at a given time, i.e. the protein products of the genome.
Secondly, instead of searching the blood the researchers explored the cerebrospinal fluid (CSF) – a much more difficult medium to access. Thirdly, the main finding of this study that a unique pattern of protein expression exists not just in CFS patients but in GWS and FMS patients as well suggests a similar pathophysiology exists in these closely related syndromes. This is big news; we know that their symptom presentation is quite similar but researchers have been mainly stymied in their efforts to explain how. The finding of a similar proteome in each suggests that the Baraniuk team has been able to find a central dysregulation common to each.
A Disease Process Proposed - One very positive aspect of these findings was their coherence. Unlike some gene expression studies the investigators were able to easily outline a pathological process involving the proteins found. The protein signature found in the CSF of CFS patients suggested that a brain injury (oromuscoid proteins) causing bleeding (heme scavenger proteins) possibly due to extracellular protein accumulations (gelsolins) in the blood vessels prompted the release of anti-hemorrhage factors (PDEF) and central nervous system repair proteins (Behabs). In short the authors suggested CFS was a cerebral amyloid-like condition with an angiopathy, i.e. a cerebral amyloid angiopathy.
Cerebral Amyloid Angiopathies
CAA’s occur when amyloids (proteins) are deposited in the arteries and arterioles and sometimes in the capillaries in the veins in the brain. Cerebral (brain) amyloid (type of protein) angiopathies (disease of the blood vessels) make up a large group of condition characterized by protein misfolding, amyloid deposits (see below) and weakening of the blood vessels resulting in hemorrhaging ranging from microhemorrages all the way to cerebral infarctions. (Yet another piece evidence implicating the blood vessels in CFS! See Phoenix Rising II; Paper of the Month). These diseases usually end in dementia or death in the 3rd to 5th decade of life but the authors posit a milder, perhaps transient or reversible form occurs in CFS. CAA usually most severely effects the occipital lobes but can also effect the hippocampus, cerebellum and basal ganglia (Rensink et. al. 2003). (Studies indicate each of these may be affected in CFS.)
Amyloid deposition usually begins around the smooth muscles lining the blood vessels. If it progresses it can puncture the vessel walls causing bleeding and in a small number of cases cause cerebral hemorrhage. Since the endothelial cells lining the blood vessels play a critical role in maintaining the blood brain barrier (BBB) amyloid deposition can also lead to increased permeability of the BBB and pathogen, cytokine, etc. and further protein leakage into the brain. Injury to the blood vessels can also lead to an inflammatory reaction resulting in macrophage infiltration and a vasculitis (inflammation of the blood vessels).
Where do these proteins come from? Most evidence points to the neurons. There is now ample evidence of brain dysfunction in CFS. Imaging studies have indicated abnormalities in the basal ganglia and two studies have found significantly reduced amounts of grey matter in the brains of CFS patients (click here for The Brain and CFS). Most studies have found evidence of increased serotonergic neurotransmission in CFS.
Some conditions including aging, increased vascular risk factors and reduced cerebral blood flows can enhance amyloid deposition. It is intriguing that two of the diseases at high risk for CAA, arteriosclerosis and diabetes, are characterized, as is CFS, by increased oxidative stress and circulatory problems. One study found reduced cerebral blood flows in CFS patients. The recent Kennedy paper covered in Phoenix Rising II (click here) indicated that CFS patients display increased oxidative stress and cardiovascular risk factors. A paper published this month posits that fibromyalgia is a disease of impaired microcirculation. These factors suggest the stage could be set for the occurrence of an amyloidic condition in CFS and that circulatory problems may be central in CFS. Dr. Hyde has for years proposed that CFS is a vasculitis-like condition (click here). Intriguingly amyloid deposition does not just occur in the brain – it can occur in blood vessels throughout the body.
A Biomarker for CFS? Probably the most significant outcome of this study was the development of a proteome ‘biosignature’[. A statistically produced model indicated that the presence of any one of five proteins (keratin 16, @-2-macroglobullin, orosomucoid-2, autotoxin, pigment epithelium-derived factor) differentiated ‘CFS’ patients from controls with a high degree of confidence. Since the protein expression of the GWS, FMS and CFS patients was so similar all their data was merged into a category called ‘CFS’. This is, of course, only initial evidence but this protein set and these protein findings are the first distinctive neurological evidence found in CFS; i.e. the first neurological findings that are distinct to CFS.
A Permeable Blood Brain Barrier (BBB) in CFS? - The authors also brought up the idea that a more permeable BBB could be allowing more proteins to enter the cerebral spinal fluid. Their theory that increased histamine activity could increase BBB permeability in CFS could explain why tricyclic antidepressants such as doxepin elixir and imipramine that are able to cross the blood brain barrier and block histamine receptor activity in the brain are effective in CFS while other histamine receptor blockers unable to pass through the BBB are not. Researchers have for years speculated whether increased permeability of the BBB in CFS patients might allow pathogens or other factors access to the brain. Spence and Khan found CFS patients exhibited a hypersensitive histamine response in the skin.
Bridging the Gap: Linking Protein and Gene Expression Studies - Although not mentioned by the authors some evidence supporting their theory can be found in some of the gene expression studies as well as other studies done in CFS. No CSF gene expression studies have yet been done (although one is planned) but several gene expression studies using peripheral blood mononuclear cells (PBMC’s) have found evidence of neuronal dysfunction in CFS.
More nervous system genes than immune genes were upregulated in the 2005 Kauschik/Kerr study. Remarkably, one of the genes found upregulated in the Kauschik/Kerr study involved gelsolin, a protein which was up regulated in the present study (see below). One of the early gene expression studies by the CDC found that a gene involved in Huntington’s disease, a devastating neurodegenerative disease involving amyloidosis, was also upregulated in CFS.
One of the proteinases upregulated, anti-chymotrypsin, is able to degrade elastase. Could anti-chymotrypsin activity suggest increased elastase activity as well? Increased elastase levels have been implicated in acute pancreatitis, an amyloidic condition as well as the RNase L fragmentation present in CFS patients.
Transforming Growth Factor Beta (TGF-B) and Amyloidosis in CFS? - The authors did not mention TGF-B but the increased levels of plasma TGF-B mostly seen in CFS studies are intriguing given TGF-B’s link to amyloidosis. Natelson, unfortunately, did not measure TGF-B in his cerebral spinal fluid study. Increased TGF-B production in transgenic mice is correlated with the degeneration of the brain blood vessels, amyloid deposition and chronic microglia activation. Baraniuk et. al. also suggested glial cell activation could account for many of t he proteins seen. Obstruction of the blood vessels in these mice eventually results in reduced cerebral blood flows, reduced metabolism and neuronal dysfunction. TGF-B production in the brain can be triggered by ischemia, trauma and or/oxidative stress. Low brain blood flows in CFS could contribute to ischemia and numerous studies now indicate increased oxidative stress in several parts of the bodies of CFS patients. Thus some of the factors triggering TGF-B production may be present in CFS.
Conclusion – The authors propose, however, that CFS is a “non-lethal, protein-misfolding, cerebrovascular amyloidosis-like syndrome“. (Thank God they came up with a simple description). Most encouragingly they state that their
“proteomic model provides initial objective evidence for the legitimacy of CFS as a distinct neurological disease”.
and in an interview Baraniuk stated
“This ushers in a whole new era for identifying [and] recognizing the legitimacy of these disorders,’
Lets hope he’s right.
Ongoing Studies - Natelson has CFS CSF fluid but has been unable to get funding to do, yes, a proteomic study on it. Hopefully this successful study will persuade government officials to rethink their position. Baraniuk reported that his study may have actually understated the proteome present in CFS because limited amounts of spinal fluid in some samples impaired their sampling ability. More studies are obviously needed to verify the compelling results of this one.
The Vernon Studies -. The Vernon group at the CDC has complete gene and protein (!) expression data as well as neuroendocrine and immune data from the saliva, blood and urine from 170 participants of the Wichita study. Their challenge, now, as they put it is ‘how to integrate the large volume of data into an accurate model of CFS pathogenesis’.
Dr. Sullivan - Dr. Sullivan, an associate professor at the University of North Carolina at Chapel Hill, began a large genomics and proteomics study in Sept 2004 that is due to be completed in early 2007 called ‘Microarrays and Proteomics in Multizygous Twins Discordant for CFS’. This will be the first study to utilize twins to examine mRNA or protein expression patterns in CFS. It is also the first to use three substrates; PBMC’s, peripheral serum and, perhaps most importantly, cerebrospinal fluid. The serum and cerebrospinal fluid will be used to identify distinctive patterns of protein production. Dr Sullivan hopes to identify biomarkers for CFS patients and develop hypotheses regarding its origin. He states that if this project is successful it ‘could lead to profound changes in the understanding of CFS‘
(For those interested in the ‘nuts and bolts’ of this issue a list of some of the proteins found in CFS patients is below).
Oxidation- related - Orosomucoid I and II- suggest a brain injury has occurred. Synthesized at sites of trauma or astroglial cell activation ORM I and II are antioxidants that sequester iron. Iron is a notable catalyst for free radical production. Since bacteria need iron? The body often attempts to sequester as much free iron as possible during bacterial infections.
Heme scavengers - Heme scavengers were present in both groups but were more frequently encountered in CFS patients. Since heme is a by-product of bleeding the authors posit sites of localized bleeding are present in brains of CFS.
Amyloidosis - A surprising number of the proteins found only in CFS patients had to do with amyloidosis, a process characterized by the extracellular accumulation of proteins in the brain (or elsewhere). Amyloidosis plays an important role in several central nervous system (CNS) diseases.
Gelsolin is a protein that caps actin, a key part of the cytoskeleton. Actin can be present as a monomer (G-actin) or as a polymer (F-actin) but only polymerized actin is incorporated into the structures that make up the cells cytoskeleton. Gelsolin is one of the two actin capping proteins that prepare actin for polymerization. Gelsolin also has numerous connections to ‘amyloidic’ diseases. Mutant gelsolin forms lead to protein misfolding and gelsolin cleavage can lead to the production of amyloid products.
Actin has an interesting history in CFS. Increased levels of particular actin fragments in the blood of CFS patients have been proposed to be a screening tool for CFS (click here). Could the increased levels of actin fragments in CFS be present because of gelsolin misfolding? As noted above when gelsolin caps actin it polymerizes it. Increased rates of non-polymerized actin (i.e. actin fragments) could, it seems, possibly be due to reduced levels of ‘normal’ gelsolin.
Transthyretin is a thyroid transport protein whose misfolding can contribute to amyloidosis. Sternberg in the NIH sponsored 2003 Neuroimmume Mechanisms and CFS conference suggested that the hypothyroid-like fatigue seen in CFS could be due reduced transthyretin efficacy.
Complement factors C3, C4 and B - are activated in the amyloidosis associated with Alzheimer’s disease. Appolipoproteins E, E4 and J, chromogranin B and microtubule-associated protein 2 are also associated with Alzheimer’s and/or Crutzfeldt-Jakob disease.
Blood Vessels – Pigment epithelium-derived factor (PDEF) has angiotensinogen activity that reduces neovascularization after blood vessel hemorrhaging, i.e. it reduces vascular permeability. A cell cycle regulator PDEF also appears to protect neurons and glial cells from apoptosis.
Prohormones - Chromogranin B, PEDF, autotoxin, Prohormones are precursors to hormones. Hormones and neuropeptides are released when proteases (protein cleaving enzymes) break them up. Increased amounts of prohormones in CFS patients suggests, then, that increased levels of proteolytic activity are present. A recent paper indicates increased proteolytic activity is present in the blood of CFS patients.
Protease Inhibitors - The counterpart to the increased proteolytic activity occurring is increased levels of protease inhibitors in CFS patients. Anti macroglobulin inhibits thrombin and other proteases. A mutant allele of @2-macroglublin promotes Alzheimer’s disease.
@-1-antichymotrypsin inhibits chymotrypsin, a serine protease involved in inflammation. Chymotrypsin is similar to elastase, the RNase L fragmenting enzyme, that appears to be increased in some CFS patients. While elastase is not its main target anti-chymotrypsin is able to inhibit elastase. Could increased anti-chymotrypsin activity suggests increased elastase activity as well?
Epithelial proteins - Six newly described keratin proteins were found in the CSF of CFS patients. The presence of keratin 16 suggests a dysfunction in the two portions of the brain fronting the BBB, choroids plexus and the leptomeningeal system. The authors suggest the presence of keratin 16 is due to immune system activation or to epithelial cell activation in the CNS of CFS patients. The epithelium is a layer of cells covering the surfaces of the skin, the mucous membranes and the glands. Could epithelial cell activation suggest trauma or injury?
Central Nervous System Repair - Greatly elevated levels Behab mRNA in gliomas and brain injury suggest Behab is involved in CNS repair. Gliomas are CNS tumors.
Rensink, A., Waal, R., Kremer, B. and M. Verbeek. 2003. Pathogenesis of cerebral amyloid angiopathy. Brain Research Reviews 43, 207-233.
CHIA EXPLICATES NOVEL ENTEROVIRAL THEORY OF CFS
Chia, J. 2005. The role of enterovirus in chronic fatigue syndrome. J. Clin. Pathol. 58, 1126-32.
In this paper Chia gives a review of the current state of science in CFS regarding enteroviruses. Chia, a physician in Southern California, begins his review by stating that his data suggests that CFS is a heterogeneous condition – this, in itself, is of course not a new assertion – but his suggestion that much of the heterogeneity seen in CFS is due to different kinds of infections, is not often heard.
|Like many of the pathogens of concern in CFS enteroviruses are ubiquitous pathogens that are generally benign but can be quite pathologic. Five major groups of enteroviruses are found, one of which contains the polioviruses; the others are group A coxsackieviruses, group B coxsackiviruses, echoviruses and (newer) enteroviruses.|
The track record of enterovirus studies on CFS is similar to that other pathogens; the data is sometimes compelling and sometimes conflicting and problems with diagnosis (pathogen characterization) muddy the field considerably. Both PCR and antibody studies have had varying results, some suggest the rate of enterovirus infection is increased in CFS while others have not.
Since enteroviruses generally infect the muscles but muscle biopsies in CFS have shown little evidence of muscle cell necrosis (death) or inflammation, enteroviruses seem to be strange pathogen to build a case for in CFS. Chia, however, asserts that since exercise is a metabolic state that favors expression of the virus the low exercise levels of CFS patients are actually an avoidance mechanism to prevent activation of the virus. Their ability to do so keeps the viral populations at low enough levels to preclude the development of frank muscle damage. Thus it is possible that enteroviruses are present. The need for Immune activation to continually suppress the virus and its consequences such as sickness behavior (fatigue, fever, aching muscles, etc.) could account for many of the symptoms in CFS.
Even if CFS patients are able to eliminate the virus some evidence suggests this may not be the end of the story. Studies have indicated that enterovirus RNA can persist in muscle tissues long after the pathogen has been eliminated. Indeed the ability of the immune system to eliminate the virus but not viral RNA suggests different processes are used to clear the two from the system. Thus the immune systems of CFS patients could be effective at clearing the body of the virus but not of the RNA left behind by the virus. This could be a real problem given the ability of enterovirus RNA to spread throughout the organs of the body during an acute infection.
Chia believes that enteroviral RNA inside the cell can produce viral proteins (but not complete virions) that trigger the antibody response seen. Glaser has a similar theory regarding EBV. He points to a recent study of Sjogren’s Syndrome, an autoimmune disease, that found increased rates of enterovirus proteins but not virions. In a study of 200 patients suffering from severe fatigue following a flu-like illness Chia found little evidence of HHV-6, EBV and CMV infection but frequent (@50%) elevation of neutralizing antibodies to enteroviruses (Coxsackie viruses and five echoviruses. Enteroviral RNA was found in the PBMC’s of 70% of these patients but only rarely in the blood. This presumably suggests it was not spreading from the PBMC’s to other sites through the blood? A large PCR study found enterovirus RNA was commonly found in CFS patients (n=236, 48%) but rarely in controls (n=118, 8%). Serial testing indicating that 38% of the CFS patients tested positive more than once suggested viral persistence occurred in a large subset of people with CFS.
Some evidence suggests that CFS patients have been able to only incompletely suppress the virus. One study that found a high proportion of ‘negative strain’ enteroviruses in CFS patients relative to controls (1:1 vs 100:1) suggested that defective control of enteroviral RNA synthesis could result in the persistence of a defective virus. This is a new twist altogether; Chia appears to suggest that incomplete immune interference with enteroviral syhthesis results in unusual forms of the pathogen in CFS.
A big question concerns why cells containing enteroviral RNA are not eliminated. Unfortunately Chia does not identify the immune processes responsible for eliminating aberrant RNA. He does suggest that enteroviruses could be hiding out long-lived ‘immunologically privileged’ cells such as macrophages, muscles, heart cells and neurons.
As with HHV-6 the success of treatment regimes designed to eliminate enteroviral infections probably provide the best evidence that these infections may play a major role in the pathology of a subset of the CFS patients. Chia reports that 8 of 14 severely ill CFS patients with enteroviral RNA in their leukocytes responded very positively to IFNa/b treatment. All relapsed, however, after the treatment was discontinued.
Summary – Chia’s theory regarding enteroviral pathology in CFS patients is fascinating. He posits that a smoldering infection causing the production of double-stranded enteroviral RNA and viral antigens could cause an inflammatory state in CFS patients that is accentuated during exercise. He states that while CFS patients rarely exhibit evidence of the live virion (virus particle) in their blood that double-stranded RNA often is found and notes that the presence of double-stranded RNA appears to be critical for the production of symptoms in HIV and hepatitis patients. His studies have shown a significant proportion of CFS patients harbor enterovirus RNA. Treatment options appear to be limited at this point by the expense of the treatment ($5,000 a month!) and the quick relapse following its completion.
You can order a DVD ($15) of a recent presentation by Chia on this topic (see news section)
A complete review of the enteroviral research and CFS will be posted to the website in the near future.
Ongoing Research - Dr. Patricia Tam is engaged in a four year study called ‘Viral dsRNA as a Mediator in Chronic Muscle Diseases’ that began in 2002, to examine the role enteroviruses play in CFS and other muscle diseases. Specifically she suggests that acute enteroviral infections are the problem in these diseases. Instead she believes that low level production of viral dsRNA products produced creates the pathology. If this study is successful Dr. Tam will have uncovered a diagnostic signature that will enable researchers to test for enterovirus activity.
EXERCISE INDUCES IMMUNE DYSFUNCTION IN CFS
Nijs, J., Meeus, M., McGregor, N., Meeusen, R., De Schutter, G., Van Hoof, E. and K. DeMeirleir. 2005. Chronic fatigue syndrome: exercise performance related to immune dysfunction. Medicine and Science in Sports and Exercise
Although CFS patients have long reported their symptoms are greatly exacerbated by exercise. study findings during exercise have been inconsistent. While some studies have found reduced peak oxygen uptake, reduced peak heart rate and increased lactate levels others have not.
Few studies, however, have examined the immune functioning during exercise. As noted above Chia has posited that activation of enteroviral RNA in the muscles impedes exercise and causes fatigue in CFS. One study examining immune functioning during exercise found activation of a branch of the immune system called the complement system was activated in CFS. Another found that fragmentation of the antiviral enzyme, RNase L, was correlated with reduced peak oxygenation during exercise. This present study, which focused on the interferon (IFN) mediated immune response (RNase L, PKR) deepened the examination of immune functioning during exercise in CFS patients.
Viral production in a cell produces double-stranded RNA (dsRNA) and the activation of three components of the IFN response; the RNase L and PKR enzymes and Mx (click here). RNase L degrades viral mRNA and PKR activates various aspects of the immune system, that help to combat the infection. One of these is inducible nitric oxide synthase (iNOS), an enzyme which produces nitric oxide (NO) a compound that in the immune system plays a major role in macrophage cytotoxicity. Monocytes/macrophages, the main immune producers of NO, produce enormous amounts of NO when activated.
Nitric oxide up regulation has been proposed by several researchers (Pall, De Meirleir) to play a major role in CFS. De Meirleir et. al. have proposed that increased NO production in CFS contributes to exercise impairment by causing an inappropriate vasodilation of the blood vessels. Blood vessel dilation is usually accomplished through the activity of endothelial NOS, not iNOS. These researchers appear to suggest that monocytes/macrophages traveling through the blood vessels produce so much NO that they prompt the blood vessels to dilate.
De Meirlier et. al. have also proposed that a channelopathy caused by RNase L fragmentation (see A Channelopathy in CFS?) could impair muscle activity by causing outflows of magnesium from muscle cells. RNase L fragmentation has thus far been found only in two closely related immune cells; monocytes/macrophages. These researchers are, by suggesting that an RNase L induced channelopathy causes Mg outflows from muscles, appears to be proposing that RNase L fragmentation also occurs in muscle cells (?).
This study examined three facets of the IFN immune response; RNase L activity and fragmentation, PKR activity and NO production by monocytes/macrophages. Lastly intracellular levels of the protease, elastase, believed to fragment RNase L was measured. There was no control group.
Findings – The study indicated that the IFN immune response was activated during exercise. This in itself is a remarkable fact; why would the immune system be activated during exercise? Could Chia’s theory of enteroviral activation during exercise apply here? All the CFS patients displayed increased elastase activity and increased rates of RNase L fragmentation and 95% displayed increased RNase L activity. PKR activation was abnormally high in only about 30% of CFS patients and NO production by monocytes or macrophages in about 50%. Intracellular elastase is used by neutrophils to kill pathogens in its cell membranes.
A correlation analysis indicated that elastase and PKR activation were associated with reduced oxygen uptake, reduced workload and reduced peak heart rate and RNase L activity and fragmentation were associated with respiratory exchange ratio (RER) when it equaled I or at rest. RER is the ratio of the net output of carbon dioxide to the net uptake of oxygen. No link was found between NO production and any of the indices of exercise.
Analysis – The authors stated that the correlation between elastase and reduced oxygen uptake makes sense given elastase’s role in various respiratory diseases. Increased extracellular elastase levels contribute to the lung dysfunction in chronic obstructive pulmonary disease (COPD) and cystic fibrosis. This study, however, measured intracellular elastase production and the authors had some difficulties explaining how increased levels of intracellular elastase could contribute to impaired lung functioning. They did note that a former study finding bronchial hyperresponsiveness in CFS was associated with cytotoxic T-cell activation (click here) and that Tc cells release elastase in order to ‘establish their cytotoxicity’. This appears to suggest that T-cell activation in the lungs could result in increased elastase levels and that could contribute to the reduced oxygen uptake seen.
This was the first time that I am aware of that elastase, the putative agent of RNase L fragmentation, has been measured in CFS. The high levels of elastase and their strong correlations with indices of exercise impairment suggest that immune activation by monocytes/macrophages plays a role in the exercise impairment found in CFS patients. PKR’s association with reduced workload and RNase L’s association with RER suggest that both components of the IFN response are also implicated in the exercise problems of CFS patients.
The problem is that without more information it is difficult to understand how and the authors gave us little help here. Increased levels of intracellular elastase could be linked to the RNase L fragmentation seen but association of RNase L fragmentation with RER was not addressed. The authors speculated that RNase L fragmentation could lead to depleted muscle magnesium levels but these were not measured.
This study was not as ‘full’ as one might have wished; the authors indicated that budgetary constraints resulted in a less than optimal sample size, there was no control group and some factors that might have shed some light on the studies findings (e.g. extracellular elastase levels) were not included. Budgetary constraints continue to handicap many innovated and committed CFS researchers.
In the evocative talk ‘Making the Breakthrough’ (click here) mentioned in the NEWS section Vance Spence of MERGE indicates that poor funding and the inattention by the public funding agencies to innovative are two of the prime impediments to ‘making the breakthrough’ in CFS. This study indicated, once again, that RNase L fragmentation is increased in CFS. It is notable, in fact, given the sometimes wildly heterogeneous findings of CFS research studies to date, that increased rates of RNase L fragmentation may, in fact, be the most consistently found measure in CFS, yet the NIH has not funded a study on RNase L in CFS for over five years and has only funded one overall. One often wonders how much of a commitment the NIH has to ‘making the breakthrough’ in CFS.
Ongoing Research - Dr. Snell - This study will examine the physical and cognitive responses of CFIDS patients to exercise and will include central nervous system activity, hormonal and cardiovascular responses during exercise, and mental function and hormonal levels after exercise. The objective will be to identify possible abnormalities that might point to the origins of many CFIDS symptoms and provide reliable markers for diagnosis and disease severity. Attention will also be given to the possible relationship between CFIDS symptomology and immune system function.
‘Making the Breakthrough’? Or More of the Same?
The NIH Grant (RFA) on the Neuroimmune Aspects of CFS
PART ONE: Beginnings
The Neuroimmune Conference of 2003
‘NEUROIMMUNE MECHANISMS AND CHRONIC FATIGUE SYDNROME
by Cort Johnson
As part of an ongoing series of papers examining the pitfalls and promises of CFS research this paper examines the granting process involving the National Institutes of Health (NIH), the primary disburser of public medical research funds in the U.S.. In particular we examine the progress of a large ($4,000,000) stand alone (RFA) grant for CFS research. Request for Applications (RFA) are one-time events that seek research proposals on specific topics. This is the first RFA that I know of for CFS and it suggests the NIH has become a bit more serious about this disease.
There is no more critical problem for CFS patients than funding. The ’1000′s’ of papers published on CFS over the past 20 years are frequently noted in discussions of the complexities and mysteries of this disorder. These reviewers rarely note, however, that scientific studies make up only a small fraction of these papers and that CFS, a multi-system disorder remains severely under funded relative to its needs. Any large grant devoted entirely to explicating the physiological mechanisms behind CFS is a cause for celebration.
Getting the grant, however, is only the first step. Using the money wisely to further our understanding of CFS is the next critical step. Both CFS advocates and NIH officials will chart the progress of the studies the grant funds closely. If the studies it funds are successful the NIH may be inclined to increase funding for CFS; if they are not, they may very well not. It is, therefore, very important that that the studies this grant funds have a good chance of explicating the biological processes underlying CFS.
Neuroimmune Mechanisms and Chronic Fatigue Syndrome.
In order to understand how the neuro-immune RFA came about and what we can expect from it we need to go back to the 2003 Conference on Neuroimmune mechanisms that inspired it. This conference was designed to foster new thinking on CFS and new, innovative, cross-disciplinary grant proposals for CFS research. Officials at the NIH have stated that one reason for the poor funding of CFS research have been the inadequate grant proposals offered them. Thus this conference, through its investigation of the dynamic interface between the central nervous and immune systems, was designed to jumpstart the field and open new ground.
Conference Makeup - the first thing to examine when dealing with the government is who is making the decisions and, in this case, who is doing the speaking? The field of CFS research is, after all, fractured by differing viewpoints. As the Conference Chair, Dedra Buchwald, stated in her overview, the answer as to what causes CFS depends on who is asked. It is important, therefore, that we find out who it was the Office on Research into Women’s Health (ORWH) deemed appropriate to illuminate the neuro-immune interface for CFS researchers? And by doing so what research interests did the agency signal they were most interested in?
This is important not only for CFS patients but also for CFS researchers. Grant proposal writing is a time-consuming and laborious process that researchers are not likely to engage in unless they have some expectation of success. By signaling or not signaling interest in their particular field of research conferences like these can turn on or turn off researchers.
It was surprising how few of the researchers speaking at this conference had done research on CFS. Ten of the fifteen speakers (Sternberg, Dhabhar, Lopez, Adler, Richardson, Toth, Opp, Park, Heitkemper, Arnold) had never published on CFS. One (Zubieta) published one paper 12 years ago and four speakers (White, Vernon, Jones and Klimas have published frequently on CFS. Of those a PubMed search revealed that none had published on neuroimmune issues in CFS. Klimas is an immunologist, Vernon has primarily done genetic research but has a strong background in immunology, Jones has done immune, genetic and epidemiological research and White has focused psychological studies on CFS. Gaab,
One cannot expect a conference designed to open up new avenues of research in CFS to consist solely of CFS researchers – that would be counter-productive. One does expect, however, that their talks address subjects germane to CFS and that a good mix of CFS researcher be present. This paper will address whether those needs were fulfilled.
Conference Emphases: Vivian Pinn the overseer of the CFS program at the Office for Research in Women’s Health (ORWH) which coordinates CFS research for the NIH, set the stage for a conference not on neuroimmune issues but neuroendocrine ones by stating how the ORWH wanted the workshop to ‘help explore ways in which the neuroendocrine system acts as an intermediary….in explaining the diverse CFS symptoms’. The stage thus was set for a conference strongly devoted to exploring endocrinological issues.
Three emphases were present in the conference, stress and the HPA axis, the autonomic nervous system, sleep and cytokines, and ‘central mechanisms’.
(A summary of the Individual presentations can be found on the full paper on the web site)
The HPA axis, stress and the immune system - The largest focus was on the ‘stress’ or the ‘stress response’ and in particular the role cortisol and the HPA axis play in modulating the immune response. Studies showing increased stress levels in CFS patients prior to their illness suggest that a disturbed stress response is a risk factor for CFS. Studies of the HPA axis have, with the exception of the mild hypocortisolism, however, been mostly un-illuminating. Cortisol, the main hormone involved in the stress response may be the most well studied topic in CFS. The hypocortisolism found in CFS, however, is characterized as ‘mild’. Indeed none of the mostly minor abnormalities found in HPA axis studies thus far suggest that it could play a major role in an illness of such severity.
The most widely published endocrine CFS researcher, A.J. Cleare, ended his 2003 review of the neuroendocrinology of CFS by stating there is ‘no convincing evidence that any HPA axis changes are specific to CFS or a primary cause of the disorder rather than being related to the many possible consequences or corollaries of the illness’, i.e. that the HPA axis changes in CFS are probably due to the stress caused by the disease rather than a cause of the disease itself. Indeed the ability of CBT to reverse some HPA axis changes in CFS suggests they are not central to the disease.
While the HPA axis may not be fundamentally disturbed it is possible that the HPA axis/immune interface may be. CFS patients could respond to small changes in HPA axis functioning with large derangements of the immune system. An over or under activation of the immune response could leave them prey to autoimmune or inflammatory conditions or increased risk from pathogens. Since immune mediators such as the pro-inflammatory cytokines (IL-1B, IL-6, TNF-a) are able to interact with the brain to cause CFS-like symptoms such as fatigue, sleepiness, muscle weakness, etc. aberrant interactions on either side of the equation (immune/central nervous system) could effect CFS.
Visser has found that both IL-4 and IL-10 production and PBMC proliferation are more inhibited by the cortisol analogue, dexamethasone, in CFS patients than in controls (Visser et. al. 1998, 2001a). Interestingly Visser found that IL-10 production triggered by bacterial lipopolysaccharides is higher in CFS. Kavelaars, on the other hand, found that dexamethasone inhibition of T-cells was reduced as was SNS inhibition of TNF-a but SNS triggered increases of IL-10 were greater. Thus there is evidence for altered neuroendoimmune mechanisms in CFS but it is mixed.
Sleep and Cytokines - Some CFS patients do sleep poorly and many do not. Several studies indicate only minor sleep perturbations for CFS patients. The most recent CDC study on sleep found that ‘while (CFS subjects are) fatigued, CFS subjects are not sleepy“. The recent NIH sponsored Buchwald twin sleep study found little difference in sleep quality between healthy twins and their CFS counterparts and stated “patients with CFS may mistake their chronic disabling fatigue for sleepiness“. Indeed it is clear that poor sleep in itself cannot account for the magnitude of the fatigue seen in CFS; people with far worse sleep disorders than occur in CFS are not nearly disabled to the extent that many CFS patients are. Increased cytokine production can, however, contribute both to impaired sleep and to reduced wakefulness and fatigue. Results have been mixed but Klimas posits that poor laboratory techniques could account for some of the negative findings in CFS. Most of the presentations involved the role cytokines may play in disrupting sleep. None, unfortunately, attempted to elucidate the role cytokine production can play in causing ‘fatigue’ a more central element in CFS. Evidence is accruing that cytokine production may play a major role in several fatigue disorders.
Central Mechanisms - Remarkably, the session titled ‘Will Understanding Central Mechanisms Enhance the Search for the Causes, Consequences and Treatments of CFS’ contained two talks on Fibromyalgia, one on Irritable Bowel Syndrome and only one centered on CFS. That talk, which focused on gene expression studies, had little to do with the issues addressed by the conference. Several suggested factors in IBS (ANS dysregulation, increased serotonin activity) that may play a role in CFS as well were addressed. Zubieta‘s talk talk involving altered opioid neurotransmission and increased pain was engaging despite its emphasis on a symptom, pain, that is not particularly significant in CFS. Zubieta nevertheless painted an intriguing scenario that could have ramifications for CFS.
CFS Researchers – Only three of the presenters (Klimas, Zubieta, White) were able to integrate findings from CFS research into their talks in a more than perfunctory fashion. Nancy Klimas’s talk on ‘Evaluating Immune Function in CFS’, is very important topic for those doing immune research in CFS, but did nothing to actually illuminate the neuroimmune interface. John Bar Zubieta’s talk involving opiate neurotransmission was engaging and was one of the few to present an explicit model for CFS. Peter White’s talk on ‘CNS and ANS Responses to Exercise in Patients with CFS‘ was certainly germane to the subject matter of the conference but instead of suggesting topics for neuroimmune research in CFS, White’s conclusion that CFS was a ‘biopsychosocial’ phenomenon rather than a ‘biomedical’ one essentially foreclosed further exploration into this area. This could hardly have surprised the organizers of the conference who apparently went to some expense to ensure White spoke; he was the only presenter located outside the U.S.
Chronic Fatigue Syndrome (?) – Despite speaking at a conference on CFS there was actually little discussion of CFS in most of the talks. Researchers either did not (Adler, Opp) or hardly mentioned (Dhabhar, Kruger, Lopez, Sternberg) CFS in their talks. Remarkably, even the Chair of one session on the autonomic nervous system, another area of great interest in CFS, David Goldstein, was unable to relate any of his findings to those of CFS or to suggest fruitful avenues of research in his introduction to the field. His remarks on CFS were limited to one paragraph.
Indeed, if it were not for the conference title one might have had trouble discerning which disease this conference was on from the titles of the presentations. One wonders why the ORWH felt it important to include a talk on the ‘HPA Axis and Autonomic Nervous System Function in Fibromyalgia‘, ‘Family Studies in Fibromyalgia‘ and ‘The Cognitive Neuroscience of Fibromyalgia‘ in a conference on CFS? There were as many talks reviewing FMS as CFS in the pathophysiology section of this conference. This does not mean these talks were not valuable but NIH sponsored conferences on CFS do not happen often and CFS patients and their advocates have the not unreasonable expectation that when one on CFS does take place that the focus will actually be on CFS.
Alternatives - While some of the talks were very informative there is an evolving field of research involving neuroimmune mechanisms and fatigue that was mostly ignored
The Symapthetic Nervous System (SNS) – The SNS and the HPA axis were acknowledged at the beginning of this conference to be the two systems most involved in stress responses in the body and the interaction between the SNS and immune system is now understood to be extensive. Several studies suggest SNS activation or dysregulation in CFS yet the discussion of stress-related immune dysfunction in this conference almost entirely concerned the HPA axis (Streeten and Bell 2000, Stewart 2000, Kavelaars 2000, Freeman and Komaroff 1997). Naschitz has been able to demonstrate abnormal autonomic nervous system functioning in CFS patients using blood pressure and heart rate measures during tilt testing. By creating a ‘hemodynamic instability index’ he has been able to successfully differentiate CFS patients from those with six other diseases including fibromyalgia. This is the most successful test of a biomarker yet but Naschitz’s work with CFS has languished due to lack of funding.
Serotonin – Increased serotonin activity in the CNS could result in fatigue, increased effort, reduced motivation, reduced libido and depression. Increased serotonin activity in the gut may lead to gastrointestinal disturbances and irritable bowel syndrome. The connection between IBS and serotonin was addressed in the conference but serotonin’s potential role in the CNS producing fatigue was not well explored. Serotonin dysregulation in CFS has been posited for over a decade and there is ever increasing evidence of increased serotonin activity in the brains of CFS patients (Cleare et. al. 2005, Yamamoto et. al. 2004, Prins et. al. 2003, Narita et. al. 2003, etc.)
Fatiguing Disorders – While there is undoubtedly a connection between fatigue and poor sleep there is little evidence that poor sleep in CFS is the cause of the fatigue seen. There was surprisingly little discussion of ‘fatigue’ in the conference but there is now a substantial literature examining the origin of fatigue in other fatiguing disorders such as multiple sclerosis (MS), cholestatic liver disease and neurological diseases. Fatigue can be the most disabling symptom in these diseases. Both MS and cholestatic liver disease appear to have an immune or autoimmune origin and both appear to affect the CNS. Intriguingly in neither of these diseases are markers of infection correlated with fatigue; this suggests that just as with CFS a dysregulated post-infectious process may cause the fatigue in these diseases.
MS, in particular, appears to share close ties with CFS. Besides the fatigue mentioned MS patients display immune activation, impaired cognition, basal ganglia abnormalities and increased rates of RNase L fragmentation. A recent paper stated the fMRI brain findings in CFS mirror those found in MS (Lange et. al. 2005). Another recent paper found that the fatigue in cholestatic liver diseases, which often arise from hepatitis infection, may be due to the CNS infiltration of TNF-a producing macrophages. A similar conclusion regarding TNF-a was recently given concerning CFS (Gaab et. al. 2005). Both these studies were published after the conference and it is hoped the reviewing committee will be cognizant of them. Presentations on the commonalties and differences of either of these diseases with CFS, given the neuroimmune mechanisms present and the overwhelming fatigue often would have been stimulating.
Basal Ganglia dysfunction and Glial Cell activation – Chaudhuri and Behan have noted that the unusual type of fatigue found in CFS involving both cognitive and physical fatigue is also commonly found in neurological diseases such as Alzheimer’s disease that involve basal ganglia dysfunction. Their model of CNS dysregulation involving glial activation in the basal ganglia of the brains of CFS patients has been borne out thus far by several neuroimaging studies yet no mention of this intriguing neuro (basal ganglia) -immune (glial cell) theory was made in this conference.
Conclusions - This conference had a somewhat strange mix of presenters. While researchers with CFS experience were rare several researchers experienced in other CFS-like illnesses such as IBS and FMS were present. Several areas of potential interest were apparently ignored while the organizers focused on the HPA axis and sleep. The talks at the conference focused on the effects HPA axis alterations can have on the immune system; none, unfortunately, focused on the opposite situation in which high cytokine levels can dysregulate the HPA axis. Little attempt, as well, was made to specifically articulate neuroimmune models that could account for CFS. The presence of Peter White an advocate of a biopsychosocial interpretation of CFS was puzzling in a conference devoted not to psychological issues but to neuroimmune mechanisms.
While the quality of the talks varied the conference was, nevertheless, full of informative and engaging presentations. The stress/immune response involving the HPA axis and the SNS has barely begun to be elucidated in CFS. Cytokines were, thankfully, a main focus of this conference. A dysregulated immune response has long been considered possible in CFS. While CFS patients do not exhibit a sleep disorder of a magnitude that could explain their fatigue and other problems it is possible that cytokine up or down regulation could contribute to the reduced wakefulness and fatigue they exhibit.
Expectations – Given the neuroimmunological research done on CFS to date what can we hope for from this RFA? An emphasis on HPA axis functioning, sleep and the ‘stress response’ seems likely. A series of grants focused solely on those topics would, however, be disappointing. One also questions, given the significant proportion of talks on illnesses other than CFS, how many of the grants will focus specifically on CFS.
Research has come a long way since 2003. Several studies have indicated increased Th2 cytokine production as well as TNF-a production in CFS. Research in other fatiguing diseases such as MS and cholestatic suggests cytokine production is a key component in the fatigue seen in those diseases. Brain and central nervous system abnormalities have also been increasingly found in CFS. Natelson found evidence of infection as well as IL-10 production in the CSF. Several studies have found evidence of increased serotonin production. The recent Baraniuk proteomics study suggests a process involving increased protease activity, amyloid production, oxidation and bleeding occurs in blood vessels of the brains of CFS. Oxidative stress, a common component of both neurological and immune diseases, has consistently been found to be increased in CFS. Beta adrenergic functioning in one set of postural tachycardia patients who have similar symptoms to CFS, is impaired. Naschitz’s novel studies of ANS functioning in CFS, now discontinued due to lack of funding, have found unique indices of cardiac functioning exist in CFS that suggest sympathetic nervous system activation and parasympathetic nervous system withdrawl. Gene expression studies continue to find evidence of both neurological and immune abnormalities. Further research, then, continues to suggest the neuroimmune interface may be important in CFS. This field holds real promise. Hopefully the RFA grants awarded will reflect that promise.
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